proteins

2026-03-31 | Growth hormone: Synthesis and regulation.

Growth hormone (GH) plays an essential role in the regulation of postnatal growth and metabolism through both direct and GH-IGF-1 axis-mediated mechanisms. GH action involves a complex interplay of endocrine, paracrine and autocrine signals that affect multiple tissues and organs. This review addresses the molecular and physiological fundamentals of GH secretion and action, as well as the multiple factors that modulate it, including central and peripheral signals, metabolic variables, physiological and pharmacological states. The relevance of GH receptor signaling and intracellular pathways involved in tissue response is discussed, as well as the mechanisms of hormone resistance that may arise in different clinical contexts. GH secretion, which is pulsatile, is subject to strict regulation by the hypothalamic-pituitary system, involving GHRH, somatostatin and ghrelin, together with negative feedback from GH and IGF-1. In addition, factors such as sleep, nutrition, stress, age or sex contribute significantly to its physiological variability. The implications of the somatotropic axis in pathological conditions such as GH deficiency, acromegaly or GH insensitivity syndromes are also explored.

Open article ↗

2026-03-30 | The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation.

Insulin-like growth factor-1 (IGF-1) signaling plays a paradoxical role in aging, acting as both a mediator of tissue repair and a driver of chronic inflammation through the senescence-associated secretory phenotype (SASP). In this review, we propose a biphasic senescence switch model in which the temporal pattern of IGF-1 exposure, acute versus chronic, determines cellular fate. Transient IGF-1 signaling supports homeostasis and repair, whereas sustained activation promotes stable senescence via reactive oxygen species (ROS)-mediated DNA damage, p53/p21 pathway activation, and a potent pro-inflammatory SASP. Central to this process is IGF-binding protein-5 (IGFBP-5), which amplifies senescence in vascular and stromal cells by linking coagulation and inflammatory signals to p53-dependent arrest. The contrasting human conditions of IGF-1 deficiency (Laron syndrome) and excess (acromegaly) illustrate the lifespan and disease risks associated with dysregulated IGF-1 signaling. Emerging evidence highlights the role of extracellular vesicles in bypassing soluble IGFBP regulation, enabling paracrine propagation of senescence even under systemic IGF-1 modulation. Ultimately, we position the IGF-1/IGFBP axis as a prime target for precision senomodulation, advocating for combined strategies that temporally tune endocrine signaling with senolytic and senomorphic therapies to mitigate chronic inflammation, delay age-related dysfunction, and extend healthspan.

Open article ↗

2026-03-25 | A cartilage-targeted IGF-1-antibody fusion protein as a new therapeutic approach for IGF-1 deficiency.

Growth hormone (GH) insensitivity syndrome (GHIS) is a childhood growth disorder characterized by an inability to generate insulin-like growth factor-1 (IGF-1) in response to GH. Consequently, GH therapy is ineffective in patients with GHIS. Patients are often treated with recombinant IGF-1 instead, which requires twice-daily injections and is associated with adverse effects including hypoglycemia. In the current study, we evaluated CV1623-1, a cartilage-targeted antibody-like IGF-1 fusion protein as a potential new treatment for GHIS and for other disorders of linear growth involving IGF-1 deficiency. Using Ghrhrlit mice as a model for IGF-1 deficiency, we found that CV1623-1 stimulated the growth plate at a lower dose and decreased dose frequency compared with IGF-1. Alternate-day injections of CV1623-1 significantly increased body weight, tail length, and tibial bone length. In addition, CV1623-1, unlike IGF-1, did not induce hypoglycemia. Taken together, our findings indicate that CV1623-1 represents a promising new drug candidate for GHIS with improved efficacy, longer duration of action, and reduced hypoglycemia compared with the current treatment, recombinant IGF-1. Preclinical studies and clinical trials would be required to further validate the safety and efficacy of CV1623-1, paving the way for its potential clinical application as a new treatment for GHIS.

