Crucial role of macrophages in matrix metalloproteinase–mediated cartilage destruction during experimental osteoarthritis : Involvement of matrix metalloproteinase 3

Abstract

Objective. To explore the involvement of synovial macrophages in early cartilage damage in osteoarthritis (OA), and to identify the role of matrix metalloproteinase 3 (MMP-3) in the pathology of early and late OA.Methods. The role of synovial macrophages in MMP-mediated damage in OA was studied by depleting synovial macrophages prior to elicitation of a collagenase-induced instability model of OA. The expression of MMP in synovium and cartilage was monitored using TaqMan analysis. In spontaneous and induced OA, cartilage pathology was scored in MMP-3-knockout mice and control mice, by histologic assessment and VDIPEN staining.Results. On day 14 following induction of OA, MMP-mediated neoepitopes were detected in cartilage from mice with mild experimental OA (mean ؎ SD positively stained surface area 20 ؎ 3.2%). Remarkably, by depleting synovial macrophages prior to induction of OA, the generation of MMP-induced neoepitopes was largely prevented (mean ؎ SD positively stained surface area 5 ؎ 1%; P< 0.001), indicating an important role for synovial macrophages in the occurrence of MMPmediated cartilage damage. We observed a strong decrease in MMP-3 and MMP-9 expression in synovial but not cartilage tissue in macrophage-depleted joints. Among 2-year-old mice, spontaneous OA-like changes in the lining layer were significantly decreased in MMP-3-knockout mice compared with control mice. Even more striking was the 67% reduction in the occurrence of severe cartilage damage in MMP-3-knockout mice. In addition, MMP-mediated VDIPEN expression was significantly decreased, indicating reduced MMPmediated cartilage breakdown.Conclusion. The results of this study prove that MMP-3 is involved in the generation of severe cartilage damage in murine OA. Synovial macrophages are crucial in early MMP activity and appear to mediate MMP production in synovium rather than cartilage.

Engineering of Functional Cartilage Tissue Using Stem Cells from Synovial Lining: A Preliminary Study

“…Histologic immunostaining also suggested there were macrophage antigens detectable in the sections from conventionally passaged SDSC-based constructs. In osteoarthritis, synovial macrophages exhibit an activated phenotype and produce degradative enzymes resulting in the destruction of cartilage [3,4]. Cartilage tissue engineering mimics some aspects of cartilage development and remodeling in vivo.…”

Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

“…73,74 Membranous microvesicles, 200-700 nm in diameter derived from plasma membranes of T cells and monocytes (also referred to as MPs) induce MMP-1, MMP-3, and MMP-9 production in synovial fibroblasts. 75,76 Increased proteases released by synovial fibroblasts in OA 75 lyse collagen and proteoglycans of the articular cartilage, thus decreasing resistance to mechanical forces generated by weight-bearing activities. Genetic factors also increase the risk of OA.…”

How Important are Innate Immunity Cells in Osteoarthritis Pathology

“…Experimental osteoarthritis was induced according to a method described by Blom et al (Blom, et al 2007). Mice received two intra-articular injections of collagenase (2 times x1U collagenase) at day 0 and 2.…”

“…Serum level of MMP-3 is associated with joint space narrowing in OA patients (Lohmander et al, 2005). MMP-3-deficient mice show significantly decreased cartilage damage (Blom et al, 2007). In rabbit model of experimental arthritis MMP-3 is initially up-regulated in the synovium contributing to the appearance of cartilage lesions while MMP-3 derived from chondrocyte exacerbate cartilage loss at late phases of OA (Mehraban et al, 1998).…”