RARE DISEASE
TRPV4-related bone disorder
TRPV4-related bone disorder
TRPV4-related bone disorder
Drug discovery
1
drug
With orphan designation
Overview
TRPV4-related bone disorders encompass a spectrum of autosomal dominant skeletal dysplasias caused by gain-of-function mutations in the TRPV4 calcium channel gene. These conditions—including metatropic dysplasia, Kozlowski-type spondylometaphyseal dysplasia, and brachyolmia—are characterized by short stature, kyphoscoliosis, platyspondyly, and metaphyseal irregularities. Mutations disrupt chondrocyte function, impairing endochondral ossification and cartilage mechanotransduction [1][5][11]. Neurological manifestations (e.g., peripheral neuropathies) may coexist with skeletal features in some patients [6][13].
Therapies
Symptomatic management: NSAIDs, physiotherapy, and orthopedic interventions (spinal fusion, joint replacements) [8][12]
Experimental approaches: TRPV4 antagonists in preclinical studies, BMP pathway modulation [3][11]
Prenatal genetic counseling and surveillance for spinal/airway complications [5][15]
Categories: rare genetic diseases
Research Papers
18 drug discovery papers about TRPV4-related bone disorder, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
18 drug discovery papers about TRPV4-related bone disorder, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-02-28 | Skeletal dysplasia-causing mutations in TRPV4 alter the chondrocyte transcriptomic response to mechanical loading.
Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel highly expressed in chondrocytes that supports cartilage development and homeostasis. Mutations in the channel can cause skeletal dysplasias, including the gain-of-function mutations V620I and T89I, which lead to brachyolmia and metatropic dysplasia, respectively. These mutations suppress hypertrophic differentiation, but the mechanisms by which they alter chondrocyte response to mechanical load remain to be elucidated. To determine the effect of these mutations on chondrocyte mechanotransduction, tissue-engineered cartilage was derived from differentiated clustered regularly interspaced short palindromic repeats (CRISPR)-edited human-induced pluripotent stem cells (hiPSCs) harboring the moderate V620I or severe T89I TRPV4 mutations. Wild-type and mutant tissue-engineered hiPSC-derived cartilage contructs were subjected to compressive mechanical loading at physiological levels, and transcriptomic signatures were assessed by RNA-sequencing. Our results demonstrate that the V620I and T89I mutations diminish the mechanoresponsiveness of chondrocytes, as evidenced by reduced gene expression downstream of TRPV4 activation, including those involved in endochondral ossification. Changes in the expression of genes involved in extracellular matrix production and organization were found to contribute toward the phenotype in V620I mutant chondrocytes, whereas dysregulated retinoic acid signaling was linked to T89I, and disrupted proliferation was common to both. Our findings suggest that dysfunctional mechanotransduction due to V620I and T89I mutations in TRPV4 contribute to the developmental phenotypes, supporting TRPV4 modulation as a potential pharmacologic target.NEW & NOTEWORTHY Gain-of-function mutations in TRPV4, a mechano- and osmosensitive ion channel, are linked to skeletal dysplasias, but their effects on chondrocyte mechanotransduction remain unknown. Using human iPSCs harboring skeletal dysplasia-causing mutations, we developed and mechanically loaded tissue-engineered cartilage. Our findings show that V620I and T89I mutations reduce chondrocyte mechanoresponsiveness, evidenced by decreased gene expression downstream of TRPV4 activation, providing insight into TRPV4-related skeletal disorders and potential pharmacological targets.
2025-01-18 | Comparison of the natural course of clinical and radiologic features in 13 patients with TRPV4-related skeletal dysplasias.
Heterozygous TRPV4 mutations cause a group of skeletal dysplasias characterized by short stature, short trunk, and skeletal deformities. The aim of this study is to compare the natural history of clinical and radiologic features of patients with different TRPV4-related skeletal dysplasias. Thirteen patients with a mutation in TRPV4 were included in the study, and 11 were followed for a median of 6.5 years. The clinical phenotype of five patients was compatible with spondylometaphyseal dysplasia Kozlowski type, three each with metatropic dysplasia and brachyolmia type 3, and one each with spondyloepiphyseal dysplasia Maroteaux type and congenital distal spinal muscular atrophy. Short stature and bone pain when running, walking, and climbing stairs occurred in patients with spondylometaphyseal dysplasia Kozlowski type and metatropic dysplasia from the age of 5 years and worsened with increasing age. Kyphosis was more pronounced with increasing age in these two groups of patients, while severe scoliosis occurred in brachyolmia type 3. In the radiographs of patients with spondylometaphyseal dysplasia Kozlowski type and metatropic dysplasia, severe platyspondyly persisted into adulthood or puberty. The patients with spondylometaphyseal dysplasia Kozlowski type exhibited irregular proximal femora leading to destruction of the femoral head towards the end of puberty, whereas metatropic dysplasia showed marked irregularity and widening of the femoral neck. We also observed that metaphyseal dysplasia in long bones other than the proximal femur was so inconspicuous that it could be ignored in patients with spondylometaphyseal dysplasia Kozlowski type. Comparison of radiologic features that change with age in five different TRPV4-related skeletal dysplasias will be of great benefit in the management of this patient group.