Open article ↗

2025-10-01 | SAT-217 Severe Short Stature and Growth Hormone (GH) Insensitivity in an Adolescent Male Associated with a Novel Homozygous Variant in the GH Receptor Gene: A Unique Case of Laron Syndrome

Abstract Disclosure: V.X. Yu: None. M.E. Geffner: Diurnal, Novo Nordisk, Neurocrine Biosciences: Research support, Advisory board/Consultant, Spruce Biosciences: Research support, Advisory board/Consultant, Ascendis: Advisory board/Consultant, Eton Pharmaceuticals: Advisory board/Consultant, Theratechnologies, Inc: Advisory board/Consultant, McGraw-Hill: Royalties, Up To Date. L.M. Randolph: BioMarin Pharmaceuticals- Advisory board/consultant. Z. Laron: None. A. Ryabets-Lienhard: Ultragenyx, Principal investigator receiving grant support for research, Takeda, Principal investigator receiving grant support for research, Alexion Pharmaceuticals, Inc., Advisory board/consultant, BioMarin Pharmaceuticals- Advisory board/consultant. Introduction: Laron syndrome (LS) is a rare autosomal recessive disorder with an estimated 500 global cases, characterized by GH resistance due to pathogenic variants in the GH receptor (GHR) gene, resulting in primary IGF-1 deficiency. Affected patients exhibit severe short stature, distinctive facial features, and extremely low levels of IGF-1 despite normal or elevated GH levels. The broad spectrum of pathogenic GHR variants in LS includes missense, nonsense, splice-site, and deletion variants that often involve the extracellular (EC) GH binding domain of the GHR (exons 1-7) and result in low GH-binding protein (GHBP) levels. We present a unique case of an adolescent male with severe LS associated with a novel missense variant in GHR exon 7, but normal GHBP levels. Case: An almost 16-yr-old male of Mexican ancestry with no known significant family history or consanguinity presented with severe relatively proportional short stature (height -7.06 SD, BMI 0.37 SD). He had an infantile face with round cheeks, depressed nasal bridge, high-pitched voice, slightly blue sclerae, Tanner Stage (TS) 2 puberty with testosterone 77 ng/dL (8-66), and bone age 11.6 yr. He was found to have undetectable IGF-1 (<10 ng/mL, 201-609) and low IGFBP-3 (0.8 mg/L, 3.5-10.0) with normal GH stimulation (peak GH 10.9 ng/mL) and GHBP (1446 pmol/L, 290-3140). TSH was elevated (6.43 mlU/mL, 0.50-5.00) with normal FT4 (1.09 ng/dL, 0.70-1.65). Genetic testing using the Discover Dysplasias gene panel (Invitae) identified a novel homozygous c.650T>G (p.Val217Gly) variant in GHR exon 7, classified as a variant of uncertain significance, in the last codon of the EC binding domain. There was no response in IGF-1 generation testing to GH 33 mg/kg/day x 7 days (IGF-1 averaged 11 ng/dL, 201-609; -5.5 SD), further supporting a diagnosis of LS. After 3 mo, height remained -7.08 SD while puberty progressed to TS3 with increased testosterone (526 ng/dL, 26-800). TSH increased further to 9.74 mlU/mL with normal FT4 1.13 ng/dL. Patient started recombinant human IGF-1 therapy at 0.1 mg/kg once daily x 1 wk, then increased to 0.18 mg/kg once daily x 1 wk and subsequently to 0.12 mg/kg twice daily (with no hypoglycemia or other side effects). Letrozole (2.5 mg daily) was also started to delay epiphyseal fusion. Conclusion: This unique case of severe Laron syndrome involves a novel homozygous missense variant of uncertain significance in the EC GH binding domain of GHR with unexpectedly normal GHBP levels, potentially expanding the scope of known GHR pathogenic variants. Its position in the last codon of the EC domain adjacent to the transmembrane domain may explain normal GHBP levels with disruption of GH action downstream. Functional studies are planned to further analyze this novel variant and confirm its pathogenicity. The co-occurrence of subclinical hypothyroidism also warrants further study regarding its contribution to the LS phenotype. Presentation: Saturday, July 12, 2025

