Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis

Abstract

Human cartilage is a complex tissue of matrix proteins that vary in amount and orientation from superficial to deep layers and from loaded to unloaded zones. A major challenge to efforts to repair cartilage by stem cell-based and other tissue engineering strategies is the inability of the resident chondrocytes to lay down new matrix with the same structural and resilient properties that it had upon its original formation. This is particularly true for the collagen network, which is susceptible to cleavage once proteoglycans are depleted. Thus, a thorough understanding of the similarities and particularly the marked differences in mechanisms of cartilage remodeling during development, osteoarthritis, and aging may lead to more effective strategies for preventing cartilage damage and promoting repair. To identify and characterize effectors or regulators of cartilage remodeling in these processes, we are using culture models of primary human and mouse chondrocytes and cell lines and mouse genetic models to manipulate gene expression programs leading to matrix remodeling and subsequent chondrocyte hypertrophic differentiation, pivotal processes which both go astray in OA disease. Matrix metalloproteinase (MMP)-13, the major type II collagen-degrading collagenase, is regulated by stress-, inflammation-, and differentiation-induced signals that not only contribute to irreversible joint damage (progression) in OA, but importantly, also to the initiation/onset phase, wherein chondrocytes in articular cartilage leave their natural growth-and differentiation-arrested state. Our work points to common mediators of these processes in human OA cartilage and in early through late stages of OA in surgical and genetic mouse models.

Attenuation of adjuvant-induced arthritis by dietary sesamol via modulation of inflammatory mediators, extracellular matrix degrading enzymes and antioxidant status

“…ROS-mediated oxidative damage is an important mechanism that underlies destructive and proliferative synovitis and articular degeneration [34]. During arthritis, TNF, IL-1b, IL-6 and COX-2-generated PGE 2 have been highly implicated in the pathological mechanisms of synovial tissue proliferation, joint destruction and apoptosis [3]. The current investigation also emphasizes on increased generation of ROS and inflammatory mediators in arthritic rats.…”

“…Arthritic joints imbibed less stain suggesting loss of GAGs and sesamoltreated rat joints stained thick as in saline control, suggesting restoration of GAGs [28]. Similarly, MMP-13, -3, -1 and -9 are significantly higher in synovial fluids and serum of arthritic patients [3]. The MMP-mediated fibronectin degradative products are found to amplify cartilage degeneration, as they in turn activate MMPs and other inflammatory signals [7,29].…”

“…Cartilage a specialized tissue mainly constitutes chondrocytes enclosed with collagen-II, hyaluronan (HA), aggrecan and other proteoglycans. The succession of arthritis ends up in deteriorated synovium and cartilage by the incessant action of Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases [2][3][4]. Furthermore, reactive oxygen species (ROS) and pro-inflammatory mediators like interleukin-1b (IL-1b), IL-6, tumor necrosis factor (TNF) and Prostaglandin E 2 (PGE 2 ) are important non-enzymatic factors that contribute in cartilage and bone degeneration by further activating synovial fibroblast to secrete inflammatory cytokines and ECM degrading enzymes [3].…”

“…The succession of arthritis ends up in deteriorated synovium and cartilage by the incessant action of Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases [2][3][4]. Furthermore, reactive oxygen species (ROS) and pro-inflammatory mediators like interleukin-1b (IL-1b), IL-6, tumor necrosis factor (TNF) and Prostaglandin E 2 (PGE 2 ) are important non-enzymatic factors that contribute in cartilage and bone degeneration by further activating synovial fibroblast to secrete inflammatory cytokines and ECM degrading enzymes [3]. In consequence, the important bone metabolic enzymes such as exoglycosidases, cathepsin D and phosphatases are also aggravated at the joints aiding in bone resorption and cartilage degeneration.…”

Regulated Transcription of Human Matrix Metalloproteinase 13 (MMP13) and Interleukin-1β (IL1B) Genes in Chondrocytes Depends on Methylation of Specific Proximal Promoter CpG Sites

“…High levels and activity of MMP-13 and other matrix-degrading enzymes in OA chondrocytes are due in part to their activated state in response to enhanced stress and inflammatory signaling (reviewed in Ref. 39). MMP13 transcription is subject to regulation by a number of transcription factors, including ELF3, RUNX2, AP-1 (cFos/cJun), p130 cas nuclear matrix transcription factor 4 (NMP-4), the canonical NF-B subunits p65/ p50, and HIF-2␣ (35, 40 -44, 50).…”