Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis

Abstract

Osteoarthritis (OA) is a common degenerative disease characterized by the destruction of articular cartilage and chronic inflammation of surrounding tissues. Matrix metalloproteinase-13 (MMP-13) is the primary MMP involved in cartilage degradation through its particular ability to cleave type II collagen. Hence, it is an attractive target for the treatment of OA. However, the detailed molecular mechanisms of OA initiation and progression remain elusive, and, currently, there are no interventions available to restore degraded cartilage. This review fully illustrates the involvement of MMP-13 in the initiation and progression of OA through the regulation of MMP-13 activity at the molecular and epigenetic levels, as well as the strategies that have been employed against MMP-13. The aim of this review is to identify MMP-13 as an attractive target for inhibitor development in the treatment of OA.

Keywords: MMP-13; cartilage; inhibitor; matrix metalloproteinases; osteoarthritis; regulation; type II collagen.

Figure 1

Role of matrix metalloproteinase-13 (MMP-13) in osteoarthritis (OA) pathogenesis. When some OA risk factors lead to increased expression of chondrocytes’ catabolic factors, like MMP-13, the balance tips toward a net loss of cartilage. MMP-13 is the primary catabolic factor involved in cartilage degradation through its particular ability to cleave type II collagen. The breakdown products of cartilage stimulate the type A synoviocytes to release inflammatory cytokines and MMPs, like tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6, and MMP-13, which, in turn, enhance a more comparable catabolic effect on chondrocyte metabolism, accelerating the progression of OA. Created with BioRender.com.

Figure 2

Structure of MMP-13. MMP-13 typically consists of a highly conserved signal peptide, a propeptide domain, a catalytic domain, a proline-rich hinge region, and a C-terminal hemopexin-like domain. The catalytic domain of MMP-13 is represented by the crystal structure. The structural zinc ion is in green, the catalytic zinc ion is in magenta, and three calcium ions are in dark grey. Three histidine residues in black sticks coordinate the catalytic zinc ion. The highly flexible S1′ specificity loop as part of hydrophobic S1′ pocket is a determining factor for the selective inhibitors of MMP-13. Created with BioRender.com.

Figure 3

Regulation of MMP-13 in OA with the molecular and epigenetic mechanism. Molecular regulation involves endogenous inhibitors, transcription factors, growth factors, proteases, receptors, and other mediators. Epigenetic regulation contains DNA methylation, histone modification, and non-coding RNAs, which include microRNAs, small interfering RNAs, and long non-coding RNAs. The arrows in the microRNAs frame mean the miRNAs have different types of regulation (solid down-arrow: direct downregulation, dotted down-arrow: indirect downregulation, dotted up-arrow: indirect upregulation). Created with BioRender.com.