RARE DISEASE
Secondary non-traumatic avascular necrosis
Secondary non-traumatic avascular necrosis
Secondary non-traumatic avascular necrosis
Synonyms: Secondary non-traumatic AVN, Secondary non-traumatic osteonecrosis
Synonyms: Secondary non-traumatic AVN, Secondary non-traumatic osteonecrosis
Synonyms: Secondary non-traumatic AVN, Secondary non-traumatic osteonecrosis
Drug discovery
3
drugs
With orphan designations
Overview
Secondary non-traumatic avascular necrosis (AVN) is characterized by bone death due to interrupted subchondral blood supply, typically affecting weight-bearing joints like hips, knees, and shoulders. It arises from risk factors including chronic corticosteroid use, alcoholism, hemoglobinopathies, autoimmune diseases, and metabolic disorders. Diagnosis relies on clinical suspicion and imaging, with MRI being the most sensitive early-detection tool.
Burden
Annual incidence estimates range from 3.26–6.51/100,000 in the US (~10,000–20,000 new cases/year) [1][9]. Accounts for ~10% of total hip replacements in patients <50 years, with lifetime costs exceeding $1 million for severe cases [5][17]. Early diagnosis remains challenging, leading to high disability rates and socioeconomic impacts [18][20].
Therapies
Early-stage: NSAIDs, bisphosphonates, hyperbaric oxygen therapy (HBO), and extracorporeal shockwave therapy (ESWT) to delay progression [2][3][8][13].
Pre-collapse: Core decompression ± stem cell/bone graft augmentation (20–35% require eventual arthroplasty) [2][8][11].
Late-stage: Joint preservation (osteotomy) or replacement (80% require arthroplasty within 2 years without intervention) [7][9][13].
Categories: rare bone diseases, rare systemic and rheumatological diseases
Research Papers
322 drug discovery papers about Secondary non-traumatic avascular necrosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
322 drug discovery papers about Secondary non-traumatic avascular necrosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-03-01 | EP4.5 Safety of Intra-articular Corticosteroid Hip Injections: A Retrospective Analysis of Avascular Necrosis Development
Abstract Background: Intra-articular corticosteroid injections (ICSI) have been shown to be an effective symptomatic non-operative treatment for hip osteoarthritis (OA) and other joint-related pain. There has been recent dispute over the true risk of complications from ICSI specifically when injected into the hip. Avascular necrosis (AVN) of the femoral head has been reported to occur in up to 30.5% of patients after undergoing hip ICSI, and up to 50.6% of patients experiencing osteoarthritis progression in as little as 3 months following injection. Purpose: To analyze the current protocol of hip ICSIs performed by two fellowship-trained non-operative sports medicine physicians and assess the rate of femoral head avascular necrosis. We hypothesized that the rate of AVN will be less than what has been recently reported in the literature. Study Design: Retrospective chart review Methods: Patients that underwent at least one intra-articular corticosteroid hip injection by two fellowship trained non-operative sports medicine physicians at this institution were identified using an institutional database. Exclusion criteria included injections with contrast dye used for imaging, injections that administered orthobiologics to the intra-articular, and non-intra-articular injections. Procedure notes were reviewed for anesthetic and steroid type, dosage, and needle size. Each chart was screened for demographic information, post-injection infections, AVN diagnosis, and subsequent hip replacement. 10 patients were identified with an AVN diagnosis. Their MRNs were sent to a board-certified radiologist at the same medical institution. The radiologist was blinded to the patient’s chart and instructed to identify the first radiograph with evidence of AVN. Patients were excluded if the reviewer did not agree with the diagnosis as it appeared in the medical chart or the AVN developed post-traumatically. Results: 449 patients, 530 hips, underwent 1.8 ± 1.4 ICSIs and 16.3% underwent THA at an average of 2.2 ± 2.3 years following their first injection. Of the 530 hips that underwent ICSI, only 1 hip demonstrated findings of AVN on radiographs following the first injection, and this patient had been taking oral prednisone for over 20 years. Conclusions: Intra-articular corticosteroid injections are a relatively safe symptomatic treatment option for hip pain secondary to both OA and non-OA pathology to be considered when other non-operative treatment options have failed. While the use of steroids comes with an inherent risk of osteonecrosis and cartilage damage, these results demonstrate that, when performed properly with ultrasound guidance and sterile technique, the risk of femoral head avascular necrosis is minimal.
2024-04-04 | Ayurveda in the Management of Avascular Necrosis of Femoral Head - A Case Report
Avascular necrosis (AVN) is defined as cellular death of bone components due to interruption of the blood supply. The bone structures then collapse, resulting in pain, loss of joint function and long-term joint damage. Treatment goals for AVN are to improve the joint, stop the bone damage, and ease pain. In modern science treatment includes NSAIDS, core decompression, bone grafting and total joint arthroplasty which have their own complications, high cost and prognosis is also very poor. In Ayurveda it can be correlated to the Asthi-Majja gatha vata. In this Raktavaha Srotorodha also occur which results in Asthi Dhatu Kshaya. Aim of study is to introduce an alternative therapeutic modality through Ayurveda which help to reduce pain, improve quality of life and prevent further damage of bone which is cost effective as well. The present case report is a single case study of a 32year old female patient who was diagnosed with Stage Ⅱ Avascular Necrosis of bilateral femoral head done at Government Ayurveda College Panchakarma Hospital, Poojappura, Thiruvananthapuram. She was treated with selected Panchakarma treatments and specific Samana oushadhis. There was significant improvement in the symptoms which was assessed using relevant tools like VAS score for pain, goniometer for range of movement and Oxford Hip score for assessment of function and pain in hip. The present case study documents that Panchakarma procedures and Samana oushadhis can be effective in AVN and improve the quality of life of patient.
2024-02-25 | Avascular Necrosis of the Hip Joint and Femoral Head Related with Long COVID-19 or Post-COVID-19: Case Report Study
BACKGROUND: Post-COVID conditions can include a wide range of ongoing health problems. As a consequence of long COVID-19 or post-COVID-19 an increase in osteonecrosis has been detected in different series of patients. CASE PRESENTATION: We present two patients diagnosed with COVID-19 and pneumonia, one with moderate and the other with severe clinical picture. They were treated with corticosteroid equivalent to prednisolone 993.5 mg (400–1587 mg) which correlates with steroid dose documented in the literature as causative for avascular necrosis (ANV) in patients with COVID-19. After the mean time of 65 days, due to pain in the groin and difficulty in movement, magnetic resonance imaging (MRI) was performed in both patients and AVN was diagnosed. Compared to our results, the literature records a longer time required for the development of AVN in patients without COVID-19, which is 6–36 months. This indicates the potency of the virus itself to cause disturbances in the microcirculation, and thus the development of AVN. The bone damage correlates with the degree of inflammation and the severity of the clinical picture. CONCLUSION: After a course of COVID-19 as part of a long COVID-19, ANV should be considered a possible complication, especially in patients who have clinical manifestations. Early detection of AVN and diagnosis using MRI on clinical suspicion would help early intervention with bisphosphonate therapy in patients with osteonecrosis of the hip. If the disease is detected in the more advanced stage, it is necessary to perform a surgical intervention and even a possible hip replacement.
2024-01-31 | Analysis of the Potential Angiogenic Mechanisms of BuShenHuoXue Decoction against Osteonecrosis of the Femoral Head Based on Network Pharmacology and Experimental Validation.
Objective Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). Methods With in vivo experiments, we established the steroid‐induced osteonecrosis of the femoral head (SONFH) model using Sprague–Dawley (SD) rats (8‐week‐old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low‐, medium‐ and high‐dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4‐week‐old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX‐containing serum and glucocorticoids: control group (CG); BSHX low‐, medium‐, and high‐dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low‐, medium‐, and high‐dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX‐containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co‐culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. Results BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs ( p < 0.05, vs. control group or model group). Different concentrations of BSHX‐containing serum significantly ameliorated the inhibition of CD31, VEGFA, KDR and VWF expression by high concentrations of Dex. BSHX‐containing serum‐induced BMSCs promoted the migration and angiogenesis of RAOECs, reversed to some extent the adverse effect of Dex on microangiogenesis in RAOECs, and increased the number of microangiogenic vessels. Furthermore, we identified VEGFA, COL1A1, COL3A1, and SPP1 as important targets of BSHX against ONFH. Conclusion BSHX upregulated the expression of angiogenic factors in the femoral head tissue of ONFH model rats and promoted the angiogenic capacity of rat RAOECs and BMSCs. This study provides an important basis for the use of BSHX for ONFH prevention and treatment.
