TRIM15 drives chondrocyte senescence and osteoarthritis progression

Chondrocyte senescence underlies osteoarthritis (OA). However, the pathogenesis of chondrocyte senescence remains largely unclear. Here we report that TRIM15 is a critical regulator in chondrocyte senescence. TIRM15 is highly expressed in chondrocytes of senescent cartilage from human OA patients and aged mice. Using gain- and loss-of-function studies, we further identify that TRIM15 facilitates chondrocyte senescence. Notably, conditional deletion of TRIM15 in chondrocytes severely impairs skeletal growth, partially due to the fact that embryonic chondrocyte senescence is disturbed. Compared with Col2a1-CreERT2/TRIM15flox/flox mice, TRIM15flox/flox mice exhibits accelerated OA phenotype, increased senescence markers and senescence-associated secretory phenotype (SASP) during aging. Mechanistically, TRIM15 binds with YAP and directly mediates K48-linked YAP ubiquitination at K254, which interrupts the interaction between YAP and AMOT, leading to enhanced YAP nuclear translocation. Intra-articular injection of AAV5-Trim15 shRNA decelerates OA progression in mice. Collectively, these findings indicate that targeting TRIM15 reshapes aging cartilage microenvironment and protects against OA. Overall design: In order to identify key genes that contribute to chondrocyte senescence and OA progression, we first performed RNA-sequencing using cartilage tissues from 3 OA individuals and 3 healthy control individuals