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bioRxiv · 10.64898/2026.05.04.722576

SHIP2 deletion in cartilage does not modulate osteoarthritis in a post-traumatic mouse model

Rojo Garcia, A. V.·Cornelis, F.·Casas-Fraile, L.·Schurmans, S.·Monteagudo, S.·Lories, R.
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Abstract

ObjectivesThe 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. We investigated whether SHIP2 contributes to structural joint remodeling in osteoarthritis (OA). MethodsA cartilage-specific conditional knockout of SHIP2 was generated using Ship2fl/fl mice crossed with AggrecanCreERT2 mice. OA was induced at 9 weeks of age via destabilization of the medial meniscus (DMM). Sham surgery served as control. 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 was evaluated as a potential compensatory mechanism. ResultsDMM surgery induced OA-like changes in all genotypes, including cartilage damage, synovial inflammation, osteophyte formation, and subchondral bone thickening. However, Ship2cCART-KO mice showed no differences in OA-related parameters compared to control littermates. COLX expression increased following DMM surgery, independent of SHIP2 deletion. SHIP1 protein levels were not elevated in SHIP2-deficient mice. ConclusionThese findings indicate that SHIP2, while essential for cartilage development, does not act as a structural disease modifier in post-traumatic OA, suggesting that within this context, SHIP2 is not required for maintaining adult articular cartilage structure and is unlikely to represent a major therapeutic target for modifying structural disease progression.

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Rojo Garcia, A. V., Cornelis, F., Casas-Fraile, L., Schurmans, S., Monteagudo, S., Lories, R.. 2026-05-07. SHIP2 deletion in cartilage does not modulate osteoarthritis in a post-traumatic mouse model. https://doi.org/10.64898/2026.05.04.722576

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