PIEZO1 variants that reduce open channel probability are associated with familial osteoarthritis.

Synovial joints respond to physical forces to maintain tissue homeostasis. Disruption of joint homeostasis results in the development of osteoarthritis (OA), a disease characterized by abnormal remodeling of joint tissues. PIEZO1 is a mechanosensitive cation channel in the joint directly regulated by mechanical stimulus. To test whether PIEZO1 is associated with OA susceptibility, we determined whether variants affecting PIEZO1 are associated with age-associated familial OA. We identified four rare coding variants affecting PIEZO1 that are associated with dominant familial OA. Single-channel analysis demonstrated that all PIEZO1 mutant channels act in a dominant-negative manner to reduce the open probability of the channel in response to pressure. We show that a GWAS mutation in PIEZO1 associated with reduced joint replacement results in increased channel activity. The familial and GWAS alleles have differential effects on gene expression in primary chondrocytes and synovial fibroblasts. Our data support the hypothesis that reduced PIEZO1 activity confers susceptibility to age-associated OA, whereas increased PIEZO1 activity may be associated with reduced OA susceptibility.