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Review
. 2016 Jul;12(7):412-20.
doi: 10.1038/nrrheum.2016.65. Epub 2016 May 19.

Ageing and the pathogenesis of osteoarthritis

Richard F Loeser  1 , John A Collins  1 , Brian O Diekman  2
Affiliations
Review

Ageing and the pathogenesis of osteoarthritis

Richard F Loeser et al. Nat Rev Rheumatol. 2016 Jul.

Abstract

Ageing-associated changes that affect articular tissues promote the development of osteoarthritis (OA). Although ageing and OA are closely linked, they are independent processes. Several potential mechanisms by which ageing contributes to OA have been elucidated. This Review focuses on the contributions of the following factors: age-related inflammation (also referred to as 'inflammaging'); cellular senescence (including the senescence-associated secretory phenotype (SASP)); mitochondrial dysfunction and oxidative stress; dysfunction in energy metabolism due to reduced activity of 5'-AMP-activated protein kinase (AMPK), which is associated with reduced autophagy; and alterations in cell signalling due to age-related changes in the extracellular matrix. These various processes contribute to the development of OA by promoting a proinflammatory, catabolic state accompanied by increased susceptibility to cell death that together lead to increased joint tissue destruction and defective repair of damaged matrix. The majority of studies to date have focused on articular cartilage, and it will be important to determine whether similar mechanisms occur in other joint tissues. Improved understanding of ageing-related mechanisms that promote OA could lead to the discovery of new targets for therapies that aim to slow or stop the progression of this chronic and disabling condition.

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Figures

Figure 1
Figure 1. Chondrocytes exhibit features of cellular senescence in the contexts of ageing and osteoarthritis
Senescence is often caused by the combination of growth and arrest signals, conditions that can occur in cartilage during ageing. Features of senescence include expression of CDKN2A (encoding p16INK4A) and positive staining for senescence-associated β-galactosidase. The functional effects of chondrocyte senescence are challenging to measure because of the low proliferation rate of chondrocytes and the overlap between features of the senescence-associated secretory phenotype (SASP) and those associated with the development of osteoarthritis (OA). Understanding the mechanism of senescence could yield therapeutic interventions to prevent development of the SASP or specifically eliminate senescent cells from joint tissues. MMPs, matrix metalloproteinases.
Figure 2
Figure 2. Mitochondrial dysfunction, oxidative stress and changes in normal cell signalling in ageing and osteoarthritis
Mitochondrial dysfunction in both ageing and osteoarthritis (OA) is characterized by reduced mitochondrial integrity (mass, number and DNA content) and impaired electron transport chain (ETC) function. These features contribute to increased production of reactive oxygen species (ROS). Concomitant reductions in mitochondrial antioxidant capacity — including reduced mitochondrial superoxide dismutase 2 (SOD2) levels and peroxiredoxin (PRX) hyperoxidation — lead to enhanced oxidative stress and ROS-mediated damage in the mitochondria (indicated by red lightning bolts). Extra-mitochondrial antioxidant systems (namely, SOD1, catalase and glutathione synthetase; not shown) are also considerably less active in ageing and OA, which exacerbates oxidative stress. ROS cause damage to proteins, lipids and DNA, increase chondrocyte catabolism and, importantly, lead to disturbances in normal cell signalling. These disturbances can include inhibition of pro-survival IGF-1 signalling and increased catabolic mitogen-activated protein kinase (MAPK) signalling. Increased levels of ROS can also result in increased protein thiol oxidation, resulting in S-sulfenylation or, when excessive, hyperoxidation of reactive protein cysteines, which might contribute to altered cell signalling. mtDNA; mitochondrial DNA; ERK, extracellular signal-regulated kinase; IGFR, insulin-like growth factor receptor; IRS-1, insulin receptor substrate 1.
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