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 of 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 metalloproteinases (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.

Fig. 1. Current summary of converging in vivo signals impacting on MMP13 leading to perturbations in physiology of resting articular chondrocyte physiology and to proliferation, hypertrophic differentiation and potentially OA disease

NF-κB activation as elaborated in the text has multiple, time-dependent perturbing affects on chondrocyte physiology, including the activation of stress-related pathways that provoke a breakdown in the growth-arrested state of articular cartilage along with the production of pro-inflammatory mediators. Continued NF-κB activation results in activation of other regulatory transcription factors, including ELF3 and HIF2α, with activated HIF2α inducing the IHH>Runx2 axis. These events together collaborate to activate MMP13 facilitating the progression of articular chondrocytes to a hypertrophic-like differentiated state in vivo, thereby also contributing to OA onset and/or progression. To simplify the Figure, this scheme is only intended to show NF-κB-dependent pathways linked to MMP-13 control that have been elucidated in vivo. Not included, but mentioned in the text, are specific upstream activators of NF-κB that have also been shown to impact MMP-13 expression in in vitro settings (including TLRs and specific PKC isoforms), and additional signaling pathways that may work in conjunction with NF-κB activation, including ERK and p38.