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Review
. 2019;65(4):387-396.
doi: 10.1159/000496688. Epub 2019 Apr 10.

Epigenetic Mechanisms Underlying the Aging of Articular Cartilage and Osteoarthritis

Mingcai Zhang  1   2 , Justin L Theleman  1 , Katherine A Lygrisse  1 , Jinxi Wang  3   4
Affiliations
Review

Epigenetic Mechanisms Underlying the Aging of Articular Cartilage and Osteoarthritis

Mingcai Zhang et al. Gerontology. 2019.

Abstract

Aging is a progressive and complicated bioprocess with overall decline in physiological function. Osteoarthritis (OA) is the most common joint disease in middle-aged and older populations. Since the prevalence of OA increases with age and breakdown of articular cartilage is its major hallmark, OA has long been thought of as "wear and tear" of joint cartilage. Nevertheless, recent studies have revealed that changes in the chondrocyte function and matrix components may reduce the material properties of articular cartilage and predispose the joint to OA. The aberrant gene expression in aging articular cartilage that is regulated by various epigenetic mechanisms plays an important role in age-related OA pathogenesis. This review begins with an introduction to the current understanding of epigenetic mechanisms, followed by mechanistic studies on the aging of joint tissues, epigenetic regulation of age-dependent gene expression in articular cartilage, and the significance of epigenetic mechanisms in OA pathogenesis. Our recent findings on age-dependent expression of 2 transcription factors, nuclear factor of activated T cell 1 (NFAT1) and SOX9, and their roles in the formation and aging of articular cartilage are summarized in the review. Chondrocyte dysfunction in aged mice, which is mediated by epigenetically regulated spontaneous reduction of NFAT1 expression in articular cartilage, is highlighted as an important advance in epigenetics and cartilage aging. Potential therapeutic strategies for age-related cartilage degeneration and OA using epigenetic molecular tools are discussed at the end.

Keywords: Aging; Articular cartilage; Epigenetics; Gene expression; Nuclear factor of activated T cell 1; Osteoarthritis.

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Conflict of interest statement

Conflicts of interest

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Age-dependent expression of SOX9 and NFAT1 in mouse articular cartilage. (A) Age-dependent Sox9 and Nfat1 mRNA levels determined by quantitative real-time PCR (qPCR).. (B) Age-dependent SOX9 and NFAT1 protein expression and localization identified by immunohistochemistry [39,42,43]. E16.5: embryonic day 16.5; m: month.
Figure 2.
Figure 2.
Chondrocyte dysfunction and matrix degeneration in articular cartilage of aged mice. (A) Aberrant gene expression in chondrocytes of aged mice; (B) Loss of proteoglycan (red, safranin O staining) and OA-like changes with fibrillation of articular surface (in magnified rectangle) and osteophyte formation at the joint margin (arrowhead), fh: femoral head; acet: acetabulum. (C) Forced overexpression of NFAT1 shows better rescue effect on the dysfunctional chondrocytes from 15-month old mice than that from 18-month old mice [43]. E16.5: embryonic day 16.5; m: month. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 3.
Figure 3.
Schematic summarization of age-dependent epigenetic regulation of NFAT1 expression in mouse articular cartilage at the mRNA protein levels and the possible mechanisms of NFAT1 reduction-mediated cartilage aging, which predispose the joint to OA under the influence of other factors, including both mechanical stress and biological alternations. Acan: aggrecan; Col2a1: collagen type II alpha 1; Col9a1: collagen type IX alpha 1; Col11a1: collagen type XI alpha 1; Igf1: insulin-like growth factor 1; GDF5: growth differentiation 5; Il1b: interleukin 1β; Adamts: a disintegrin and metalloproteinase with thrombospondin motifs; Mmp: matrix metalloproteinase
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