2023-06-30 | Structure of human TRPV4 in complex with GTPase RhoA.
Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases.
2023-06-12 | TRPV4 regulates osteoblast differentiation and mitochondrial function that are relevant for channelopathy
Different ion channels present in the osteoblast regulate the cellular functions including bio-mineralization, a process that is a highly stochastic event. Cellular events and molecular signaling involved in such process is poorly understood. Here we demonstrate that TRPV4, a mechanosensitive ion channel is endogenously present in an osteoblast cell line (MC3T3-E1) and in primary osteoblasts. Pharmacological activation of TRPV4 enhanced intracellular Ca2+-level, expression of osteoblast-specific genes and caused increased bio-mineralization. TRPV4 activation also affects mitochondrial Ca2+-levels and mitochondrial metabolisms. We further demonstrate that different point mutants of TRPV4 induce different mitochondrial morphology and have different levels of mitochondrial translocation, collectively suggesting that TRPV4-mutation-induced bone disorders and other channelopathies are mostly due to mitochondrial abnormalities. These findings may have broad biomedical implications.
2023-03-15 | Structural insights into TRPV4-Rho GTPase signaling complex function and disease
Crosstalk between ion channels and small GTPases is critical during homeostasis and disease 1 , but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions 2-5 . Gain-of-function mutations also cause hereditary neuromuscular disease 6-11 . Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the apo, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that the interaction strength between TRPV4 and RhoA tunes TRPV4-mediated calcium homeostasis and actin remodeling, and that disruption of TRPV4-RhoA interactions leads to TRPV4-related neuromuscular disease, findings that will guide TRPV4 therapeutics development.
proteins
2024-03-11 | Osteocyte-mediated mechanical response controls osteoblast differentiation and function
Low bone mass is a pervasive global health concern, with implications for osteoporosis, frailty, disability, and mortality. Lifestyle factors, including sedentary habits, metabolic dysfunction, and an aging population, contribute to the escalating prevalence of osteopenia and osteoporosis. The application of mechanical load to bone through physical activity and exercise prevents bone loss, while sufficient mechanical load stimulates new bone mass acquisition. Osteocytes, cells embedded within the bone, receive mechanical signals and translate these mechanical cues into biological signals, termed mechano-transduction. Mechano-transduction signals regulate other bone resident cells, such as osteoblasts and osteoclasts, to orchestrate changes in bone mass. This review explores the mechanisms through which osteocyte-mediated response to mechanical loading regulates osteoblast differentiation and bone formation. An overview of bone cell biology and the impact of mechanical load will be provided, with emphasis on the mechanical cues, mechano-transduction pathways, and factors that direct progenitor cells toward the osteoblast lineage. While there are a wide range of clinically available treatments for osteoporosis, the majority act through manipulation of the osteoclast and may have significant disadvantages. Despite the central role of osteoblasts to the deposition of new bone, few therapies directly target osteoblasts for the preservation of bone mass. Improved understanding of the mechanisms leading to osteoblastogenesis may reveal novel targets for translational investigation.
2021-06-15 | Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes
ABSTRACT Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype. There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations upregulated several anterior HOX genes and downregulated antioxidant genes CAT and GSTA1 throughout chondrogenesis. BMP4 treatment upregulated several essential hypertrophic genes in WT chondrocytes; however, this hypertrophic maturation response was inhibited in mutant chondrocytes. These results indicate that the TRPV4 mutations alter BMP signaling in chondrocytes and prevent proper chondrocyte hypertrophy, as a potential mechanism for dysfunctional skeletal development. Our findings provide potential therapeutic targets for developing treatments for TRPV4-mediated skeletal dysplasias.
2016-02-14 | Mechanobiology of TGFβ signaling in the skeleton
Physical and biochemical cues play fundamental roles in the skeleton at both the tissue and cellular levels. The precise coordination of these cues is essential for skeletal development and homeostasis, and disruption of this coordination can drive disease progression. The growth factor TGFβ is involved in both the regulation of and cellular response to the physical microenvironment. It is essential to summarize the current findings regarding the mechanisms by which skeletal cells integrate physical and biochemical cues so that we can identify and address remaining gaps that could ultimately improve skeletal health. In this review, we describe the role of TGFβ in mechanobiological signaling in bone and cartilage at the tissue and cellular levels. We provide detail on how static and dynamic physical cues at the macro-level are transmitted to the micro-level, ultimately leading to regulation at each level of the TGFβ pathway and to cell differentiation. The continued integration of engineering and biological approaches is needed to answer many remaining questions, such as the mechanisms by which cells generate a coordinated response to physical and biochemical cues. We propose one such mechanism, through which the combination of TGFβ and an optimal physical microenvironment leads to synergistic induction of downstream TGFβ signaling.
small molecules
2025-02-28 | Skeletal dysplasia-causing mutations in TRPV4 alter the chondrocyte transcriptomic response to mechanical loading.
Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel highly expressed in chondrocytes that supports cartilage development and homeostasis. Mutations in the channel can cause skeletal dysplasias, including the gain-of-function mutations V620I and T89I, which lead to brachyolmia and metatropic dysplasia, respectively. These mutations suppress hypertrophic differentiation, but the mechanisms by which they alter chondrocyte response to mechanical load remain to be elucidated. To determine the effect of these mutations on chondrocyte mechanotransduction, tissue-engineered cartilage was derived from differentiated clustered regularly interspaced short palindromic repeats (CRISPR)-edited human-induced pluripotent stem cells (hiPSCs) harboring the moderate V620I or severe T89I TRPV4 mutations. Wild-type and mutant tissue-engineered hiPSC-derived cartilage contructs were subjected to compressive mechanical loading at physiological levels, and transcriptomic signatures were assessed by RNA-sequencing. Our results demonstrate that the V620I and T89I mutations diminish the mechanoresponsiveness of chondrocytes, as evidenced by reduced gene expression downstream of TRPV4 activation, including those involved in endochondral ossification. Changes in the expression of genes involved in extracellular matrix production and organization were found to contribute toward the phenotype in V620I mutant chondrocytes, whereas dysregulated retinoic acid signaling was linked to T89I, and disrupted proliferation was common to both. Our findings suggest that dysfunctional mechanotransduction due to V620I and T89I mutations in TRPV4 contribute to the developmental phenotypes, supporting TRPV4 modulation as a potential pharmacologic target.NEW & NOTEWORTHY Gain-of-function mutations in TRPV4, a mechano- and osmosensitive ion channel, are linked to skeletal dysplasias, but their effects on chondrocyte mechanotransduction remain unknown. Using human iPSCs harboring skeletal dysplasia-causing mutations, we developed and mechanically loaded tissue-engineered cartilage. Our findings show that V620I and T89I mutations reduce chondrocyte mechanoresponsiveness, evidenced by decreased gene expression downstream of TRPV4 activation, providing insight into TRPV4-related skeletal disorders and potential pharmacological targets.
2025-01-18 | Comparison of the natural course of clinical and radiologic features in 13 patients with TRPV4-related skeletal dysplasias.
Heterozygous TRPV4 mutations cause a group of skeletal dysplasias characterized by short stature, short trunk, and skeletal deformities. The aim of this study is to compare the natural history of clinical and radiologic features of patients with different TRPV4-related skeletal dysplasias. Thirteen patients with a mutation in TRPV4 were included in the study, and 11 were followed for a median of 6.5 years. The clinical phenotype of five patients was compatible with spondylometaphyseal dysplasia Kozlowski type, three each with metatropic dysplasia and brachyolmia type 3, and one each with spondyloepiphyseal dysplasia Maroteaux type and congenital distal spinal muscular atrophy. Short stature and bone pain when running, walking, and climbing stairs occurred in patients with spondylometaphyseal dysplasia Kozlowski type and metatropic dysplasia from the age of 5 years and worsened with increasing age. Kyphosis was more pronounced with increasing age in these two groups of patients, while severe scoliosis occurred in brachyolmia type 3. In the radiographs of patients with spondylometaphyseal dysplasia Kozlowski type and metatropic dysplasia, severe platyspondyly persisted into adulthood or puberty. The patients with spondylometaphyseal dysplasia Kozlowski type exhibited irregular proximal femora leading to destruction of the femoral head towards the end of puberty, whereas metatropic dysplasia showed marked irregularity and widening of the femoral neck. We also observed that metaphyseal dysplasia in long bones other than the proximal femur was so inconspicuous that it could be ignored in patients with spondylometaphyseal dysplasia Kozlowski type. Comparison of radiologic features that change with age in five different TRPV4-related skeletal dysplasias will be of great benefit in the management of this patient group.
2023-06-30 | Structure of human TRPV4 in complex with GTPase RhoA.
Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases.
