# Small molecule inhibition rescues the skeletal dysplasia phenotype of Trpv4 mutant mice

## TL;DR

A drug inhibiting the TRPV4 calcium channel improves skeletal abnormalities in mice with a genetic disorder causing short stature and scoliosis.

## Contribution

The study demonstrates that TRPV4 inhibition is a potential therapeutic strategy for TRPV4-related skeletal dysplasias.

## Key findings

- Inhibiting TRPV4 with GSK2798745 improved skeletal abnormalities in mutant mice.
- TRPV4 mutations disrupt endochondral ossification and chondrocyte development.
- Calcium signaling pathways are affected in TRPV4 skeletal dysplasias.

## Abstract

The TRPV4 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 Trpv4 mutation. Embryonic, chondrocyte-specific induction of the mutation using Col2a1-Cre resulted in a skeletal dysplasia affecting the long bones, spine, and craniofacial skeletal elements, consistent with the human skeletal dysplasia phenotypes produced by TRPV4 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 TRPV4 skeletal dysplasias.

Genetic skeletal disorders with short stature and scoliosis could be treated by a drug that inhibits the activated TRPV4 calcium channel mutated in these diseases