Open article ↗

2025-07-21 | Disabilities and Handicaps of Patients with Laron Syndrome

Background: Laron Syndrome (LS) is a rare hereditary disease of dwarfism occurring with few exceptions in Jewish, Muslim and Asian populations or their descendants spread over all continents. It is caused by deletions or mutations in the GH-Receptor gene resulting in high serum levels of a structurally and biologically normal, but inactive GH and low to undetectable IGF-I. Aim: To summarize the disabilities and handicaps observed in patients with LS, from infancy through adult age. Results: Diagnosing, treating and following a cohort of 76 patients with LS, many since infancy into adult age, enabled our department to study not only their growth and social achievements, but also the difficulties these patients encounter in life. The longstanding IGF-I deficiency caused somatic and biochemical changes which lead to disabilities starting already in infancy and becoming more severe with advancing age. The most serious handicaps LS patients have are dwarfism, progressive obesity, diabetes, fatty liver, cardiovascular disease, neurological and orthopedic problems, leading to difficulties in vocational training, occupation and social life, all lowering the Quality of Life (QoL) of these patients. Conclusion: Early initiation of IGF-I replacement treatment of patients with Laron Syndrome prevents and reverses part of the handicaps of the longstanding IGF-I deficiency.

Open article ↗

small molecules

2026-08-08 | The Laron Syndrome Mouse Model Reveals a Potential Contribution of Methylglyoxal-Derived Glycative Stress to IGF-1-Driven Prostate Cancer Progression

Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression.

Open article ↗

2026-02-12 | CYP11A1-derived Non-canonical Secosteroids and Circadian–Endocrine Regulation: A Scoping Review

Background: Vitamin D is traditionally characterized as a nutrient essential for calcium homeostasis. However, emerging evidence suggests that the cutaneous CYP11A1-driven secosteroid pathway serves as a "chemical proxy" for sunlight, linking environmental UV radiation to the synchronization of the mammalian circadian clock and systemic endocrine axes. Objective: This review delineates the role of CYP11A1-derived vitamin D metabolites [e.g., 20[OH]D₃ and 20,23[OH]₂D₃] as photoneuroendocrine signals that modulate core clock gene expression and regulate the hypothalamic-pituitary-adrenal [HPA], hypothalamic-pituitary-thyroid [HPT], and growth hormone [GH] axes. Methods: A systematic synthesis was performed following PRISMA 2020 guidelines using PubMed and Scopus. We integrated enzymological data on CYP11A1 substrate flexibility with molecular evidence regarding nuclear receptor interactions [VDR, RORα/γ, AhR] and clinical observations of hormonal rhythmicity. Bioinformatic centralities were assessed via ClusterProfiler and cytoHubba. Results: CYP11A1 initiates a non-canonical pathway in the skin, metabolizing vitamin D₃, lumisterol, and tachysterol into non-calcemic hydroxyderivatives. These metabolites function as inverse agonists of the orphan nuclear receptors RORα and RORγ, which directly suppress BMAL1 transcription and modulate the amplitude of the peripheral circadian oscillator. Mechanistically, this axis interacts with the NAMPT–NAD⁺ metabolic loop, coupling photic cues to mitochondrial oxidative metabolism. Clinical evidence indicates that while serum 25[OH]D₃ acts as a tonic nutritional marker, cutaneous secosteroids provide phasic signals that stabilize the pulsatile secretion of GH and the rhythmicity of TSH and cortisol. Vitamin D deficiency is thus re-characterized as a state that permits the attenuation of endocrine amplitude rather than causing primary hormone deficiency. The key mechanistic evidence is largely preclinical and that clinical implications remain investigational. Conclusions: The CYP11A1-secosteroid axis represents a paradigm shift from nutrition to photoneuroendocrinology. These non-calcemic metabolites act as endogenous chronobiotics that align systemic physiology with the environmental light-dark cycle. Clinical Implications: These findings support the use of non-calcemic vitamin D analogs as targeted chronotherapeutics for circadian misalignment, metabolic syndrome, and autoimmune disorders. In pediatric populations, maintaining adequate sunlight exposure and secosteroid signaling is critical for the stability of growth and stress-response axes.

Open article ↗

2025-12-21 | Oligosaccharides ameliorate insulin resistance and hepatic metabolism by promoting the leptin/POMC axis to accelerate short stature growth and development.

