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

Implications for OA Treatment

As the body of evidence has built up implicating MetS in shaping our inflammatory response in the context of OA, an important question is whether weight loss and an associated reversal of MetS could lead to the halting of OA disease progression. Numerous studies have been conducted assessing the impact of weight loss on metabolic dysfunction with implications for macrophage activation and systemic inflammation. Diet-induced weight loss over a 3-month period significantly reduced circulating saturated FFA levels.[58] Weight loss has also been shown to significantly reduce circulating AGEs, demonstrated by reductions in HbA1c (glycated haemoglobin).[59] As these are known to activate TLR4 and RAGEs, respectively, weight loss may decrease the activation and polarisation of M1 macrophages and hence reduce inflammation. In support of this, OA patients experiencing weight loss following bariatric surgery had significantly reduced serum leptin, IL-6, and high-sensitivity C-reactive protein levels, and increased serum adiponectin levels.[60] This was associated with decreased pain and improved function scores, as well as increased levels of N-terminal propeptide of type IIA collagen, indicative of cartilage production, and decreased levels of cartilage oligomeric matrix protein, indicative of cartilage degradation.[60] Weight loss can thus decrease systemic inflammation and alleviate symptoms of knee OA.

In addition to weight loss, there has been interest in drugs such as metformin, used in the treatment of diabetes for many years. Metformin primarily acts to reduce hepatic gluconeogenesis whilst also increasing glucose utilisation by the intestine, thus reduce AGE formation implicated in the activation and polarisation of M1 macrophages.[61] Furthermore, its molecular mechanism of action involves activating AMPK,[61] which may have further protective roles in the context of OA, as discussed above. Metformin has recently been used in a prospective cohort study and was shown to reduce cartilage loss in OA patients over a 4-year period.[62] Whilst it did fail to reach significance for the reduction in total knee replacement after 6 years, this may be due to the relatively small number of participants in the study who were currently taking metformin and thus remains a promising avenue for future research to determine the influence metformin may have on OA progression. It must also be acknowledged, however, that there are drawbacks to metformin use. Significant proportions of patients started upon the drug are unable to tolerate the side effects that often accompany its initiation, most notably gastrointestinal upset.[63]

Whilst old drugs such as metformin could potentially be repurposed for treating OA, there is a need for further strategies to combat OA. One such strategy is utilising dietary ω-3 PUFA derivatives to influence macrophage polarisation and OA disease progression. Mice fed different ratios of ω-6 polyunsaturated fatty acids (PUFAs) compared to ω-3 PUFAs to induce obesity showed significant differences in the severity of OA, synovitis, and wound healing. Those with greater levels of ω-6 PUFAs had significantly worse outcomes, as well as increased leptin and decreased adiponectin levels.[64] However, this is controversial with others demonstrating mice fed with a ω-6-rich diet over a 24-week period to have no increased risk of synovitis when compared to those fed with ω-3 PUFAs.[65] Despite these differing results, PUFA derivatives have been trialled therapeutically. The ω-3 PUFA derivative resolvin D1 (RvD1) has been reported to re-polarise macrophages to an M2 phenotype with decreased production of IL-8, IL-1β, and CCL2.[66] Mice receiving a HFD and treated intra-articularly with RvD1 showed decreased susceptibility to post-traumatic OA compared to mice injected with vehicle.[67] This provides insight that RvD1-like molecules could mediate re-polarisation of macrophages and reduction in inflammation. Results from a 2016 clinical trial showed oral ω-3 to be beneficial in reducing patient pain scores in OA but failed to demonstrate any benefit in reducing cartilage loss.[68] Further investigation is therefore warranted to determine whether, with a potential intra-articular route of administration, OA progression could be slowed, thus paving the way to a potential DMOAD.