Piezo1 in hypertrophic chondrocytes regulates osteoclastogenesis in endochondral ossification

Ion channels of the Piezo family are key mechanosensors in diverse tissues, including bone. Recent studies have demonstrated that Piezo1 in differentiating chondrocytes is critical for endochondral ossification during bone development and regeneration. During endochondral ossification, chondrocytes undergo hypertrophy prior to apoptosis or transdifferentiation into bone-forming osteoblasts, thereby significantly contributing to new bone formation. Here, we investigated the specific role of Piezo1 in hypertrophic chondrocytes using a mouse model with conditional Piezo1 deficiency under control of the collagen X promoter (Piezo1^Col10a1-Cre ). These mice exhibited a pronounced osteopenic bone phenotype and impaired callus maturation. Notably, hypertrophic chondrocyte apoptosis and chondrocyte-to-osteoblast transdifferentiation remained unaffected during endochondral ossification in Piezo1^Col10a1-Cre mice. Instead, these mice displayed markedly increased osteoclast numbers in the primary spongiosa beneath the growth plates and within the fracture callus. Further in vivo and in vitro analysis revealed that Piezo1 regulates osteoclastogenesis by repressing receptor activator of NF-κB ligand and inducing osteoprotegerin expression in hypertrophic chondrocytes. Collectively, our findings identify Piezo1 as an important regulator of hypertrophic chondrocyte-osteoclast communication during endochondral bone formation.