Leptin and pro-opiomelanocortin (POMC) signaling critically regulates metabolism and growth. The potential of oligosaccharides to modulate this axis and its physiological impacts remains unclear. Male wild-type (WT) and leptin-deficient (ob/ob) mice received daily oral oligosaccharides for 8 weeks. Lentiviral POMC overexpression (LV-POMC) or control (LV-NC) was administered to ob/ob mice. Metabolic function was assessed via glucose/insulin tolerance tests (GTT/ITT). Serum/tissue levels of leptin, POMC, metabolic markers, growth hormones, and bone regulators were quantified by enzyme-linked immunosorbent assay and Western blot. Femur length was recorded, and trabecular architecture was evaluated by hematoxylin-eosin staining. Oligosaccharides increased leptin and POMC levels in WT but not ob/ob mice. Oligosaccharides improved insulin sensitivity, hepatic metabolism (reduced triglycerides, aspartate aminotransferase, alanine aminotransferase, and free fatty acids), and bone growth (increased femur length, osteoprotegerin; decreased receptor activator of nuclear factor kappa-B ligand/cathepsin K) in WT mice. These benefits were absent in ob/ob mice. Crucially, POMC overexpression in ob/ob mice rescued metabolic dysfunction (improved GTT/ITT and normalized hepatic markers), restored growth hormone balance (reduced adrenocorticotropic hormone/cortisol and increased insulin-like growth factor 1), and reversed bone defects. Oligosaccharides exert insulin-sensitizing, hepatoprotective, and growth-promoting effects via leptin-dependent POMC activation. POMC restoration rescues deficits in leptin deficiency, establishing the leptin/POMC axis as the essential mechanistic pathway.

Open article ↗

2025-07-01 | G-protein-coupled estrogen receptor-1 facilitates chondrocyte proliferation in pubertal epiphyseal growth plate via PTHrP/Ihh regulation.

Oestrogen drives long-bone development through various oestrogen receptors. G-protein-coupled oestrogen receptor-1 (GPER-1), a membrane oestrogen receptor, mediates longitudinal bone growth during early puberty; however, the underlying mechanisms remain unclear. Therefore, this study elucidated the mechanisms underlying GPER-1-mediated bone growth. A GPER-1 agonist (G1), GPER-1 antagonist (G15), and chondrocyte-specific GPER-1 knockout experiment (Col2a1-Cre; GPER-1f/f, CKO) were used to investigate the role of GPER-1 in growth plate chondrocytes from C57BL/6 mice (total number = 48). We investigated the effects of GPER-1 activation or inhibition on the tibial growth plate and bone growth, including changes in proliferation and hypertrophy, and the expression of parathyroid hormone-related peptide (PTHrP), Indian hedgehog (Ihh), and their ratio (PTHrP/Ihh). G1 treatment-induced GPER-1 activation increased tibial growth plate thickness, proliferative zone thickness, and chondrocyte proliferation in mice. The hypertrophic zone thickness and type X collagen-stained area decreased in four-week-old G1-treated mice compared with the control group. GPER-1 activation increased the PTHrP/Ihh ratio in the growth plates of four- and eight-week-old mice. In contrast, blocking or deleting GPER-1 decreased the proliferative zones of the growth plate, proliferative chondrocytes, and PTHrP/Ihh. Additionally, the hyperopic zones of the growth plates increased with GPER-1 deficiency. In vitro micromass-3D cultured chondrocyte studies confirmed that G1 treatment increased proliferation, decreased hypertrophy, and increased PTHrP/Ihh protein levels. This study demonstrates that GPER-1 maintains proliferation but suppresses chondrocyte hypertrophy in growth plates by upregulating PTHrP/Ihh during early puberty in male and female mice. Our findings suggest that GPER-1 may serve as a potential target for therapeutic modulation of linear bone growth during puberty.

Open article ↗

2025-05-15 | A high-fat diet suppresses growth hormone synthesis and secretion by influencing the Vit D receptor and Pit1.

