Synovial Fluid From Patients With Early Osteoarthritis Modulates Fibroblast-like Synoviocyte Responses to Toll-like Receptor 4 and Toll-like Receptor 2 Ligands via Soluble CD14

Initial inflammatory responses to infection are mediated by receptors for pathogen-associated molecular patterns, including Toll-like receptors (TLRs). Cell- surface TLRs include TLR-2 and TLR-4; TLR-2 binds lipopeptides from prokaryotic cell walls, and TLR-4 recognizes lipopolysaccharide (LPS) from gram- negative bacteria. Binding of ligands to TLRs initiates intracellular signaling that results in inflammatory gene transcription. Recent studies in various models of tissue injury and repair, including ischemia-reperfusion, noninfectious lung injury, and femoral fracture, have implicated TLRs in inflammatory responses after noninfectious injury. In these settings, TLRs may be triggered by endogenous danger signals (damage-associated molecular patterns[/fusion_text][/fusion_builder_column][/fusion_builder_row][/fusion_builder_container][fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ layout=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none” last=”no” hover_type=”none” link=”” border_position=”all”][fusion_text][DAMPs]) produced by tissue injury and cellular stress.

DAMPs that interact with TLRs, particularly TLR-2 and TLR-4, include extracellular matrix components such as low molecular weight fragments of hyaluronan (HA), tenascin-C (TN-C), and the cellular products high mobility group box chromosomal protein 1 (HMGB-1) and Hsp96. TN-C and Hsp96 activate synovial fibroblasts via TLRs in the setting of rheumatoid arthritis (RA). Both DAMPs and TLRs are expressed in OA joint tissues, including synovial membrane and cartilage. Murine chondrocyte nitric oxide and matrix metalloproteinase production were diminished in response to low molecular weight HA and HMGB-1 in TLR-2/TLR-4– double-knockout mice, suggesting a role for TLRs in chondrocyte catabolic responses. The importance of TLR responses in fibroblast-like synoviocytes (FLS) is less clear in OA and joint injury, as most studies have focused on FLS responses in RA. However, synovial fibroblasts from both OA and RA patients respond to TLR ligands with increased chemokine production, an activity that has obvious implications for development of synovitis in both inflammatory and “noninflammatory” arthritis.

Given the strong association between joint injury and risk of OA development and progression (21), we hypothesized that endogenous activation of TLRs stimulates inflammatory responses in patients with OA or joint injuries (22). We anticipated that endogenous TLR ligand(s) present in synovial fluid (SF) from patients with OA could lead to inflammatory activation of FLS. We collected SF samples from patients with early-stage OA cartilage damage undergoing arthroscopic surgery for meniscal tears. We then tested the ability of SF to induce inflammatory cytokine production in 2 in vitro systems: 1) TLR-negative cell lines transfected with TLR-2 or TLR-4, and 2) primary FLS cultures.

Full Article: Synovial Fluid From Patients With Early Osteoarthritis Modulates Fibroblast-like Synoviocyte Responses to Toll-like Receptor 4 and Toll-like Receptor 2 Ligands via Soluble CD14