Casas-Fraile, L. | Search bioRxiv

bioRxiv2026

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

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.

molecular biology↗

bioRxiv2021

Hypoxia induces transcription of DOT1L in articular cartilage to protect against osteoarthritis

Osteoarthritis is the most prevalent joint disease worldwide and a leading source of pain and disability. To date, this disease lacks curative treatment as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identify transcription factors and networks that regulate DOT1L gene expression using a novel bioinformatics pipeline. Thereby, we unravel an undiscovered link between the hypoxia pathway and DOT1L. We provide unprecedented evidence that hypoxia enhances DOT1L expression and H3K79 methylation via hypoxia-inducible factor-1 alpha (HIF-1). Importantly, we demonstrate that DOT1L contributes to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restores DOT1L function and stalls disease progression. Collectively, our data unravel a novel molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.

cell biology↗