2023-07-24 | Astaxanthin as a Potent Antioxidant for Promoting Bone Health: An Up-to-Date Review
In recent years, bone loss and its associated diseases have become a significant public health concern due to increased disability, morbidity, and mortality. Oxidative stress and bone loss are correlated, where oxidative stress suppresses osteoblast activity, resulting in compromised homeostasis between bone formation and resorption. This event causes upregulation of bone remodeling turnover rate with an increased risk of fractures and bone loss. Therefore, supplementation of antioxidants can be proposed to reduce oxidative stress, facilitate the bone remodeling process, suppress the initiation of bone diseases, and improve bone health. Astaxanthin (3,3'-dihydroxy-4-4'-diketo-β-β carotene), a potent antioxidant belonging to the xanthophylls family, is a potential ROS scavenger and could be a promising therapeutic nutraceutical possessing various pharmacological properties. In bone, astaxanthin enhances osteoblast differentiation, osteocytes numbers, and/or differentiation, inhibits osteoclast differentiation, cartilage degradation markers, and increases bone mineral density, expression of osteogenic markers, while reducing bone loss. In this review, we presented the up-to-date findings of the potential anabolic effects of astaxanthin on bone health in vitro, animal, and human studies by providing comprehensive evidence for its future clinical application, especially in treating bone diseases.
proteins
2023-11-17 | Erythropoietin suppresses osteoblast apoptosis and ameliorates steroid-induced necrosis of the femoral head in rats by inhibition of STAT1-caspase 3 signaling pathway
Abstract Background Steroid-induced avascular necrosis of the femoral head (SANFH) is characterized by osteoblast apoptosis, leading to a loss of bone structure and impaired hip joint function. It has been demonstrated that erythropoietin (EPO) performs a number of biological roles. Objective We examined the effects of EPO on SANFH and its regulation of the STAT1-caspase 3 signaling pathway. Method In vitro, osteoblasts were treated with dexamethasone (Dex) or EPO. We identified the cytotoxicity of EPO by CCK-8, the protein expression of P-STAT1, cleaved-caspase9, cleaved-caspase3, Bcl-2, BAX, and cytochrome c by Western blotting, and evaluated the apoptosis of osteoblasts by flow cytometry. In vivo, we analyzed the protective effect of EPO against SANFH by hematoxylin and eosin (H&E), Immunohistochemical staining, and Micro-computed tomography (CT). Results In vitro, EPO had no apparent toxic effect on osteoblasts. In Dex-stimulated cells, EPO therapy lowered the protein expression of BAX, cytochrome c, p-STAT1, cleaved-caspase9, and cleaved-caspase3 while increasing the expression of Bcl-2. EPO can alleviate the apoptosis induced by Dex. In vivo, EPO can lower the percentage of empty bone lacunae in SANFH rats. Conclusion The present study shows that EPO conferred beneficial effects in rats with SANFH by inhibiting STAT1-caspase 3 signaling, suggesting that EPO may be developed as a treatment for SANFH.
2022-09-20 | Multiple Drilling with Recombinant Human Bone Morphogenetic Protein-2 in Korean Patients with Non-Traumatic Osteonecrosis of the Femoral Head: A Prospective Randomized Pilot Study with a Minimum Two-Year Follow-Up
We sought to determine whether multiple drilling (MD) combined with the injection of recombinant human bone morphogenetic protein-2 (rhBMP-2) and β-tricalcium phosphate (β-TCP) could improve survival of the femoral head in pre-collapse lesions of non-traumatic osteonecrosis of the femoral head (ONFH) as compared with MD alone. We conducted a single-site, off-label, comparative and prospective cohort study between November 2017 and May 2019. We enrolled 25 hips (25 patients) with non-traumatic ONFH (Ficat-Arlet stage 2A or less). We performed a survival analysis, and the primary outcome was the occurrence of femoral head collapse on follow-up radiograph. Our cohort consisted of 11 men and 9 women of age 52.5 ± 8.8 years and a body mass index of 24.3 ± 3.0 kg/m2. The femoral heads were preserved in 9 hips (45.0%) and collapsed in 11 hips (55.0%) at the final follow-up; mean survival to collapse was 6.9 (range 2.8-13.5) months. There were no significant differences in the survival of the femoral head between the MD alone group and the MD with rhBMP-2 and β-TCP group (five hips survived, 50% vs. four hips survived, 40%, respectively; p = 0.83). MD combined with the injection of rhBMP-2 and β-TCP did not improve femoral head survival compared to MD alone in the pre-collapse non-traumatic ONFH lesion.
2019-11-12 | LncRNA AWPPH participates in the development of non‑traumatic osteonecrosis of femoral head by upregulating Runx2
AWPPH is a newly discovered long noncoding (lnc)RNA that plays an oncogenic role in development of several types of malignancies, whiles its involvement in non‑traumatic osteonecrosis of femoral head (ONFH) is unknown. Therefore, the present study aimed to investigate the functionality of AWPPH in non‑traumatic ONFH. Blood and mesenchymal stem cells (MSCs) were obtained from both non‑traumatic ONFH patients and healthy controls, and expression of AWPPH in those tissues was detected by RT‑qPCR. Receiver operating characteristic curve analysis was performed to investigate the diagnostic value of lncRNA AWPPH expression for non‑traumatic ONFH. Bone morphogenic protein (BMP‑2) was used to treat MSCs to induce osteogenic differentiation and the effects on lncRNA AWPPH expression was detected by RT‑qPCR. LncRNA AWPPH overexpression and short hairpin (sh)RNA silencing cell lines were established and the effects on runt‑related transcription factor 2 (Runx2) expression were detected by western blotting. It was demonstrated that AWPPH was significantly downregulated in non‑traumatic ONFH patients compared with in healthy controls in both MSCs and serum. Expression of AWPPH in MSCs and serum is a sensitive diagnostic marker for non‑traumatic ONFH. Expression of AWPPH exhibited no significant correlation with patients' age, gender and living habits, but was significantly correlated with course of disease. BMP‑2 treatment significantly increased the expression level of AWPPH in human MSCs from bone marrow (hMSC‑BM). AWPPH overexpression promoted, while AWPPH short hairpin RNA silencing inhibited the expression of Runx2 expression in hMSC‑BM cells. Therefore, it was concluded that lncRNA AWPPH may participate in the development of ONFH by upregulating Runx2.
2019-04-21 | IGF-1 reverses the osteogenic inhibitory effect of dexamethasone on BMP9-induced osteogenic differentiation in mouse embryonic fibroblasts via PI3K/AKT/COX-2 pathway
Glucocorticoid-Induced Osteoporosis (GIOP) is a prevalent clinical complication caused by large dose administration of glucocorticoids, such as Dexamethasone (Dex) and Prednisone. GIOP may lead to fractures and even Osteonecrosis of the Femoral Head (ONFH). It has been reported that glucocorticoids inhibit osteogenesis via the suppression of osteogenic differentiation in Mesenchymal Stem Cells (MSCs), but the precise mechanism underlying this suppression awaits further investigation. Meanwhile, novel and efficacious therapies are recommended to cope with GIOP. In this study, we demonstrated that Dex had the inhibitory effect on Bone Morphogenetic Protein 9 (BMP9)-induced ALP activities and matrix mineralization in Mouse Embryonic Fibroblasts (MEFs). In addition, the study confirmed that Dex decreased the expression of osteogenic markers such as Runx2 and OPN. However, the inhibitory effect of Dex on these osteogenic markers can be reversed when combined with insulin-like growth factor 1 (IGF-1). Regarding the inhibitory mechanism, we found that the level of AKT and p-AKT can be decreased by Dex and that Ly294002, the PI3K inhibitor, can block the reversal effect of IGF-1. Moreover, the knockdown or inhibition of COX-2 produced similar results to those of Ly294002. Our findings indicated that IGF-1 may reverse the osteogenic inhibitory effect of Dex via PI3K/AKT pathway, which may be associated with the up-regulation of COX-2. This study may provide new clinical management strategy for GIOP cases.
2018-08-07 | Effects of erythropoietin for precaution of steroid-induced femoral head necrosis in rats
Steroids such as glucocorticoid have been widely used for their excellent anti-inflammatory, anti-immune, and anti-shock properties. However, the long-term use in high doses has been found to cause necrosis of femoral head and other serious adverse reactions. Thus, it is of great importance to safely use these medications on patients without inducing bone necrosis. In this preclinical study, we examined the effects of erythropoietin (EPO) to attenuate the induction of steroid-induced femoral bone necrosis using rats to build up the in-vivo models. Rats were randomly divided into three groups: negative control group (group A), disease group (group B), and EPO group (group C). 20 mg/kg methylprednisolone was administrated into group B and group C for 6 weeks with two intramuscular injections per week per rat. Group C was further given daily intraperitoneal injections of rHuEPO during this period. Group A received only injection of saline at the same schedule. 12 weeks after the initial drug administration, the rats’ femoral tissues were harvested for HE staining, immunohistochemistry studies for PECAM-1(also CD31) expression and Western Blotting for VEGF expression. Histology studies showed that compared with the disease group, EPO group had significant improvement and bone morphology being much closer to the negative control group. Immunohistochemical studies revealed that EPO group had statistically much more expression of PECAM-1 than the other groups did. Western Blot demonstrated that the EPO group had significantly higher VEGF expression than the disease group. Results suggested that simultaneous injection of EPO could partially prevent steroid-induced ANFH.
cell therapies
2023-12-31 | New Technique of Reverse Bone Grafting With Core Decompression and Enriching With Regenerative Medicine Techniques for Grade 2 and Grade 3 Avascular Necrosis of Both Hips
Early avascular necrosis (AVN) of the hip poses a significant clinical challenge, requiring prompt recognition and intervention to mitigate long-term complications. A case report describing a 30-year-old man with bilateral hip AVN is presented here. In addition, to reverse bone grafting and core decompression of both hips, the patient had platelet-rich plasma (PRP) infiltration in the right hip and bone marrow aspirate concentrate (BMAC) infiltration in the left hip. This method attempted to stop the disease's development and promote hip regeneration in both. Significant pain reduction and postoperative functional gains in both hips are seen in this instance. These results highlight the potential of combined orthopedic and regenerative therapies in young individuals with hip AVN and highlight the necessity of early intervention for maintaining long-term hip function.
2023-12-07 | Exosomes from bone marrow mesenchymal stem cells ameliorate glucocorticoid-induced osteonecrosis of femoral head by transferring microRNA-210 into bone microvascular endothelial cells
Abstract Objectives Bone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model. Methods BMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-Exos miRNA−210 mimic and BMSC-Exos miRNA−210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-Exos miRNA−210 mimic and BMSC-Exos miRNA−210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague–Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-Exos miRNA−210 mimic or BMSC-Exos miRNA−210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model. Results Different concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-Exos miRNA−210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-Exos miRNA−210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-Exos miRNA−210 mimic , could increase microvascular density and enhance bone remodeling of femoral heads. Conclusions BMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.