A long-term high-fat diet (HFD) leads to excessive lipid deposition, which may cause many diseases, including NAFLD, diabetes, and thyroid dysfunction. In addition, HFD leads to a decrease in serum growth hormone (GH) levels to further increase lipid deposition and obesity. However, the mechanism of such reduction of GH has not been fully elucidated. Male Sprague-Dawley rats were fed a regular diet (CD) or a high-fat diet (HFD) for 29 weeks. GH synthesis and secretion were evaluated in pituitary and blood samples, respectively. An in vitro model was constructed by treating cultured cells with palmitic acid (PA). Vit D receptor (VDR) plasmids (OE-VDR), paricalcitol and VDR knockdown virus (sh-VDR) were used to overexpress or depress the activation of VDR during PA treatment of GH3 cells. The GH content, lipid content, and relevant expression of different molecules were measured in pituitary and cell samples. A HFD decreased the levels of circulating GH and the expression of Gh in the anterior pituitary gland tissues of rats. In vitro, PA treatment decreased Pit1 and Gh expression in cultured GH3 cells. VDR expression was reduced in the rat pituitary tissues under HFD conditions and in PA-treated GH3 cells. The overexpression and knockdown of VDR increased and decreased the expression of Pit1 and Gh, respectively. Paricalcitol antagonized the decrease in the expression of Pit1 and Gh caused by PA treatment. HFD induced lipid deposition in the pituitary may cause GH deficiency, and VDR - Pit1 may be at least partially involved in the process.

Open article ↗

cell therapies

2022-03-10 | Therapeutic application of Sertoli cells for treatment of various diseases.

Sertoli cells (SCs) are immune privileged cells found in the testis that function to immunologically protect maturing germ cells from immune destruction. This immune protection is due to the blood-testis-barrier, which prevents infiltration of cytotoxic immune cells and antibodies, and SC production of immunomodulatory factors, that favor a tolerogenic environment. The ability of SCs to create an immune privileged environment has led to the exploration of their potential use in the treatment of various diseases. SCs have been utilized to create a tolerogenic ectopic microenvironment, to protect co-grafted cells, and to deliver therapeutic proteins through gene therapy. To date, numerous studies have reported the potential use of SCs for the treatment of diabetes, neurodegenerative disorders, and restoration of spermatogenesis. Additionally, SCs have been investigated as a delivery vehicle for therapeutic products to treat other diseases like Laron syndrome, muscular dystrophy, and infections. This review will provide an overview of these therapeutic applications.

Open article ↗

2012-09-03 | Reversal of experimental Laron Syndrome by xenotransplantation of microencapsulated porcine Sertoli cells

Recombinant human IGF-1 currently represents the only available treatment option for the Laron Syndrome, a rare human disorder caused by defects in the gene encoding growth hormone receptor, resulting in irreversibly retarded growth. Unfortunately, this treatment therapy, poorly impacts longitudinal growth (13% in females and 19% in males), while burdening the patients with severe side effects, including hypoglycemia, in association with the unfair chore of taking multiple daily injections that cause local intense pain. In this study, we have demonstrated that a single intraperitoneal graft of microencapsulated pig Sertoli cells, producing pig insulin-like growth factor-1, successfully promoted significant proportional growth in the Laron mouse, a unique animal model of the human Laron Syndrome. These findings indicate a novel, simply, safe and successful method for the cell therapy-based cure of the Laron Syndrome, potentially applicable to humans.

Open article ↗

1995-12-21 | Long-term expression of the biologically active growth hormone in genetically modified fibroblasts after implantation into a hypophysectomized rat.

We employed the hypophysectomized rats as an animal model to explore the feasibility of using genetically engineered fibroblast cells for growth hormone gene therapy. An internal ribosome entry site (IRES)-directed bicistronic retroviral vector, PSN, which contained a porcine growth hormone (pGH) cDNA at the first cistron and a Neo(r) gene at the second cistron was used to infect primary rat embryo fibroblast (REF) cells. The infected cells (5 x 10(6) cells/rat) were injected directly into the peritoneum of syngeneic hypophysectomized rats. We demonstrate that the implanted PSN-infected REF cells could secrete biologically active pGH in vivo, leading to significant growth of the tibia at day 15 and day 57 post-implantation. We also treated the PSN-infected REF cells with collagen to form a tissue-like structure. The skin-like discs were grafted underneath the skin on the back of rats and cells were retrieved at different times. Using two criteria, semiquantitative reverse transcription-polymerase chain reaction on the pGH RNA extracted from the explants and G418 resistance conferred from the explanted cells, we demonstrate that pGH was expressed in the implanted fibroblasts up to 70 days. Despite the fact that the total pGH RNA level was reduced in the explants of long-time post-implantation, which was probably due to the reduction of transduced cells retained in the explants, the specific efficiencies of pGH RNA expression from these explants were maintained as high as the primary PSN-infected REF prior implantation. These results suggest that fibroblast cells are capable of expressing the foreign genes persistently in vivo.

