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 (Notch2tm1.1Ecan) was used to test whether the HCS mutation increases the susceptibility to osteoarthritis. The knee of three-month-old Notch2tm1.1Ecan 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 Notch2tm1.1Ecan mice, documenting Notch signal activation. Periarticular bone and cartilage structures were unaffected in Notch2tm1.1Ecan 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 Notch2tm1.1Ecan mice compared to wild type littermates. Moreover, destabilized Notch2tm1.1Ecan mutants exhibited histological signs of moderate to severe cartilage degeneration, demonstrating joint sensitization to the development of osteoarthritis. Chondrocyte cultures from Notch2tm1.1Ecan mutants expressed increased Il6 mRNA levels following exposure to JAGGED1, possibly explaining the susceptibility of Notch2tm1.1Ecan mice to osteoarthritis. In conclusion, Notch2tm1.1Ecan mutants are sensitized to the development of osteoarthritis in destabilized joints and NOTCH2 activation may play a role in the pathogenesis of the disease.

Expression of complement regulatory proteins in the developing human kidney.

Complement homologous restriction factor CD59 and complement receptor CD35 are typically involved in the regulation of the host defense system. Recent observations in the human fetal kidney suggest a further role for complement cell surface regulators CD35 and CD59 in kidney development and maturation. We investigated this possible role by localizing CD35 and CD59 protein and mRNA in the developing and adult kidney. Adult tissue and fetal tissue ontogeny were analyzed using immunohistochemistry and in situ hybridization. CD35 protein and mRNA were localized to the podocyte of the glomerulus in the human fetal and adult kidney. Expression was initiated after vascularization of the early developing glomerulus. CD59 protein and mRNA were observed as early as 8 weeks' gestation and were localized primarily to the ureteric duct epithelium in the fetal kidney and predominantly to the collecting duct in the adult. Interestingly, CD59 expression was translocated from the basolateral surface in the fetal kidney to the apical surface in the adult kidney. The specific spatial and temporal expression of CD35 and CD59 suggests a possible role for these complement regulatory proteins in renal cell differentiation.