2023-10-31 | Effectiveness of Platelet-Rich Plasma as an Adjunct to Core Decompression to Treatment Outcomes and Femoral Head Preservation in Avascular Necrosis of the Hip: A Meta-Analysis of Randomized Controlled Trials
Background: Avascular necrosis (AVN) of the femoral head results from intraosseous pathology causing functional impairment. Early diagnosis allows conservative treatment like core decompression, delaying total hip arthroplasty. Objective: This meta-analysis aims to summarize platelet-rich plasma's (PRP) impact as an adjunct to core decompression (CD) on treatment outcomes and femoral head preservation in hip AVN. Methods: The study conducted a comprehensive literature search using PubMed, Cochrane Library, Science Direct, Google Scholar and Med Line, including randomized controlled trials (RCTs) and previous meta-analyses from various databases. Using a random effects model, it compared PRP+CD with bone grafting to CD with bone grafting alone in AVN patients, evaluating function, pain scores, disease progression and the need for hip surgery. Results: The meta-analysis examined 1041 records and included three studies. The primary outcomes were function and pain scores using Harris Hip Scoring (HHS) and Visual Analog Scale (VAS). Postoperative HHS scores at final follow-up favored the PRP+CD group significantly over CD alone. Postoperative VAS scores showed a trend towards higher scores in the CD alone group. The PRP+CD group demonstrated higher survival from disease progression compared to CD alone. Overall, the study suggests that PRP+CD led to better functional outcomes and disease progression outcomes than CD alone in AVN of the hip. Conclusion: The PRP+CD treatment group showed significant benefits in AVN patients compared to CD alone, including higher HHS scores, improved disease progression survival and reduced need for hip surgery. Although PRP+CD resulted in decreased VAS scores, the difference was not statistically significant. Keywords : Avascular Necrosis/AVN, Osteonecrosis, Femoral Head, Platelet-Rich Plasma, Core Decompression and Randomized Controlled Trial
2023-05-22 | CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Exosomes Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions
The onset and progression of human inflammatory joint diseases are strongly controlled by the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived Mesenchymal Stem/Stromal Cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic ef-fects are largely exerted via their CD10-bound exosomal secretome (IFP-MSC EXOs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC EXOs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their exosomal miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low EXOs on stimulated by inflammatory/fibrotic cues synoviocytes monocultures and cocultures with IFP-MSC de-rived chondropellets. Finally, CD10High EXOs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low EXOs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, particularly the immune system. Stimulated synoviocytes exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High EXOs treatment of stimulated chondropellets/synoviocytes cocultures indicated a significant chondroprotective effects. Therapeutically, CD10High EXOs treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High EXOs possess immuno-modulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for EXOs-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).
2020-08-27 | An in vitro Chondro-osteo-vascular Triphasic Model of the Osteochondral Complex
Abstract The generation of engineered models of the osteochondral complex to study its pathologies and develop possible treatments is hindered by the distinctly different properties of articular cartilage and subchondral bone, with the latter characterized by vascularization. In vitro models of the osteochondral complex have been mainly engineered as biphasic constructs containing just cartilage and bone cells, a condition very dissimilar from the in vivo environment. The different cellular components of the osteochondral complex are governed by interacting biochemical signaling; hence, to study the crosstalk among chondrocytes, osteoblasts, and endothelial cells, we have developed a novel triphasic model of the osteochondral tissue interface. Wet-spun poly(ε-caprolactone) (PCL) and PCL/hydroxyapatite (HA) scaffolds in combination with a methacrylated gelatin (gelMA) hydrogel were used as the polymeric backbone of the constructs. The scaffold components were engineered with human bone marrow derived mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs), and differentiated using a dual chamber microphysiological system (MPS) bioreactor that allows the simultaneous, separate flow of media of different compositions for induced differentiation of each compartment towards a cartilaginous or osseous lineage. Within the engineered Microphysiological Vascularized Osteochondral System (microVOCS), hMSCs showed spatially distinct chondrogenic and osteogenic markers in terms of histology and gene expression. HUVECs formed a stable capillary-like network in the engineered bone compartment and enhanced both chondrogenic and osteogenic differentiation of hMSCs, resulting in the generation of an in vitro system that mimics a vascularized osteochondral interface tissue.
oligonucleotides
2024-03-30 | Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1
Abstract This study is to probe into the meaning of serum miR-532-5p in nontraumatic osteonecrosis of the femoral head (ONFH), and a molecular mechanism of miR-532-5p in the development of nontraumatic ONFH. This study enrolled 96 patients diagnosed with nontraumatic ONFH and 96 patients with femoral neck fracture. The levels of miR-532-5p, ABL1, MMP-3, MMP-13, and cleaved-caspase3 were determined. Radiographic progression was assessed by ARCO staging system. Visual analog scale (VAS) and Harris hip score (HHS) were employed for evaluation of the symptomatic severity of nontraumatic ONFH. Cell viability and apoptosis in chondrocytes isolated from clinical samples were investigated with CCK-8 and flow cytometry. The levels of lactic dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA), mitochondrial membrane potential (Δ Ψ m), and reactive oxygen species (ROS) were determined. miR-532-5p was downregulated in tissues and serum of patients with nontraumatic ONFH, negatively related with ARCO staging and VAS, and positively correlated with HHS. Cell apoptosis, LDH, MDA, and ROS strengthened, while cell viability, Δ Ψ m, and SOD reduced in chondrocytes of nontraumatic ONFH patients. ABL1 was upregulated in cartilage tissues from nontraumatic ONFH patients. miR-532-5p targeted ABL1, and overexpressed miR-532-5p alleviated nontraumatic ONFH-induced oxidative stress damage of chondrocytes by restraining ABL1. miR-532-5p ameliorated oxidative stress injury in nontraumatic ONFH by inhibiting ABL1.
2024-03-20 | TRIM21 silencing inhibits the apoptosis and expedites the osteogenic differentiation of dexamethasone‑induced MC3T3‑E1 cells by activating the Keap1/Nrf2 pathway
Steroid‑induced osteonecrosis of the femoral head (ONFH) is a serious complication caused by long‑term or excessive use of glucocorticoids. The present study aimed to ascertain the effects of tripartite motif‑containing protein 21 (TRIM21) on the process of steroid‑induced ONFH and its hidden action mechanism. TRIM21 expression in dexamethasone (Dex)‑treated mouse MC3T3‑E1 preosteoblast cells was examined using reverse transcription‑quantitative PCR and western blotting. The Cell Counting Kit‑8 (CCK‑8) method and lactate dehydrogenase release assay were used to respectively measure cell viability and injury. Flow cytometry analysis was used to assay cell apoptosis. Caspase 3 activity was evaluated using a specific assay, while alkaline phosphatase and Alizarin red S staining were used to evaluate osteogenesis. 2,7‑dichloro‑dihydrofluorescein diacetate fluorescence probe was used to estimate reactive oxygen species generation. Specific assay kits were used to appraise oxidative stress levels. In addition, the expression of apoptosis‑, osteogenic differentiation‑ and Kelch‑like ECH‑associated protein 1 (Keap1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling‑associated proteins was assessed using western blotting. In Nrf2 inhibitor (ML385)‑pretreated MC3T3‑E1 cells exposed to Dex, cell apoptosis, osteogenesis and oxidative stress were detected again as aforementioned. Results revealed that TRIM21 expression was raised in Dex‑induced MC3T3‑E1 cells and TRIM21 deletion improved the viability and osteogenic differentiation, whereas it hampered the oxidative stress and apoptosis in MC3T3‑E1 cells with Dex induction. In addition, silencing of TRIM21 activated Keap1/Nrf2 signaling. Moreover, ML385 partially abrogated the effects of TRIM21 depletion on the oxidative stress, apoptosis and osteogenic differentiation in MC3T3‑E1 cells exposed to Dex. In conclusion, TRIM21 silencing might activate Keap1/Nrf2 signaling to protect against steroid‑induced ONFH.
2023-09-08 | Fibroblast growth factor 23 regulates hypoxia‑induced osteoblast apoptosis through the autophagy‑signaling pathway
Hypoxia can lead to programmed osteoblast death. Prevention of osteoblast apoptosis caused by hypoxia is of great significance in the study of the occurrence and development of bone necrosis. The present study aimed to investigate the effects and mechanism of fibroblast growth factor 23 (FGF23) on hypoxia‑induced apoptosis in primary osteoblasts and MC3T3‑E1 cells osteoblasts. Cells were transfected with a plasmid carrying the FGF23 gene and a cell model of hypoxia‑induced apoptosis was established. FGF23 mRNA levels were measured using reverse transcription‑quantitative (RT‑q) PCR and western blotting was used to assess protein levels. Apoptosis was analyzed by MTT assay, fluorescein diacetate and ethidium bromide staining, flow cytometry and RT‑qPCR and western blotting were used to verify the mRNA and protein levels of apoptosis‑ and autophagy‑related gene mRNA. The targeted relationship between miR‑17‑5p and FGF23 was confirmed using the StarBase database, TargetScan database and a luciferase reporter assay. FGF23 decreased cell survival and increased the rate of apoptosis. The mRNA and protein expression of the pro‑apoptotic genes Bax and caspases 3 and 9 increased, whereas that of the anti‑apoptotic Bcl‑2 decreased. The expressions of the autophagy‑associated proteins beclin‑1, light chain 3‑II (LC3‑II) and the LC3‑II/LC3‑I ratio were significantly increased. In addition, a luciferase reporter assay confirmed that FGF23 directly regulated micro RNA (miR)‑17‑5p. The effects of FGF23 silencing were reversed by miR‑17‑5p inhibition. FGF23 may regulate hypoxia‑induced osteoblast apoptosis by targeting miR‑17‑5p through the autophagy‑signaling pathway. This provides a rationale for FGF23 as a potential therapeutic target for osteonecrosis of the femoral head.
