Mice harboring a Hajdu Cheney Syndrome mutation are sensitized to osteoarthritis.

Osteoarthritis is a joint disease characterized by cartilage degradation, altered gene expression and inflammation. NOTCH1 and NOTCH2 receptors and the JAGGED1 ligand regulate chondrocyte biology; however, the contribution of Notch signaling to osteoarthritis is controversial. Hajdu Cheney Syndrome (HCS) is a rare genetic disorder affecting the skeleton and associated with NOTCH2 mutations that lead to NOTCH2 gain-of-function. A murine model of the disease (Notch2) was used to test whether the HCS mutation increases the susceptibility to osteoarthritis. The knee of three-month-old Notch2 male mice and control sex-matched littermates was destabilized by resection of the medial meniscotibial ligament, and changes in the joint analyzed two months thereafter. Expression of Notch target genes was increased in the femoral heads of Notch2 mice, documenting Notch signal activation. Periarticular bone and cartilage structures were unaffected in Notch2 mutants subjected to sham surgery, indicating that NOTCH2 gain-of-function had no discernible impact on joint structure under basal conditions. However, destabilization of the medial meniscus increased osteophyte volume and thickened subchondral bone in Notch2 mice compared to wild type littermates. Moreover, destabilized Notch2 mutants exhibited histological signs of moderate to severe cartilage degeneration, demonstrating joint sensitization to the development of osteoarthritis. Chondrocyte cultures from Notch2 mutants expressed increased Il6 mRNA levels following exposure to JAGGED1, possibly explaining the susceptibility of Notch2 mice to osteoarthritis. In conclusion, Notch2 mutants are sensitized to the development of osteoarthritis in destabilized joints and NOTCH2 activation may play a role in the pathogenesis of the disease.