2023-06-12 | TRPV4 regulates osteoblast differentiation and mitochondrial function that are relevant for channelopathy
Different ion channels present in the osteoblast regulate the cellular functions including bio-mineralization, a process that is a highly stochastic event. Cellular events and molecular signaling involved in such process is poorly understood. Here we demonstrate that TRPV4, a mechanosensitive ion channel is endogenously present in an osteoblast cell line (MC3T3-E1) and in primary osteoblasts. Pharmacological activation of TRPV4 enhanced intracellular Ca2+-level, expression of osteoblast-specific genes and caused increased bio-mineralization. TRPV4 activation also affects mitochondrial Ca2+-levels and mitochondrial metabolisms. We further demonstrate that different point mutants of TRPV4 induce different mitochondrial morphology and have different levels of mitochondrial translocation, collectively suggesting that TRPV4-mutation-induced bone disorders and other channelopathies are mostly due to mitochondrial abnormalities. These findings may have broad biomedical implications.
2023-03-15 | Structural insights into TRPV4-Rho GTPase signaling complex function and disease
Crosstalk between ion channels and small GTPases is critical during homeostasis and disease 1 , but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions 2-5 . Gain-of-function mutations also cause hereditary neuromuscular disease 6-11 . Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the apo, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that the interaction strength between TRPV4 and RhoA tunes TRPV4-mediated calcium homeostasis and actin remodeling, and that disruption of TRPV4-RhoA interactions leads to TRPV4-related neuromuscular disease, findings that will guide TRPV4 therapeutics development.
proteins
2024-03-11 | Osteocyte-mediated mechanical response controls osteoblast differentiation and function
Low bone mass is a pervasive global health concern, with implications for osteoporosis, frailty, disability, and mortality. Lifestyle factors, including sedentary habits, metabolic dysfunction, and an aging population, contribute to the escalating prevalence of osteopenia and osteoporosis. The application of mechanical load to bone through physical activity and exercise prevents bone loss, while sufficient mechanical load stimulates new bone mass acquisition. Osteocytes, cells embedded within the bone, receive mechanical signals and translate these mechanical cues into biological signals, termed mechano-transduction. Mechano-transduction signals regulate other bone resident cells, such as osteoblasts and osteoclasts, to orchestrate changes in bone mass. This review explores the mechanisms through which osteocyte-mediated response to mechanical loading regulates osteoblast differentiation and bone formation. An overview of bone cell biology and the impact of mechanical load will be provided, with emphasis on the mechanical cues, mechano-transduction pathways, and factors that direct progenitor cells toward the osteoblast lineage. While there are a wide range of clinically available treatments for osteoporosis, the majority act through manipulation of the osteoclast and may have significant disadvantages. Despite the central role of osteoblasts to the deposition of new bone, few therapies directly target osteoblasts for the preservation of bone mass. Improved understanding of the mechanisms leading to osteoblastogenesis may reveal novel targets for translational investigation.
2021-06-15 | Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes
ABSTRACT Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype. There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations upregulated several anterior HOX genes and downregulated antioxidant genes CAT and GSTA1 throughout chondrogenesis. BMP4 treatment upregulated several essential hypertrophic genes in WT chondrocytes; however, this hypertrophic maturation response was inhibited in mutant chondrocytes. These results indicate that the TRPV4 mutations alter BMP signaling in chondrocytes and prevent proper chondrocyte hypertrophy, as a potential mechanism for dysfunctional skeletal development. Our findings provide potential therapeutic targets for developing treatments for TRPV4-mediated skeletal dysplasias.
2016-02-14 | Mechanobiology of TGFβ signaling in the skeleton
Physical and biochemical cues play fundamental roles in the skeleton at both the tissue and cellular levels. The precise coordination of these cues is essential for skeletal development and homeostasis, and disruption of this coordination can drive disease progression. The growth factor TGFβ is involved in both the regulation of and cellular response to the physical microenvironment. It is essential to summarize the current findings regarding the mechanisms by which skeletal cells integrate physical and biochemical cues so that we can identify and address remaining gaps that could ultimately improve skeletal health. In this review, we describe the role of TGFβ in mechanobiological signaling in bone and cartilage at the tissue and cellular levels. We provide detail on how static and dynamic physical cues at the macro-level are transmitted to the micro-level, ultimately leading to regulation at each level of the TGFβ pathway and to cell differentiation. The continued integration of engineering and biological approaches is needed to answer many remaining questions, such as the mechanisms by which cells generate a coordinated response to physical and biochemical cues. We propose one such mechanism, through which the combination of TGFβ and an optimal physical microenvironment leads to synergistic induction of downstream TGFβ signaling.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for TRPV4-related bone disorder.
1 orphan drug designation for TRPV4-related bone disorder.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
1-({(5S,7S,8R)-8-Fluoro-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl}methyl)-1H-1,3-benzimidazole-6-carbonitrile | — | EMA | 2026-07-24 | — | Arriello s.r.o. |
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