Osteoarthritis (OA) , one of the most common skeletal disorders characterized by cartilage degradation and osteophyte formation in joints, is induced by accumulated mechanical stress ; however, little is known about the underlying molecular mechanism. Several experimental OA models in mice by producing instability in the knee joints have been developed to apply approaches from mouse genetics. Our mouse genetic approaches found that the induction of a transcriptional activator Runx2 in chondrocytes under mechanical stress contributes to the pathogenesis of OA through chondrocyte hypertrophy. In addition, chondrocyte apoptosis has recently been identified as being involved in OA progression. We hereby propose that these endochondral ossification signals may be important for the OA progression, suggesting that the related molecules can clinically be therapeutic targets of this disease.