2023-04-24 | Endoplasmic reticulum activation of the caspase-12/9/3 cascade via ATG5 leads to sterogenic femoral head necrosis
Abstract Programmed osteocyte death might be a pathogenesis of steroid-related avascular necrosis of the femoral head (SANFH). Autophagy-related gene 5 (ATG5) can activate the unfolded protein response pathway under endoplasmic reticulum stress (ERS) to participate in cell regulation, but the regulatory mechanism remains unclear. We examined the role of ERS in SANFH pathogenesis by studying the ATG5 participation mechanism in osteoblast apoptosis regulation to provide a theoretical basis for developing new SANFH therapeutic targets. Rat bone marrow mesenchymal stem cells cultured in vitro underwent osteogenic induction and alizarin red staining. The resultant osteoblasts were divided into Control, SANFH (methylprednisolone-treated), SANFH+ATG5 small interfering RNA (siRNA) (methylprednisolone-treated ATG5 siRNA transfection) groups. Beclin 1, MAP1LC3, ATG5, PERK, and caspase-3, -9, and -12 mRNA and protein expression levels were detected, the osteoblast survival rate was measured, and apoptosis was detected. The relationship between Beclin 1, MAP1LC3, ATG5, PERK, and caspase-3, -9, and -12 mRNA and protein expression levels and osteoblast apoptosis was analyzed. The SANFH group had enhanced expression of the autophagy-related genes Beclin 1 and MAP1LC3 and numerous autophagosomes were formed. Osteoblast injury stimulated ERS. ATG5 siRNA inhibited the glucocorticoid-induced osteoblast autophagy and ERS. The ER stimulated the caspase-12/9/3 cascade through ATG5 to enhance apoptosis and improve persistent ERS. The continuous action of methylprednisolone increased Beclin 1 and MAP1LC3 gene expression, resulting in bone cell injury and stimulating ERS. The ER activated the caspase-12/9/3 cascade via ATG5 under persistent and unchangeable ERS, leading to apoptosis and SANFH.
2022-10-31 | Advances in regenerative medicine applications of tetrahedral framework nucleic acid-based nanomaterials: an expert consensus recommendation
Abstract With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids (tFNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, tFNAs have been widely applied in the biomedical field as three-dimensional DNA nanomaterials. Surprisingly, tFNAs exhibit positive effects on cellular biological behaviors and tissue regeneration, which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity, tFNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization, intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic tFNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic tFNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone, cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.
other
2024-03-27 | Causal relationship between immune cells and Osteonecrosis: a bidirectional Mendelian randomization study
Abstract Objectives Research indicates a close association between aberrant immune reactions in osteonecrotic tissues and immune cell infiltration, yet the causal relationship between them remains elusive. We aim to determine whether a causality exists between immune cell infiltration and osteonecrosis. Methods A comprehensive Mendelian Randomization (MR) analysis was conducted to determine the causal relationship between immune cell characteristics and osteonecrosis in this study. Utilizing publicly available genetic data, we explored the causal relationships between 731 immune cell features and 604 cases from the FinnGen Finnish database, as well as 257 cases from the UK Biobank database with osteonecrosis data. The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. Additionally, meta-analysis was performed on significantly associated immune cells with osteonecrosis outcomes (False Discovery Rate FDR < 0.05). Results By leveraging bidirectional MR, we revealed that 11 cell types exhibited a significantly associated (FDR < 0.05) association with the potential to either increase or decrease the risk of osteonecrosis. The occurrence and progression of osteonecrosis were found to have a significant causal relationship with the increase or decrease in six immune cell types (FDR < 0.05). Meta-analysis was conducted on the differential results between the FinnGen and UK Biobank datasets. Ultimately, CD20-% lymphocytes, CD62L- monocyte % monocytes, CD33br HLA DR + CD14- % CD33br HLA DR+, EM CD4 + activated cells and DP (CD4 + CD8+) % T cells were identified to increase or decrease the odds of osteonecrosis. Notably, osteonecrosis was associated with a potential decrease in CD45 on immature MDSC cell content. Conclusion From a genetic perspective, we demonstrated a close association between immune cells and osteonecrosis. These findings significantly enhance our understanding of the interplay between immune cell infiltration and the risk of osteonecrosis, contributing to the potential design of therapeutic strategies from an immunological standpoint.
2024-02-22 | Fibroblast growth factor 23 inhibition attenuates steroid-induced osteonecrosis of the femoral head through pyroptosis
Abstract Steroid-induced osteonecrosis of the femoral head (SONFH) is the predominant cause of non-traumatic osteonecrosis of the femoral head (ONFH). Impaired blood supply and reduced osteogenic activity of the femoral head are the key pathogenic mechanisms of SONFH. Fibroblast growth factor 23 (FGF23) levels are not only a biomarker for early vascular lesions caused by abnormal mineral metabolism, but can also act directly on the peripheral vascular system, leading to vascular pathology. The aim of this study was to observe the role of FGF23 on bone microarchitecture and vascular endothelium, and to investigate activation of pyroptosis in SONFH. Lipopolysaccharide (LPS) combined with methylprednisolone (MPS) was applied for SONFH mouse models, and adenovirus was used to increase or decrease the level of FGF23. Micro-CT and histopathological staining were used to observe the structure of the femoral head, and immunohistochemical staining was used to observe the vascular density. The cells were further cultured in vitro and placed in a hypoxic environment for 12h to simulate the microenvironment of vascular injury during SONFH. The effect of FGF23 on osteogenic differentiation was evaluated using alkaline phosphatase staining, alizarin red S staining and expression of bone formation-related proteins. Matrigel tube formation assay in vitro and immunofluorescence were used to detect the ability of FGF23 to affect endothelial cell angiogenesis. Steroids activated the pyroptosis signaling pathway, promoted the secretion of inflammatory factors in SONFH models, led to vascular endothelial dysfunction and damaged the femoral head structure. In addition, FGF23 inhibited the HUVECs angiogenesis and BMSCs osteogenic differentiation. FGF23 silencing attenuated steroid-induced osteonecrosis of the femoral head by inhibiting the pyroptosis signaling pathway, and promoting osteogenic differentiation of BMSCs and angiogenesis of HUVECs in vitro.
2023-12-19 | Identifying the causal relationship between immune factors and osteonecrosis: A Two-Sample Mendelian Randomization Study
Backgrounds: A wealth of evidence intimates a profound connection between the immune system and osteonecrosis, albeit the specific immune factors underlying this connection remain largely veiled. Methods A bidirectional Mendelian randomization (MR) study was conducted based on genome-wide association study (GWAS) summary data to identify causal links between 731 immune factors and osteonecrosis including drug-induced osteonecrosis. Preliminary MR analysis was accomplished utilizing the inverse-variance weighted method (IVW) under a multiplicative random effects model, and heterogeneity and potential horizontal pleiotropy were evaluated through Cochrane's Q-test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Results Upon false discovery rate correction, the gene-predicted level of one immune factor (CD62L- monocyte %monocyte) exhibited a significant positive correlation with osteonecrosis, while eight immune traits associated with monocytes, dendritic cells, and NK cells demonstrated significant causal effects with drug-induced osteonecrosis. Reverse MR revealed no significant correlations. Conclusion This MR research provides genetic evidence for the causal associations between a broad spectrum of immune factors and osteonecrosis. Such a study aids in unraveling the intricate interaction patterns between the immune and skeletal systems, elucidating the pathogenesis of osteonecrosis, and identifying potential novel therapeutic approaches.
2022-12-13 | The role of immune cells in modulating chronic inflammation and osteonecrosis
Osteonecrosis occurs when, under continuous stimulation by adverse factors such as glucocorticoids or alcohol, the death of local bone and marrow cells leads to abnormal osteoimmune function. This creates a chronic inflammatory microenvironment, which interferes with bone regeneration and repair. In a variety of bone tissue diseases, innate immune cells and adaptive immune cells interact with bone cells, and their effects on bone metabolic homeostasis have attracted more and more attention, thus developing into a new discipline - osteoimmunology. Immune cells are the most important regulator of inflammation, and osteoimmune disorder may be an important cause of osteonecrosis. Elucidating the chronic inflammatory microenvironment regulated by abnormal osteoimmune may help develop potential treatments for osteonecrosis. This review summarizes the inflammatory regulation of bone immunity in osteonecrosis, explains the pathophysiological mechanism of osteonecrosis from the perspective of osteoimmunology, and provides new ideas for the treatment of osteonecrosis.
