SHIP2 deletion in cartilage does not modulate osteoarthritis in male mice

The inositol phosphatase SHIP2 plays a crucial role in skeletal development and chondrocyte differentiation, and mutations in INPPL1 (encoding SHIP2) cause opsismodysplasia, a chondrodysplasia with marked cartilage abnormalities. Given its function in cartilage biology, we investigated whether SHIP2 contributes to osteoarthritis (OA) pathogenesis in mice.

A cartilage-specific conditional knockout of SHIP2 was generated using Ship2 ^fl/fl mice crossed with AggrecanCre ^ERT2 mice. OA was induced at 9 weeks of age via destabilization of the medial meniscus (DMM). Sham surgery served as control. Male mice were sacrificed 12 weeks post-surgery. Histological evaluation of articular cartilage, synovium, osteophytes, and subchondral bone was performed. Chondrocyte hypertrophy was assessed by type X collagen (COLX) staining, and SHIP1 expression was evaluated as a potential compensatory mechanism.

DMM surgery induced OA-like changes in all genotypes, including cartilage damage, synovial inflammation, osteophyte formation, and subchondral bone thickening. However, Ship2 ^cCART-KO mice showed no significant differences in any OA-related parameter compared to control littermates. COLX expression increased following DMM surgery, independent of SHIP2 deletion. SHIP1 protein levels were not elevated in SHIP2-deficient mice.

Despite its known role in cartilage development, SHIP2 deletion in adult cartilage does not affect OA severity or progression in a surgical mouse model. These findings suggest that SHIP2 is not involved in maintaining adult articular cartilage homeostasis and is unlikely to represent a therapeutic target in OA.