Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis

Abstract

Osteoarthritis (OA) is a multifactorial disease subject to the effects of many genes and environmental factors. Alterations in the normal pattern of chondrocyte gene control in cartilage facilitate the onset and progression of OA. Stable changes in patterns of gene expression, not associated with alterations in DNA sequences, occur through epigenetic changes, including DNA methylation, histone modifications, and alterations in chromatin structure, as well as by microRNA (miRNA)-mediated mechanisms. Moreover, the ability of the host to repair damaged cartilage is reflected in alterations in gene control circuits, suggestive of an epigenetic and miRNA-dependent tug-of-war between tissue homeostasis and OA disease pathogenesis. Herein, we summarize epigenetic and miRNA-mediated mechanisms impacting on OA progression and in this context offer potential therapeutic strategies for OA treatment.

Figure 1. Major phenotypic changes by which normal cartilage tissue becomes compromised in osteoarthritis (OA)

Normal articular cartilage subjected to stresses such as inflammation, mechanical stress, genetic aberrations, and age-related degeneration can slowly develop phenotypic characteristics of OA tissue. These include increased stress and inflammatory signaling, proliferation of chondrocytes resulting in chondrocyte clusters, and degradation of the extracellular matrix (ECM). The role of the subchondral bone in osteoarthritis and its interactions with cartilage have been reviewed by Goldring and Goldring [88].

Figure 2. Major epigenetic players and microRNAs (miRNAs) that help to drive the genesis of articular chondrocytes from osteo-chondro progenitors

The ECM and physiological status of chondrocyte before and after progression to OA are shown. Note that the pericellular matrix surrounding normal chondrocytes is absent in OA cartilage. Statements with question marks indicate regulatory mechanisms based on in vitro evidence that require further validation in vivo.

Figure 3. The path towards osteoarthritis (OA)

Summary of the epigenetic markers and associated regulatory alterations impacting on the physiology of growth- and differentiation-arrested normal articular chondrocytes leading them down a path towards OA disease. Again as in Figure 2, the presence of a pericellular matrix surrounding normal chondrocytes is absent in OA cartilage. *miR-25 was found to be up-modulated by Jones et al. [58] and suppressed by Iliopoulos et al. [56] in OA cartilage.