2012-10-05 | There are many potential medical therapies for atraumatic osteonecrosis
Atraumatic osteonecrosis is a common complication of SLE and is seen in other connective tissue diseases, in patients treated with high doses of CSs, in HIV-infected patients and in alcoholic patients. Standard care is confined to analgesia, core decompression if the condition is early and affects the femoral head and joint replacement. However, consideration of the underlying biological mechanisms leads to the recognition of many potential therapies that might either prevent progression or, even, reverse the process if it is not yet too far advanced. These potential therapies merit detailed consideration. Critical points are that (i) histopathological evidence shows that the initial cellular event is apoptosis of osteocytes; and (ii) another requisite, as homeostasis requires that death and rebirth of osteocytes be balanced, is an accompanying inadequate proliferative capacity of osteoblasts. Thus, a logical approach to treatment includes measures that (i) reduce apoptosis of osteocytes and (ii) enhance proliferation of osteoblasts/pre-osteoblasts. Measures to reduce the ongoing apoptosis of osteocytes require reinforcing the effects of members of the Bcl-2 family (Bcl-2 itself and Mcl-1), the Wnt/catenin pathways (using an available sclerostin antibody) and HSPs (by application of local heat using US, deep wave diathermy or infrared), as well as administration of bisphosphonates and nitrates. Measures to enhance proliferation of osteoblasts/pre-osteoblasts include the use of stem cells, extracorporeal shock wave therapy, aspirin, the proteosome inhibitor bortezomib, melatonin and application of local heat. Use of VEGF would encourage proliferation of blood vessels and osteogenesis. Certain drugs that inhibit osteoblast proliferation should be avoided, including NSAIDs, serotonin reuptake inhibitors and thiazolidinediones.
small molecules
2025-03-01 | EP4.5 Safety of Intra-articular Corticosteroid Hip Injections: A Retrospective Analysis of Avascular Necrosis Development
Abstract Background: Intra-articular corticosteroid injections (ICSI) have been shown to be an effective symptomatic non-operative treatment for hip osteoarthritis (OA) and other joint-related pain. There has been recent dispute over the true risk of complications from ICSI specifically when injected into the hip. Avascular necrosis (AVN) of the femoral head has been reported to occur in up to 30.5% of patients after undergoing hip ICSI, and up to 50.6% of patients experiencing osteoarthritis progression in as little as 3 months following injection. Purpose: To analyze the current protocol of hip ICSIs performed by two fellowship-trained non-operative sports medicine physicians and assess the rate of femoral head avascular necrosis. We hypothesized that the rate of AVN will be less than what has been recently reported in the literature. Study Design: Retrospective chart review Methods: Patients that underwent at least one intra-articular corticosteroid hip injection by two fellowship trained non-operative sports medicine physicians at this institution were identified using an institutional database. Exclusion criteria included injections with contrast dye used for imaging, injections that administered orthobiologics to the intra-articular, and non-intra-articular injections. Procedure notes were reviewed for anesthetic and steroid type, dosage, and needle size. Each chart was screened for demographic information, post-injection infections, AVN diagnosis, and subsequent hip replacement. 10 patients were identified with an AVN diagnosis. Their MRNs were sent to a board-certified radiologist at the same medical institution. The radiologist was blinded to the patient’s chart and instructed to identify the first radiograph with evidence of AVN. Patients were excluded if the reviewer did not agree with the diagnosis as it appeared in the medical chart or the AVN developed post-traumatically. Results: 449 patients, 530 hips, underwent 1.8 ± 1.4 ICSIs and 16.3% underwent THA at an average of 2.2 ± 2.3 years following their first injection. Of the 530 hips that underwent ICSI, only 1 hip demonstrated findings of AVN on radiographs following the first injection, and this patient had been taking oral prednisone for over 20 years. Conclusions: Intra-articular corticosteroid injections are a relatively safe symptomatic treatment option for hip pain secondary to both OA and non-OA pathology to be considered when other non-operative treatment options have failed. While the use of steroids comes with an inherent risk of osteonecrosis and cartilage damage, these results demonstrate that, when performed properly with ultrasound guidance and sterile technique, the risk of femoral head avascular necrosis is minimal.
2024-04-04 | Ayurveda in the Management of Avascular Necrosis of Femoral Head - A Case Report
Avascular necrosis (AVN) is defined as cellular death of bone components due to interruption of the blood supply. The bone structures then collapse, resulting in pain, loss of joint function and long-term joint damage. Treatment goals for AVN are to improve the joint, stop the bone damage, and ease pain. In modern science treatment includes NSAIDS, core decompression, bone grafting and total joint arthroplasty which have their own complications, high cost and prognosis is also very poor. In Ayurveda it can be correlated to the Asthi-Majja gatha vata. In this Raktavaha Srotorodha also occur which results in Asthi Dhatu Kshaya. Aim of study is to introduce an alternative therapeutic modality through Ayurveda which help to reduce pain, improve quality of life and prevent further damage of bone which is cost effective as well. The present case report is a single case study of a 32year old female patient who was diagnosed with Stage Ⅱ Avascular Necrosis of bilateral femoral head done at Government Ayurveda College Panchakarma Hospital, Poojappura, Thiruvananthapuram. She was treated with selected Panchakarma treatments and specific Samana oushadhis. There was significant improvement in the symptoms which was assessed using relevant tools like VAS score for pain, goniometer for range of movement and Oxford Hip score for assessment of function and pain in hip. The present case study documents that Panchakarma procedures and Samana oushadhis can be effective in AVN and improve the quality of life of patient.
2024-02-25 | Avascular Necrosis of the Hip Joint and Femoral Head Related with Long COVID-19 or Post-COVID-19: Case Report Study
BACKGROUND: Post-COVID conditions can include a wide range of ongoing health problems. As a consequence of long COVID-19 or post-COVID-19 an increase in osteonecrosis has been detected in different series of patients. CASE PRESENTATION: We present two patients diagnosed with COVID-19 and pneumonia, one with moderate and the other with severe clinical picture. They were treated with corticosteroid equivalent to prednisolone 993.5 mg (400–1587 mg) which correlates with steroid dose documented in the literature as causative for avascular necrosis (ANV) in patients with COVID-19. After the mean time of 65 days, due to pain in the groin and difficulty in movement, magnetic resonance imaging (MRI) was performed in both patients and AVN was diagnosed. Compared to our results, the literature records a longer time required for the development of AVN in patients without COVID-19, which is 6–36 months. This indicates the potency of the virus itself to cause disturbances in the microcirculation, and thus the development of AVN. The bone damage correlates with the degree of inflammation and the severity of the clinical picture. CONCLUSION: After a course of COVID-19 as part of a long COVID-19, ANV should be considered a possible complication, especially in patients who have clinical manifestations. Early detection of AVN and diagnosis using MRI on clinical suspicion would help early intervention with bisphosphonate therapy in patients with osteonecrosis of the hip. If the disease is detected in the more advanced stage, it is necessary to perform a surgical intervention and even a possible hip replacement.
2024-01-31 | Analysis of the Potential Angiogenic Mechanisms of BuShenHuoXue Decoction against Osteonecrosis of the Femoral Head Based on Network Pharmacology and Experimental Validation.
Objective Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). Methods With in vivo experiments, we established the steroid‐induced osteonecrosis of the femoral head (SONFH) model using Sprague–Dawley (SD) rats (8‐week‐old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low‐, medium‐ and high‐dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4‐week‐old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX‐containing serum and glucocorticoids: control group (CG); BSHX low‐, medium‐, and high‐dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low‐, medium‐, and high‐dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX‐containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co‐culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. Results BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs ( p < 0.05, vs. control group or model group). Different concentrations of BSHX‐containing serum significantly ameliorated the inhibition of CD31, VEGFA, KDR and VWF expression by high concentrations of Dex. BSHX‐containing serum‐induced BMSCs promoted the migration and angiogenesis of RAOECs, reversed to some extent the adverse effect of Dex on microangiogenesis in RAOECs, and increased the number of microangiogenic vessels. Furthermore, we identified VEGFA, COL1A1, COL3A1, and SPP1 as important targets of BSHX against ONFH. Conclusion BSHX upregulated the expression of angiogenic factors in the femoral head tissue of ONFH model rats and promoted the angiogenic capacity of rat RAOECs and BMSCs. This study provides an important basis for the use of BSHX for ONFH prevention and treatment.
2023-07-24 | Astaxanthin as a Potent Antioxidant for Promoting Bone Health: An Up-to-Date Review
In recent years, bone loss and its associated diseases have become a significant public health concern due to increased disability, morbidity, and mortality. Oxidative stress and bone loss are correlated, where oxidative stress suppresses osteoblast activity, resulting in compromised homeostasis between bone formation and resorption. This event causes upregulation of bone remodeling turnover rate with an increased risk of fractures and bone loss. Therefore, supplementation of antioxidants can be proposed to reduce oxidative stress, facilitate the bone remodeling process, suppress the initiation of bone diseases, and improve bone health. Astaxanthin (3,3'-dihydroxy-4-4'-diketo-β-β carotene), a potent antioxidant belonging to the xanthophylls family, is a potential ROS scavenger and could be a promising therapeutic nutraceutical possessing various pharmacological properties. In bone, astaxanthin enhances osteoblast differentiation, osteocytes numbers, and/or differentiation, inhibits osteoclast differentiation, cartilage degradation markers, and increases bone mineral density, expression of osteogenic markers, while reducing bone loss. In this review, we presented the up-to-date findings of the potential anabolic effects of astaxanthin on bone health in vitro, animal, and human studies by providing comprehensive evidence for its future clinical application, especially in treating bone diseases.
proteins
2023-11-17 | Erythropoietin suppresses osteoblast apoptosis and ameliorates steroid-induced necrosis of the femoral head in rats by inhibition of STAT1-caspase 3 signaling pathway
Abstract Background Steroid-induced avascular necrosis of the femoral head (SANFH) is characterized by osteoblast apoptosis, leading to a loss of bone structure and impaired hip joint function. It has been demonstrated that erythropoietin (EPO) performs a number of biological roles. Objective We examined the effects of EPO on SANFH and its regulation of the STAT1-caspase 3 signaling pathway. Method In vitro, osteoblasts were treated with dexamethasone (Dex) or EPO. We identified the cytotoxicity of EPO by CCK-8, the protein expression of P-STAT1, cleaved-caspase9, cleaved-caspase3, Bcl-2, BAX, and cytochrome c by Western blotting, and evaluated the apoptosis of osteoblasts by flow cytometry. In vivo, we analyzed the protective effect of EPO against SANFH by hematoxylin and eosin (H&E), Immunohistochemical staining, and Micro-computed tomography (CT). Results In vitro, EPO had no apparent toxic effect on osteoblasts. In Dex-stimulated cells, EPO therapy lowered the protein expression of BAX, cytochrome c, p-STAT1, cleaved-caspase9, and cleaved-caspase3 while increasing the expression of Bcl-2. EPO can alleviate the apoptosis induced by Dex. In vivo, EPO can lower the percentage of empty bone lacunae in SANFH rats. Conclusion The present study shows that EPO conferred beneficial effects in rats with SANFH by inhibiting STAT1-caspase 3 signaling, suggesting that EPO may be developed as a treatment for SANFH.
