Ageing and the pathogenesis of osteoarthritis

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.

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…Chondrocytes also display features of senescence with aging and OA, likely in response to macromolecular damage that accumulates in these long‐lived cells (Martin & Buckwalter, 2001; McCulloch, Litherland & Rai, 2017; Price et al., 2002; Rose et al., 2012). OA progression is driven by inflammatory cytokines that initiate a cascade of matrix degradation, and the prominent role for SASP factors such as matrix metalloproteinase 13 (MMP‐13) and interleukin 1 alpha (IL‐1α) implicates senescent cells in the joint as a source of these catabolic molecules (Loeser, Collins & Diekman, 2016). The functional role of p16 INK4a in cartilage aging and OA is less clear, although knockdown and overexpression studies in cultured chondrocytes have confirmed that p16 INK4a expression is associated with the production of catabolic factors involved in dedifferentiation and OA (Philipot et al., 2014; Zhou, Lou & Zhang, 2004).…”

Knee osteoarthritis has doubled in prevalence since the mid-20th century

“…Two recent public health trends, however, are commonly assumed to be dominant factors (6,7). First, because knee OA's prevalence increases with age (8), the rise in life expectancy in the United States since the early 20th century is thought to have led to high knee OA levels among the elderly, with the presumption that, as people age, their senescing joint tissues accumulate more wear and tear from loading (9). Second, high body mass index (BMI) has become epidemic in the United States in recent decades and is a wellknown risk factor for knee OA (8), probably because of the combined effects of joint overloading and adiposity-induced inflammation (10).…”

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

“…It becomes clear that multiple environmental factors are critical to epigenetic regulation of OA. They include aging, inflammation, and joint mechanics (Loeser, Collins & Diekman, 2016). However, it is not clear how these diverse factors regulate epigenetics of OA.…”

“…Instead, inflammation has been proposed to play an important role in OA pathogenesis (Loeser et al., 2016; Rainbow, Ren & Zeng, 2012). Aging is associated with inflammation through acquisition of a senescence‐associated secretory phenotype (SASP) with IL‐6 and IL‐1 being the most prominent cytokines (Coppe, Desprez, Krtolica & Campisi, 2010).…”