Open article ↗

gene therapies

2026-06-15 | GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes.

Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40-45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.

Open article ↗

2025-11-25 | Growth hormone regulates the stem cell population in the growth plate.

Growth hormone (GH) is a key systemic regulator of longitudinal bone growth and is widely used in pediatric endocrinology, including in patients without GH deficiency. Its primary target is the growth plate-a cartilaginous structure driving bone elongation-yet the cellular mechanisms underlying GH action remain incompletely understood. Here, we identify a direct role for GH in regulating a recently defined population of cartilaginous stem cells within the growth plate. Using multiple transgenic mouse models, we show that GH reduces the pool of slow-cycling, label-retaining stem cells by promoting their differentiation into transient progenitors. Clonal and lineage-tracing analyses reveal that these stem cells renew via population asymmetry and that GH promotes their committed cell division, leading to stem cell depletion. Conversely, genetic deletion of the GH receptor in stem cells impairs their ability to generate chondrocytes, confirming a direct GH effect. These findings support a general principle by which endocrine cues regulate tissue regeneration, establish a mechanistic link between GH signaling and cartilaginous stem cells, and provide a potential explanation for certain related clinical observations, such as the declining long-term efficacy of GH therapy.

Open article ↗

2022-02-01 | First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model

The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.

Open article ↗

2017-07-19 | Genome-wide profiling of congenital insulin-like growth factor-1 deficient patients: translational implications in cancer prevention and metabolism

Laron syndrome (LS) is a rare genetic disorder identified in the 1950s by Professor Zvi Laron. LS results from mutation of the growth hormone receptor (GH-R) gene, leading to congenital insulin-like growth factor-1 (IGF1) deficiency and dwarfism. Recent epidemiological studies have shown that LS patients do not develop cancer, emphasizing the crucial role of the IGF1 axis in cancer biology. Genome-wide profiling of LS patients conducted in our laboratory led to the identification of genes and signaling pathways that are over- or under-represented in LS compared to healthy controls of the same age range and ethnic group. Differentially expressed genes may be responsible for the association between lifetime low IGF1 values and protection from cancer. This experiment of nature may provide invaluable information that might translate into novel therapeutic approaches in modern oncology.

Open article ↗

2016-11-11 | Partial correction of the dwarf phenotype by non-viral transfer of the growth hormone gene in mice: Treatment age is critical.

Non-viral transfer of the growth hormone gene to different muscles of immunodeficient dwarf (lit/scid) mice is under study with the objective of improving phenotypic correction via this particular gene therapy approach. Plasmid DNA was administered into the exposed quadriceps or non-exposed tibialis cranialis muscle of lit/scid mice followed by electroporation, monitoring several growth parameters. In a 6-month bioassay, 50μg DNA were injected three times into the quadriceps muscle of 80-day old mice. A 50% weight increase, with a catch-up growth of 21%, together with a 16% increase for nose-to-tail and tail lengths (catch-up=19-21%) and a 24-28% increase for femur length (catch-up=53-60%), were obtained. mIGF1 serum levels were ~7-fold higher than the basal levels for untreated mice, but still ~2-fold lower than in non-dwarf scid mice. Since treatment age was found to be particularly important in a second bioassay utilizing 40-day old mice, these pubertal mice were compared in a third bioassay with adult (80-day old) mice, all treated twice with 50μg DNA injected into each tibialis cranialis muscle, via a less invasive approach. mIGF1 concentrations at the same level as co-aged scid mice were obtained 15days after administration in pubertal mice. Catch-up growth, based on femur length (77%), nose-to-tail (36%) and tail length (39%) increases was 40 to 95% higher than those obtained upon treating adult mice. These data pave the way for the development of more effective pre-clinical assays in pubertal dwarf mice for the treatment of GH deficiency via plasmid-DNA muscular administration.

Open article ↗

other

2021-12-13 | MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH-IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.

Open article ↗