New insights on the MMP-13 regulatory network in the pathogenesis of early osteoarthritis

Abstract

Osteoarthritis (OA) is the most common joint disorder and affects approximately half of the aged population. Current treatments for OA are largely palliative until the articular cartilage has been deeply damaged and irreversible morphological changes appear. Thus, effective methods are needed for diagnosing and monitoring the progression of OA during its early stages when therapeutic drugs or biological agents are most likely to be effective. Various proteinases involved in articular cartilage degeneration in pre-OA conditions, which may represent the earliest reversible measurable changes, are considered diagnostic and therapeutic targets for early OA. Of these proteinases, matrix metalloproteinase 13 (MMP-13) has received the most attention, because it is a central node in the cartilage degradation network. In this review, we highlight the main MMP-13-related changes in OA chondrocytes, including alterations in the activity and expression level of MMP-13 by upstream regulatory factors, DNA methylation, various non-coding RNAs (ncRNAs), and autophagy. Because MMP-13 and its regulatory networks are suitable targets for the development of effective early treatment strategies for OA, we discuss the specific targets of MMP-13, including upstream regulatory proteins, DNA methylation, non-coding RNAs, and autophagy-related proteins of MMP-13, and their therapeutic potential to inhibit the development of OA. Moreover, the various entities mentioned in this review might be useful as early biomarkers and for personalized approaches to disease prevention and treatment by improving the phenotyping of early OA patients.

Keywords: Autophagy; DNA methylation; MMP-13; Matrix metalloproteinases; Non-coding RNA; Osteoarthritis.

Fig. 1

Regulatory network of MMP-13 in OA chondrocytes. In the illustration, the dotted lines indicate an indirect effect on MMP-13 and the solid lines indicate a direct effect on a downstream target. Green lines indicate promotion and red lines inhibition of MMP-13. The yellow background indicates increasing expression level and the gray background decreasing expression level in OA chondrocytes

Fig. 2

Model for DNA methylation of the MMP-13 promoter. CREB binds to the MMP-13 promoter when the −104 CpG is demethylated. HIF-2α binds to the MMP-13 promoter when the −110 CpG is demethylated. C/EBPβ and RunX2 bind between base pairs −103 and −97 and −138 and −132, respectively, and cooperate to promote MMP-13 mRNA transcription. At the same time, HIF-2α promotes C/EBPβ mRNA transcription by binding between base pairs −103 and −46 of the C/EBPβ promoter