UC San Diego

Changes within the synovium and cartilage associated with low-grade inflammation modulate the pathogenesis of OA, and many studies have shown that the inflammatory cytokines/chemokines IL-1[beta], TNF[alpha], CXCL1 and CXCL8 significantly contribute to the disease progression. The Receptor for Advanced Glycation Endproducts (RAGE) and S100/calgranulins have been implicated in the pathogenesis of chronic arterial, renal, and neurological degenerative states associated with low-grade tissue inflammation. Therefore, the studies in this dissertation proposed that the association of RAGE and its ligands (specifically S100A11) are important in the pathogenesis of OA. RAGE and S100A11 expression were upregulated in OA cartilage compared to normal cartilage. CXCL8-, TNF[alpha]-, and S100A11-induced chondrocyte hypertrophy were suppressed by treatment with soluble RAGE (sRAGE) or RAGE-specific blocking antibodies. Finally, it was determined that S100A11 induced MKK3 and p38 MAPK activation.S100/ calgranulins normally exist as homo/heterodimers and the type of bond formed and subsequent conformation affect their activities. As it was previously determined that S100A11 was a substrate for Transglutaminase 2 (TG2), an S100A11 transamidation mutant was created (S100A11 K3R/ Q102N), which formed only monomers. In mouse cartilage explants and chondrocytes, S100A11 K3R/Q102N mutant lost the capacity to signal via the p38 MAPK pathway or induce chondrocyte hypertrophy and glycosaminoglycans (GAG) release. S100A11 failed to induce hypertrophy and GAG release in RAGE-/- and TG2-/- cartilages. The role of RAGE in the pathogenesis of OA was examined in vivo. Instability was induced surgically on RAGE-/- and congenic wild-type controls with an anterior cruciate ligament tear (ACL-T) through a blind "stab" incision. Cartilage degeneration, osteophyte formation and type X collagen expression significantly increased as instability increased, but there was no significant difference between RAGE-/- and congenic wild-type controls. Though RAGE gene deletion does not protect cartilage from degeneration in the ACL-T model of OA, the function of RAGE has not been assessed in another model of surgically-induced OA. In addition, the role of RAGE ligands, involvement of other receptors that recognize RAGE ligands and sRAGE have not been addressed. Taken together, the studies in this dissertation demonstrate critical roles for RAGE and S100A11 in modulating pathologic chondrocyte hypertrophic differentiation and dysregulated matrix catabolism