Mice harboring a Hajdu Cheney Syndrome mutation are sensitized to osteoarthritis

Abstract

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.

Notch in skeletal physiology and disease

“…In an alternate murine model of HCS, an increased expression of interleukin 6 was reported in bone marrow cells, and this cytokine could contribute to the enhanced bone resorption observed [40]. Notch2 tm1.1Ecan mutant mice are sensitized to the development of osteoarthritis, a mechanism that may also involve an enhanced expression of interleukin 6 by the chondrocyte of HCS mutant mice [41]. …”

The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor α

“…Heterozygous Notch2 tm1.1Ecan mice exhibit cancellous and cortical bone osteopenia due to increased osteoclast number and bone resorption (5). Notch2 tm1.1Ecan mice also display a reallocation of B cells to the marginal zone of the spleen, shortening of the limbs, and sensitization to the development of osteoarthritis in destabilized joints (24,25). This is possibly because of increased expression of interleukin (IL) 6, revealing a propensity to an enhanced inflammatory response (24).…”

“…Notch2 tm1.1Ecan mice also display a reallocation of B cells to the marginal zone of the spleen, shortening of the limbs, and sensitization to the development of osteoarthritis in destabilized joints (24,25). This is possibly because of increased expression of interleukin (IL) 6, revealing a propensity to an enhanced inflammatory response (24). Notch2 tm1.1Ecan does not exhibit apparent acro-osteolysis, and homozygous mice display craniofacial dysmorphism and newborn lethality.…”

Hajdu–Cheney Syndrome: A Systematic Review of the Literature

“…In 2012, Zanotti et al [ 12 ] studied bone development in HCS, highlighting the importance of NOTCH in these processes and the fact that mutations on this gene lead to a loss of bone mass and acroosteolysis. In 2014, Zanotti et al [ 34 ] further managed to inactivate NOTCH signaling by crossing homozygotic mice with mice where the promoter osterix governs the expression of Cre, while in 2018 [ 35 ], they presented their mouse model of HCS ( NOTCH2 tm1.1Ecan) to study the link between the disease and osteoarthritis. Vollersen et al [ 36 ] developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) on the murine gene NOTCH2 .…”