Ubiquitin-specific protease 26 facilitates endochondral ossification by driving chondrocyte hypertrophy and mineralization.

Chondrocyte hypertrophy and mineralization are essential for endochondral ossification; however, the mechanisms underlying these processes remain incompletely understood. In this study, we have identified the facilitated role of ubiquitin-specific protease 26 (USP26) in endochondral ossification by stimulating chondrocyte hypertrophy and mineralization. Ultimately, this promotes skeletal development, bone fracture healing, and the occurrence of osteoarthritis. Mechanistically, USP26 decreases FBP2 undergoing K63-linked ubiquitination, leading to a reduction in the protein level of FBP2. This reduction promotes mitochondrial biogenesis and oxidative phosphorylation, thus facilitating chondrocyte hypertrophy and mineralization and aiding in the process of endochondral ossification. Furthermore, our study found that compression loading induces USP26 to initiate chondrocyte hypertrophy and mineralization through the phosphorylation of estrogen receptor-α at serine 118. These findings suggest that USP26, acting as a mechanosensor, facilitates chondrocyte hypertrophy and mineralization by maintaining mitochondrial biogenesis through the reduction of FBP2. Identifying USP26 as a potential therapeutic target for physiological skeletal growth, bone fracture healing, and osteoarthritis.