2022-09-20 | Multiple Drilling with Recombinant Human Bone Morphogenetic Protein-2 in Korean Patients with Non-Traumatic Osteonecrosis of the Femoral Head: A Prospective Randomized Pilot Study with a Minimum Two-Year Follow-Up
We sought to determine whether multiple drilling (MD) combined with the injection of recombinant human bone morphogenetic protein-2 (rhBMP-2) and β-tricalcium phosphate (β-TCP) could improve survival of the femoral head in pre-collapse lesions of non-traumatic osteonecrosis of the femoral head (ONFH) as compared with MD alone. We conducted a single-site, off-label, comparative and prospective cohort study between November 2017 and May 2019. We enrolled 25 hips (25 patients) with non-traumatic ONFH (Ficat-Arlet stage 2A or less). We performed a survival analysis, and the primary outcome was the occurrence of femoral head collapse on follow-up radiograph. Our cohort consisted of 11 men and 9 women of age 52.5 ± 8.8 years and a body mass index of 24.3 ± 3.0 kg/m2. The femoral heads were preserved in 9 hips (45.0%) and collapsed in 11 hips (55.0%) at the final follow-up; mean survival to collapse was 6.9 (range 2.8-13.5) months. There were no significant differences in the survival of the femoral head between the MD alone group and the MD with rhBMP-2 and β-TCP group (five hips survived, 50% vs. four hips survived, 40%, respectively; p = 0.83). MD combined with the injection of rhBMP-2 and β-TCP did not improve femoral head survival compared to MD alone in the pre-collapse non-traumatic ONFH lesion.
2019-11-12 | LncRNA AWPPH participates in the development of non‑traumatic osteonecrosis of femoral head by upregulating Runx2
AWPPH is a newly discovered long noncoding (lnc)RNA that plays an oncogenic role in development of several types of malignancies, whiles its involvement in non‑traumatic osteonecrosis of femoral head (ONFH) is unknown. Therefore, the present study aimed to investigate the functionality of AWPPH in non‑traumatic ONFH. Blood and mesenchymal stem cells (MSCs) were obtained from both non‑traumatic ONFH patients and healthy controls, and expression of AWPPH in those tissues was detected by RT‑qPCR. Receiver operating characteristic curve analysis was performed to investigate the diagnostic value of lncRNA AWPPH expression for non‑traumatic ONFH. Bone morphogenic protein (BMP‑2) was used to treat MSCs to induce osteogenic differentiation and the effects on lncRNA AWPPH expression was detected by RT‑qPCR. LncRNA AWPPH overexpression and short hairpin (sh)RNA silencing cell lines were established and the effects on runt‑related transcription factor 2 (Runx2) expression were detected by western blotting. It was demonstrated that AWPPH was significantly downregulated in non‑traumatic ONFH patients compared with in healthy controls in both MSCs and serum. Expression of AWPPH in MSCs and serum is a sensitive diagnostic marker for non‑traumatic ONFH. Expression of AWPPH exhibited no significant correlation with patients' age, gender and living habits, but was significantly correlated with course of disease. BMP‑2 treatment significantly increased the expression level of AWPPH in human MSCs from bone marrow (hMSC‑BM). AWPPH overexpression promoted, while AWPPH short hairpin RNA silencing inhibited the expression of Runx2 expression in hMSC‑BM cells. Therefore, it was concluded that lncRNA AWPPH may participate in the development of ONFH by upregulating Runx2.
2019-04-21 | IGF-1 reverses the osteogenic inhibitory effect of dexamethasone on BMP9-induced osteogenic differentiation in mouse embryonic fibroblasts via PI3K/AKT/COX-2 pathway
Glucocorticoid-Induced Osteoporosis (GIOP) is a prevalent clinical complication caused by large dose administration of glucocorticoids, such as Dexamethasone (Dex) and Prednisone. GIOP may lead to fractures and even Osteonecrosis of the Femoral Head (ONFH). It has been reported that glucocorticoids inhibit osteogenesis via the suppression of osteogenic differentiation in Mesenchymal Stem Cells (MSCs), but the precise mechanism underlying this suppression awaits further investigation. Meanwhile, novel and efficacious therapies are recommended to cope with GIOP. In this study, we demonstrated that Dex had the inhibitory effect on Bone Morphogenetic Protein 9 (BMP9)-induced ALP activities and matrix mineralization in Mouse Embryonic Fibroblasts (MEFs). In addition, the study confirmed that Dex decreased the expression of osteogenic markers such as Runx2 and OPN. However, the inhibitory effect of Dex on these osteogenic markers can be reversed when combined with insulin-like growth factor 1 (IGF-1). Regarding the inhibitory mechanism, we found that the level of AKT and p-AKT can be decreased by Dex and that Ly294002, the PI3K inhibitor, can block the reversal effect of IGF-1. Moreover, the knockdown or inhibition of COX-2 produced similar results to those of Ly294002. Our findings indicated that IGF-1 may reverse the osteogenic inhibitory effect of Dex via PI3K/AKT pathway, which may be associated with the up-regulation of COX-2. This study may provide new clinical management strategy for GIOP cases.
2018-08-07 | Effects of erythropoietin for precaution of steroid-induced femoral head necrosis in rats
Steroids such as glucocorticoid have been widely used for their excellent anti-inflammatory, anti-immune, and anti-shock properties. However, the long-term use in high doses has been found to cause necrosis of femoral head and other serious adverse reactions. Thus, it is of great importance to safely use these medications on patients without inducing bone necrosis. In this preclinical study, we examined the effects of erythropoietin (EPO) to attenuate the induction of steroid-induced femoral bone necrosis using rats to build up the in-vivo models. Rats were randomly divided into three groups: negative control group (group A), disease group (group B), and EPO group (group C). 20 mg/kg methylprednisolone was administrated into group B and group C for 6 weeks with two intramuscular injections per week per rat. Group C was further given daily intraperitoneal injections of rHuEPO during this period. Group A received only injection of saline at the same schedule. 12 weeks after the initial drug administration, the rats’ femoral tissues were harvested for HE staining, immunohistochemistry studies for PECAM-1(also CD31) expression and Western Blotting for VEGF expression. Histology studies showed that compared with the disease group, EPO group had significant improvement and bone morphology being much closer to the negative control group. Immunohistochemical studies revealed that EPO group had statistically much more expression of PECAM-1 than the other groups did. Western Blot demonstrated that the EPO group had significantly higher VEGF expression than the disease group. Results suggested that simultaneous injection of EPO could partially prevent steroid-induced ANFH.
cell therapies
2023-12-31 | New Technique of Reverse Bone Grafting With Core Decompression and Enriching With Regenerative Medicine Techniques for Grade 2 and Grade 3 Avascular Necrosis of Both Hips
Early avascular necrosis (AVN) of the hip poses a significant clinical challenge, requiring prompt recognition and intervention to mitigate long-term complications. A case report describing a 30-year-old man with bilateral hip AVN is presented here. In addition, to reverse bone grafting and core decompression of both hips, the patient had platelet-rich plasma (PRP) infiltration in the right hip and bone marrow aspirate concentrate (BMAC) infiltration in the left hip. This method attempted to stop the disease's development and promote hip regeneration in both. Significant pain reduction and postoperative functional gains in both hips are seen in this instance. These results highlight the potential of combined orthopedic and regenerative therapies in young individuals with hip AVN and highlight the necessity of early intervention for maintaining long-term hip function.
2023-12-07 | Exosomes from bone marrow mesenchymal stem cells ameliorate glucocorticoid-induced osteonecrosis of femoral head by transferring microRNA-210 into bone microvascular endothelial cells
Abstract Objectives Bone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model. Methods BMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-Exos miRNA−210 mimic and BMSC-Exos miRNA−210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-Exos miRNA−210 mimic and BMSC-Exos miRNA−210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague–Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-Exos miRNA−210 mimic or BMSC-Exos miRNA−210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model. Results Different concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-Exos miRNA−210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-Exos miRNA−210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-Exos miRNA−210 mimic , could increase microvascular density and enhance bone remodeling of femoral heads. Conclusions BMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.
