The Burden of Metabolic Syndrome on Osteoarthritic Joints

Bruce M. Dickson; Anke J. Roelofs; Justin J. Rochford; Heather M. Wilson; Cosimo De Bari


Arthritis Res Ther. 2019;21(289) 

In This Article

The Effect of MetS on Chondrocytes

The metabolic perturbations associated with MetS, in addition to influencing macrophage polarisation and activity as outlined above, can contribute to OA pathogenesis by directly affecting chondrocytes. Both decreased AMPK and hyperactivation of mTORC1 resulting from MetS can negatively affect chondrocytes. A recent study in cartilage-specific AMPK knockout mice demonstrated increased degradation of cartilage in both age-related OA and post-traumatic OA due, at least in part, to the loss of protection from the catabolic effects of IL-1β activating NF-ϰB and resulting in the production of MMPs.[48] This has been corroborated by the selective AMPK activator, A769669, shown to significantly reduce cartilage breakdown in human chondrocytes exposed to IL-1β and TNF.[49] mTORC1 hyperactivation has been implicated in the development of OA through its suppression of autophagy. Autophagy, as a mechanism for recycling damaged cellular organelles, is vital for cell survival. Rapamycin blockade of mTORC1 activity has been shown to significantly increase autophagy within articular chondrocytes and reduce OA severity, accompanied by reductions in both synovitis and ADAMTS-5 expression in the articular cartilage.[50] Elevated levels of FFAs may also directly affect chondrocytes within the OA joint. When human chondrocytes are cultured in the presence of saturated FFAs, it results in the increased expression of the inflammatory cytokines IL-6 and IL-8. Concurrently, superoxide radical, reactive nitrogen species, and hydrogen peroxide were all upregulated within the human chondrocytes.[51] Furthermore, leptin has been shown to affect chondrocytes via its ability to stimulate chondrocytes to produce numerous catabolic and inflammatory factors. Gene expression analysis of cartilage from rats with leptin-induced OA and healthy controls revealed increased expression of genes encoding for MMPs, inflammatory cytokines, and apoptotic factors in the leptin-induced OA group.[52] Similarly, human chondrocytes stimulated with leptin upregulate MMP1, MMP3, and MMP-13,[53] and increase nitric oxide synthase type II when leptin is combined with IL-1β.[54] Finally, leptin has been reported to induce cell senescence in chondrocyte progenitors by activating the p53/p21 pathway and inhibiting Sirt1 (responsible for degrading p53), resulting in impaired ability to migrate and differentiate into chondrocytes.[55] Cell senescence is increased in OA cartilage, and senescence is emerging as an important player in OA pathogenesis. It occurs as a result of cell cycle arrest in response to cellular stressors, leading to cellular hypertrophy and resistance to cell death signals. Importantly, cell senescence contributes to chronic inflammation through promoting the senescence-associated secretory phenotype (SASP). Chondrocytes exhibiting SASP produce IL-1, IL-6, CCL2, and MMPs amongst other factors, leading not only to cartilage breakdown and synovitis but, in a paracrine manner, inducing further chondrocyte senescence.[56] The importance of these processes was demonstrated when senescent cell clearance, either through genetic ablation or treatment with the senolytic agent UBX0101, attenuated the development of OA in mice following ACL transection or with age.[57] Beneficial effects of UBX0101 treatment were also observed in human OA chondrocytes in vitro,[57] and this agent is currently in a phase I clinical trial for knee OA ( Taken together, these data highlight the role of MetS on OA not only via the activation and polarisation of macrophages but also via direct detrimental effects on chondrocytes.