{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:33:42Z","timestamp":1781627622958,"version":"3.54.5"},"reference-count":76,"publisher":"American Society for Clinical Investigation","issue":"2","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Actio Biosciences","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Luskin Orthopaedic Institute for Children","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Orthopaedic Hospital Research Center","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"O\u2019Neal family","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,23]]},"abstract":"<jats:p>\n                    The\n                    <jats:italic>TRPV4<\/jats:italic>\n                    skeletal dysplasias are characterized by short stature, short limbs with prominent large joints, and progressive scoliosis. They result from dominant missense mutations that activate the TRPV4 calcium permeable ion channel. As a platform to understand the mechanism of disease and to test the hypothesis that channel inhibition could treat these disorders, we developed a knock-in mouse that conditionally expresses the p.R594H\n                    <jats:italic>Trpv4<\/jats:italic>\n                    mutation. Embryonic, chondrocyte-specific induction of the mutation using\n                    <jats:italic>Col2a1-Cre<\/jats:italic>\n                    resulted in a skeletal dysplasia affecting the long bones, spine, and craniofacial skeletal elements, consistent with the human skeletal dysplasia phenotypes produced by\n                    <jats:italic>TRPV4<\/jats:italic>\n                    mutations. Cartilage growth plate histological abnormalities included disorganized proliferating chondrocyte columns and reduced hypertrophic chondrocyte development, reflecting abnormal endochondral ossification. In vivo treatment with the TRPV4-specific inhibitor GSK2798745 markedly improved the radiographic skeletal phenotype and rescued the growth plate histological abnormalities. ScRNA-Seq of chondrocyte transcripts from affected mice identified calcium-mediated effects on multiple signaling pathways as potential mechanisms underlying the defects in linear and cartilage appositional growth observed in both mutant mice and patients. These results provide preclinical evidence demonstrating TRPV4 inhibition as a rational, mechanism-based therapeutic strategy to ameliorate disease progression and severity in the\n                    <jats:italic>TRPV4<\/jats:italic>\n                    skeletal dysplasias.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.182439","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T19:00:43Z","timestamp":1769108443000},"source":"Crossref","is-referenced-by-count":1,"title":["Small molecule inhibition rescues the skeletal dysplasia phenotype of Trpv4 mutant mice"],"prefix":"10.1172","volume":"11","author":[{"given":"Lisette","family":"Nevarez","sequence":"first","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor K.","family":"Ismaili","sequence":"additional","affiliation":[{"name":"Actio Biosciences, San 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