2023-10-31 | Effectiveness of Platelet-Rich Plasma as an Adjunct to Core Decompression to Treatment Outcomes and Femoral Head Preservation in Avascular Necrosis of the Hip: A Meta-Analysis of Randomized Controlled Trials
Background: Avascular necrosis (AVN) of the femoral head results from intraosseous pathology causing functional impairment. Early diagnosis allows conservative treatment like core decompression, delaying total hip arthroplasty. Objective: This meta-analysis aims to summarize platelet-rich plasma's (PRP) impact as an adjunct to core decompression (CD) on treatment outcomes and femoral head preservation in hip AVN. Methods: The study conducted a comprehensive literature search using PubMed, Cochrane Library, Science Direct, Google Scholar and Med Line, including randomized controlled trials (RCTs) and previous meta-analyses from various databases. Using a random effects model, it compared PRP+CD with bone grafting to CD with bone grafting alone in AVN patients, evaluating function, pain scores, disease progression and the need for hip surgery. Results: The meta-analysis examined 1041 records and included three studies. The primary outcomes were function and pain scores using Harris Hip Scoring (HHS) and Visual Analog Scale (VAS). Postoperative HHS scores at final follow-up favored the PRP+CD group significantly over CD alone. Postoperative VAS scores showed a trend towards higher scores in the CD alone group. The PRP+CD group demonstrated higher survival from disease progression compared to CD alone. Overall, the study suggests that PRP+CD led to better functional outcomes and disease progression outcomes than CD alone in AVN of the hip. Conclusion: The PRP+CD treatment group showed significant benefits in AVN patients compared to CD alone, including higher HHS scores, improved disease progression survival and reduced need for hip surgery. Although PRP+CD resulted in decreased VAS scores, the difference was not statistically significant. Keywords : Avascular Necrosis/AVN, Osteonecrosis, Femoral Head, Platelet-Rich Plasma, Core Decompression and Randomized Controlled Trial
2023-05-22 | CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Exosomes Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions
The onset and progression of human inflammatory joint diseases are strongly controlled by the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived Mesenchymal Stem/Stromal Cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic ef-fects are largely exerted via their CD10-bound exosomal secretome (IFP-MSC EXOs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC EXOs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their exosomal miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low EXOs on stimulated by inflammatory/fibrotic cues synoviocytes monocultures and cocultures with IFP-MSC de-rived chondropellets. Finally, CD10High EXOs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low EXOs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, particularly the immune system. Stimulated synoviocytes exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High EXOs treatment of stimulated chondropellets/synoviocytes cocultures indicated a significant chondroprotective effects. Therapeutically, CD10High EXOs treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High EXOs possess immuno-modulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for EXOs-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).
2020-08-27 | An in vitro Chondro-osteo-vascular Triphasic Model of the Osteochondral Complex
Abstract The generation of engineered models of the osteochondral complex to study its pathologies and develop possible treatments is hindered by the distinctly different properties of articular cartilage and subchondral bone, with the latter characterized by vascularization. In vitro models of the osteochondral complex have been mainly engineered as biphasic constructs containing just cartilage and bone cells, a condition very dissimilar from the in vivo environment. The different cellular components of the osteochondral complex are governed by interacting biochemical signaling; hence, to study the crosstalk among chondrocytes, osteoblasts, and endothelial cells, we have developed a novel triphasic model of the osteochondral tissue interface. Wet-spun poly(ε-caprolactone) (PCL) and PCL/hydroxyapatite (HA) scaffolds in combination with a methacrylated gelatin (gelMA) hydrogel were used as the polymeric backbone of the constructs. The scaffold components were engineered with human bone marrow derived mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs), and differentiated using a dual chamber microphysiological system (MPS) bioreactor that allows the simultaneous, separate flow of media of different compositions for induced differentiation of each compartment towards a cartilaginous or osseous lineage. Within the engineered Microphysiological Vascularized Osteochondral System (microVOCS), hMSCs showed spatially distinct chondrogenic and osteogenic markers in terms of histology and gene expression. HUVECs formed a stable capillary-like network in the engineered bone compartment and enhanced both chondrogenic and osteogenic differentiation of hMSCs, resulting in the generation of an in vitro system that mimics a vascularized osteochondral interface tissue.
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2024-03-30 | Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1
Abstract This study is to probe into the meaning of serum miR-532-5p in nontraumatic osteonecrosis of the femoral head (ONFH), and a molecular mechanism of miR-532-5p in the development of nontraumatic ONFH. This study enrolled 96 patients diagnosed with nontraumatic ONFH and 96 patients with femoral neck fracture. The levels of miR-532-5p, ABL1, MMP-3, MMP-13, and cleaved-caspase3 were determined. Radiographic progression was assessed by ARCO staging system. Visual analog scale (VAS) and Harris hip score (HHS) were employed for evaluation of the symptomatic severity of nontraumatic ONFH. Cell viability and apoptosis in chondrocytes isolated from clinical samples were investigated with CCK-8 and flow cytometry. The levels of lactic dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA), mitochondrial membrane potential (Δ Ψ m), and reactive oxygen species (ROS) were determined. miR-532-5p was downregulated in tissues and serum of patients with nontraumatic ONFH, negatively related with ARCO staging and VAS, and positively correlated with HHS. Cell apoptosis, LDH, MDA, and ROS strengthened, while cell viability, Δ Ψ m, and SOD reduced in chondrocytes of nontraumatic ONFH patients. ABL1 was upregulated in cartilage tissues from nontraumatic ONFH patients. miR-532-5p targeted ABL1, and overexpressed miR-532-5p alleviated nontraumatic ONFH-induced oxidative stress damage of chondrocytes by restraining ABL1. miR-532-5p ameliorated oxidative stress injury in nontraumatic ONFH by inhibiting ABL1.
2024-03-20 | TRIM21 silencing inhibits the apoptosis and expedites the osteogenic differentiation of dexamethasone‑induced MC3T3‑E1 cells by activating the Keap1/Nrf2 pathway
Steroid‑induced osteonecrosis of the femoral head (ONFH) is a serious complication caused by long‑term or excessive use of glucocorticoids. The present study aimed to ascertain the effects of tripartite motif‑containing protein 21 (TRIM21) on the process of steroid‑induced ONFH and its hidden action mechanism. TRIM21 expression in dexamethasone (Dex)‑treated mouse MC3T3‑E1 preosteoblast cells was examined using reverse transcription‑quantitative PCR and western blotting. The Cell Counting Kit‑8 (CCK‑8) method and lactate dehydrogenase release assay were used to respectively measure cell viability and injury. Flow cytometry analysis was used to assay cell apoptosis. Caspase 3 activity was evaluated using a specific assay, while alkaline phosphatase and Alizarin red S staining were used to evaluate osteogenesis. 2,7‑dichloro‑dihydrofluorescein diacetate fluorescence probe was used to estimate reactive oxygen species generation. Specific assay kits were used to appraise oxidative stress levels. In addition, the expression of apoptosis‑, osteogenic differentiation‑ and Kelch‑like ECH‑associated protein 1 (Keap1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling‑associated proteins was assessed using western blotting. In Nrf2 inhibitor (ML385)‑pretreated MC3T3‑E1 cells exposed to Dex, cell apoptosis, osteogenesis and oxidative stress were detected again as aforementioned. Results revealed that TRIM21 expression was raised in Dex‑induced MC3T3‑E1 cells and TRIM21 deletion improved the viability and osteogenic differentiation, whereas it hampered the oxidative stress and apoptosis in MC3T3‑E1 cells with Dex induction. In addition, silencing of TRIM21 activated Keap1/Nrf2 signaling. Moreover, ML385 partially abrogated the effects of TRIM21 depletion on the oxidative stress, apoptosis and osteogenic differentiation in MC3T3‑E1 cells exposed to Dex. In conclusion, TRIM21 silencing might activate Keap1/Nrf2 signaling to protect against steroid‑induced ONFH.
2023-09-08 | Fibroblast growth factor 23 regulates hypoxia‑induced osteoblast apoptosis through the autophagy‑signaling pathway
Hypoxia can lead to programmed osteoblast death. Prevention of osteoblast apoptosis caused by hypoxia is of great significance in the study of the occurrence and development of bone necrosis. The present study aimed to investigate the effects and mechanism of fibroblast growth factor 23 (FGF23) on hypoxia‑induced apoptosis in primary osteoblasts and MC3T3‑E1 cells osteoblasts. Cells were transfected with a plasmid carrying the FGF23 gene and a cell model of hypoxia‑induced apoptosis was established. FGF23 mRNA levels were measured using reverse transcription‑quantitative (RT‑q) PCR and western blotting was used to assess protein levels. Apoptosis was analyzed by MTT assay, fluorescein diacetate and ethidium bromide staining, flow cytometry and RT‑qPCR and western blotting were used to verify the mRNA and protein levels of apoptosis‑ and autophagy‑related gene mRNA. The targeted relationship between miR‑17‑5p and FGF23 was confirmed using the StarBase database, TargetScan database and a luciferase reporter assay. FGF23 decreased cell survival and increased the rate of apoptosis. The mRNA and protein expression of the pro‑apoptotic genes Bax and caspases 3 and 9 increased, whereas that of the anti‑apoptotic Bcl‑2 decreased. The expressions of the autophagy‑associated proteins beclin‑1, light chain 3‑II (LC3‑II) and the LC3‑II/LC3‑I ratio were significantly increased. In addition, a luciferase reporter assay confirmed that FGF23 directly regulated micro RNA (miR)‑17‑5p. The effects of FGF23 silencing were reversed by miR‑17‑5p inhibition. FGF23 may regulate hypoxia‑induced osteoblast apoptosis by targeting miR‑17‑5p through the autophagy‑signaling pathway. This provides a rationale for FGF23 as a potential therapeutic target for osteonecrosis of the femoral head.
2023-04-24 | Endoplasmic reticulum activation of the caspase-12/9/3 cascade via ATG5 leads to sterogenic femoral head necrosis
Abstract Programmed osteocyte death might be a pathogenesis of steroid-related avascular necrosis of the femoral head (SANFH). Autophagy-related gene 5 (ATG5) can activate the unfolded protein response pathway under endoplasmic reticulum stress (ERS) to participate in cell regulation, but the regulatory mechanism remains unclear. We examined the role of ERS in SANFH pathogenesis by studying the ATG5 participation mechanism in osteoblast apoptosis regulation to provide a theoretical basis for developing new SANFH therapeutic targets. Rat bone marrow mesenchymal stem cells cultured in vitro underwent osteogenic induction and alizarin red staining. The resultant osteoblasts were divided into Control, SANFH (methylprednisolone-treated), SANFH+ATG5 small interfering RNA (siRNA) (methylprednisolone-treated ATG5 siRNA transfection) groups. Beclin 1, MAP1LC3, ATG5, PERK, and caspase-3, -9, and -12 mRNA and protein expression levels were detected, the osteoblast survival rate was measured, and apoptosis was detected. The relationship between Beclin 1, MAP1LC3, ATG5, PERK, and caspase-3, -9, and -12 mRNA and protein expression levels and osteoblast apoptosis was analyzed. The SANFH group had enhanced expression of the autophagy-related genes Beclin 1 and MAP1LC3 and numerous autophagosomes were formed. Osteoblast injury stimulated ERS. ATG5 siRNA inhibited the glucocorticoid-induced osteoblast autophagy and ERS. The ER stimulated the caspase-12/9/3 cascade through ATG5 to enhance apoptosis and improve persistent ERS. The continuous action of methylprednisolone increased Beclin 1 and MAP1LC3 gene expression, resulting in bone cell injury and stimulating ERS. The ER activated the caspase-12/9/3 cascade via ATG5 under persistent and unchangeable ERS, leading to apoptosis and SANFH.
