The emerging role of TRPV4 in skeletal biology: Mechanotransduction, mutation, and therapeutic potential.

The transient receptor potential vanilloid 4 (TRPV4) ion channel is a pivotal regulator of calcium homeostasis, with its pleiotropic functions being increasingly elucidated across diverse physiological systems. Emerging evidence now underscores its indispensable role within the skeletal system, where it transduces multifaceted stimuli-notably mechanical loading and osmotic stress-into precise calcium signals that orchestrate skeletal development and homeostasis across various cell lineages. Pathogenic mutations in TRPV4 disrupt this critical signaling, giving rise to a broad spectrum of skeletal dysplasias and revealing distinct genotype-phenotype correlations. This review systematically integrates contemporary insights into the mechanistic actions of TRPV4 in osteoblasts, chondrocytes, and other skeletal cell types, delineating how specific mutations culminate in defined skeletal pathologies. Furthermore, we catalog established and emerging pharmacological modulators of TRPV4 and critically evaluate their potential within the therapeutic pipeline for skeletal dysplasia.