TLRs and ligands present In the OA joint
1. Understanding the role of Toll-like receptors (TLR) in OA pathogenesis
Our work has helped to uncover a role for the TLR pathway as a critical trigger of inflammation in OA. TLRs are pattern-recognition receptors (PRRs) of the innate immune response, which initiate inflammation in response to infection and tissue injury. Our lab discovered elevated levels of the TLR co-receptor CD14 in patients with early knee OA, and since that discovery, CD14 and other markers of TLR activation have been shown to predict inflammation and severity of disease in patients. Our work in a murine model of OA showed that attenuation of TLR activation through deficiency of CD14 protected mice from progression of cartilage damage and functional decline. We are now testing methods to target CD14 and TLR-mediated inflammation in the joint after a pre-disposing injury, with the goal of developing novel therapies to improve joint function AND prevent development of OA after injury.
2. Understanding the consequences of synovial fibrosis
As we seek to better understand how pathologic changes to the synovial membrane affect its ability to maintain the health of the joint, a new area of interest in the lab focuses on elucidating the consequences of synovial fibrosis, a prominent feature of osteoarthritic joint pathology. It is known that the sensation of mechanical and physical forces is vital to cell function. In the highly mechanical microenvironment of musculoskeletal tissue a loss of naïve tissue architecture is a hallmark of disease. This introduces new mechanical and physical forces to all cells, both resident and infiltrating, during musculoskeletal tissue disease. During OA macrophages are key cellular mediators of synovial inflammation and influence pathologic cartilage and bone responses. Recent studies suggest that distinct macrophage clusters occupy specific niches within the synovium, deriving from both circulating monocyte and monocyte-independent lineages. Using methods of engineered mechanically tunable in-vitro systems and in-vivo models of OA disease progression, our goal is to understand how the dynamic physical environment changes in osteoarthritic synovium and differentially modulates resident and infiltrating macrophage function.
OA synovium with prominent fibrosis of the sublining