2022-10-31 | Advances in regenerative medicine applications of tetrahedral framework nucleic acid-based nanomaterials: an expert consensus recommendation
Abstract With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids (tFNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, tFNAs have been widely applied in the biomedical field as three-dimensional DNA nanomaterials. Surprisingly, tFNAs exhibit positive effects on cellular biological behaviors and tissue regeneration, which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity, tFNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization, intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic tFNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic tFNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone, cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.
other
2024-03-27 | Causal relationship between immune cells and Osteonecrosis: a bidirectional Mendelian randomization study
Abstract Objectives Research indicates a close association between aberrant immune reactions in osteonecrotic tissues and immune cell infiltration, yet the causal relationship between them remains elusive. We aim to determine whether a causality exists between immune cell infiltration and osteonecrosis. Methods A comprehensive Mendelian Randomization (MR) analysis was conducted to determine the causal relationship between immune cell characteristics and osteonecrosis in this study. Utilizing publicly available genetic data, we explored the causal relationships between 731 immune cell features and 604 cases from the FinnGen Finnish database, as well as 257 cases from the UK Biobank database with osteonecrosis data. The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. Additionally, meta-analysis was performed on significantly associated immune cells with osteonecrosis outcomes (False Discovery Rate FDR < 0.05). Results By leveraging bidirectional MR, we revealed that 11 cell types exhibited a significantly associated (FDR < 0.05) association with the potential to either increase or decrease the risk of osteonecrosis. The occurrence and progression of osteonecrosis were found to have a significant causal relationship with the increase or decrease in six immune cell types (FDR < 0.05). Meta-analysis was conducted on the differential results between the FinnGen and UK Biobank datasets. Ultimately, CD20-% lymphocytes, CD62L- monocyte % monocytes, CD33br HLA DR + CD14- % CD33br HLA DR+, EM CD4 + activated cells and DP (CD4 + CD8+) % T cells were identified to increase or decrease the odds of osteonecrosis. Notably, osteonecrosis was associated with a potential decrease in CD45 on immature MDSC cell content. Conclusion From a genetic perspective, we demonstrated a close association between immune cells and osteonecrosis. These findings significantly enhance our understanding of the interplay between immune cell infiltration and the risk of osteonecrosis, contributing to the potential design of therapeutic strategies from an immunological standpoint.
2024-02-22 | Fibroblast growth factor 23 inhibition attenuates steroid-induced osteonecrosis of the femoral head through pyroptosis
Abstract Steroid-induced osteonecrosis of the femoral head (SONFH) is the predominant cause of non-traumatic osteonecrosis of the femoral head (ONFH). Impaired blood supply and reduced osteogenic activity of the femoral head are the key pathogenic mechanisms of SONFH. Fibroblast growth factor 23 (FGF23) levels are not only a biomarker for early vascular lesions caused by abnormal mineral metabolism, but can also act directly on the peripheral vascular system, leading to vascular pathology. The aim of this study was to observe the role of FGF23 on bone microarchitecture and vascular endothelium, and to investigate activation of pyroptosis in SONFH. Lipopolysaccharide (LPS) combined with methylprednisolone (MPS) was applied for SONFH mouse models, and adenovirus was used to increase or decrease the level of FGF23. Micro-CT and histopathological staining were used to observe the structure of the femoral head, and immunohistochemical staining was used to observe the vascular density. The cells were further cultured in vitro and placed in a hypoxic environment for 12h to simulate the microenvironment of vascular injury during SONFH. The effect of FGF23 on osteogenic differentiation was evaluated using alkaline phosphatase staining, alizarin red S staining and expression of bone formation-related proteins. Matrigel tube formation assay in vitro and immunofluorescence were used to detect the ability of FGF23 to affect endothelial cell angiogenesis. Steroids activated the pyroptosis signaling pathway, promoted the secretion of inflammatory factors in SONFH models, led to vascular endothelial dysfunction and damaged the femoral head structure. In addition, FGF23 inhibited the HUVECs angiogenesis and BMSCs osteogenic differentiation. FGF23 silencing attenuated steroid-induced osteonecrosis of the femoral head by inhibiting the pyroptosis signaling pathway, and promoting osteogenic differentiation of BMSCs and angiogenesis of HUVECs in vitro.
2023-12-19 | Identifying the causal relationship between immune factors and osteonecrosis: A Two-Sample Mendelian Randomization Study
Backgrounds: A wealth of evidence intimates a profound connection between the immune system and osteonecrosis, albeit the specific immune factors underlying this connection remain largely veiled. Methods A bidirectional Mendelian randomization (MR) study was conducted based on genome-wide association study (GWAS) summary data to identify causal links between 731 immune factors and osteonecrosis including drug-induced osteonecrosis. Preliminary MR analysis was accomplished utilizing the inverse-variance weighted method (IVW) under a multiplicative random effects model, and heterogeneity and potential horizontal pleiotropy were evaluated through Cochrane's Q-test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Results Upon false discovery rate correction, the gene-predicted level of one immune factor (CD62L- monocyte %monocyte) exhibited a significant positive correlation with osteonecrosis, while eight immune traits associated with monocytes, dendritic cells, and NK cells demonstrated significant causal effects with drug-induced osteonecrosis. Reverse MR revealed no significant correlations. Conclusion This MR research provides genetic evidence for the causal associations between a broad spectrum of immune factors and osteonecrosis. Such a study aids in unraveling the intricate interaction patterns between the immune and skeletal systems, elucidating the pathogenesis of osteonecrosis, and identifying potential novel therapeutic approaches.
2022-12-13 | The role of immune cells in modulating chronic inflammation and osteonecrosis
Osteonecrosis occurs when, under continuous stimulation by adverse factors such as glucocorticoids or alcohol, the death of local bone and marrow cells leads to abnormal osteoimmune function. This creates a chronic inflammatory microenvironment, which interferes with bone regeneration and repair. In a variety of bone tissue diseases, innate immune cells and adaptive immune cells interact with bone cells, and their effects on bone metabolic homeostasis have attracted more and more attention, thus developing into a new discipline - osteoimmunology. Immune cells are the most important regulator of inflammation, and osteoimmune disorder may be an important cause of osteonecrosis. Elucidating the chronic inflammatory microenvironment regulated by abnormal osteoimmune may help develop potential treatments for osteonecrosis. This review summarizes the inflammatory regulation of bone immunity in osteonecrosis, explains the pathophysiological mechanism of osteonecrosis from the perspective of osteoimmunology, and provides new ideas for the treatment of osteonecrosis.
2012-10-05 | There are many potential medical therapies for atraumatic osteonecrosis
Atraumatic osteonecrosis is a common complication of SLE and is seen in other connective tissue diseases, in patients treated with high doses of CSs, in HIV-infected patients and in alcoholic patients. Standard care is confined to analgesia, core decompression if the condition is early and affects the femoral head and joint replacement. However, consideration of the underlying biological mechanisms leads to the recognition of many potential therapies that might either prevent progression or, even, reverse the process if it is not yet too far advanced. These potential therapies merit detailed consideration. Critical points are that (i) histopathological evidence shows that the initial cellular event is apoptosis of osteocytes; and (ii) another requisite, as homeostasis requires that death and rebirth of osteocytes be balanced, is an accompanying inadequate proliferative capacity of osteoblasts. Thus, a logical approach to treatment includes measures that (i) reduce apoptosis of osteocytes and (ii) enhance proliferation of osteoblasts/pre-osteoblasts. Measures to reduce the ongoing apoptosis of osteocytes require reinforcing the effects of members of the Bcl-2 family (Bcl-2 itself and Mcl-1), the Wnt/catenin pathways (using an available sclerostin antibody) and HSPs (by application of local heat using US, deep wave diathermy or infrared), as well as administration of bisphosphonates and nitrates. Measures to enhance proliferation of osteoblasts/pre-osteoblasts include the use of stem cells, extracorporeal shock wave therapy, aspirin, the proteosome inhibitor bortezomib, melatonin and application of local heat. Use of VEGF would encourage proliferation of blood vessels and osteogenesis. Certain drugs that inhibit osteoblast proliferation should be avoided, including NSAIDs, serotonin reuptake inhibitors and thiazolidinediones.
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Drug Discovery Landscape
3 orphan drug designations for Secondary non-traumatic avascular necrosis.
3 orphan drug designations for Secondary non-traumatic avascular necrosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Allogenic umbilical cord-derived osteoblast cells | cell therapies | EMA | 2025-01-16 | — | Opis S.r.l. |
Autologous adult live cultured osteoblasts | cell therapies | EMA | 2019-02-26 | — | Scendea (NL) B.V. |
Human allogeneic bone marrow derived osteoblastic-like cells | cell therapies | EMA | 2013-08-05 | — | BioSenic |
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