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

Abstract and Introduction


Background: The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes.

Main text: A skewing of macrophages towards a pro-inflammatory M1 phenotype within synovial and adipose tissues is thought to play a role in OA pathogenesis. The metabolic perturbations typical of MetS are important drivers of pro-inflammatory macrophage polarisation and activity. This is mediated via alterations in the levels and activities of the cellular nutrient sensors 5' adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1), intracellular accumulation of metabolic intermediates such as succinate and citrate, and increases in free fatty acids (FFAs) and hyperglycaemia-induced advanced glycation end-products (AGEs) that bind to receptors on the macrophage surface. Altered levels of adipokines, including leptin and adiponectin, further influence macrophage polarisation. The metabolic alterations in MetS also affect the cartilage through direct effects on chondrocytes by stimulating the production of pro-inflammatory and catabolic factors and possibly by suppressing autophagy and promoting cellular senescence.

Conclusions: The influence of MetS on OA pathogenesis involves a wide range of metabolic alterations that directly affect macrophages and chondrocytes. The relative burden of intra-articular versus systemic adipose tissue in the MetS-associated OA remains to be clarified. Understanding how altered metabolism interacts with joints affected by OA is crucial for the development of further strategies for treating this debilitating condition, such as supplementing existing therapies with metformin and utilising ω-3 fatty acid derivatives to restore imbalances in ω-3 and ω-6 fatty acids.


Osteoarthritis (OA) is a painful and debilitating degenerative joint disease characterised by progressive loss of articular cartilage, synovitis, subchondral bone sclerosis, and osteophyte formation. An increasing body of evidence indicates that chronic low-level inflammation plays an important role in the pathogenesis of OA. The presence of synovitis, characterised by infiltration of immune cells, angiogenesis, and synovial hypertrophy/hyperplasia, has been linked not only to increased joint pain but also to disease progression.[1,2]

The prevalence of OA increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee.[3] The metabolic syndrome (MetS), frequently associated with central obesity, could promote inflammatory processes implicated in the pathogenesis of OA. This narrative review will discuss the influence of MetS and obesity on OA, with a specific focus on the mechanisms through which MetS can influence inflammatory processes, particularly the activation and polarisation of macrophages, including perturbations in cellular nutrient sensing, adipokine production, and long-chain fatty acids. It will also appraise the role of weight loss in the management of OA and the potential of dietary fatty acids as targets for future therapies.