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

Association Between MetS and OA

Evidence From Epidemiological Studies

MetS can be defined as the presence of any three of the following risk factors: elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, or hypertension.[4] MetS is accompanied by chronic low-grade systemic inflammation.[5] The clinical importance of this has been increasingly recognised, with conditions driven by chronic inflammation such as psoriasis linked to MetS.[6] For OA, the strongest epidemiological links are found between MetS and OA of the knee.[7] A greater body mass, commonly associated with MetS, and a resulting increase in the forces acting on the load-bearing joints may be in part responsible for this association. However, obesity also increases the risk of development of OA in non-weight-bearing joints of the hand.[7] Irrespective of a patient's BMI, hyperlipidaemia and hypertension as individual MetS components have been linked to the development of OA.[8] These and other studies[9] thus provide evidence linking MetS to OA independent of a patient's BMI.

Evidence From Preclinical Studies and the Role of Inflammation

The link between MetS and OA is supported by preclinical studies. A commonly used experimental model in rodents is a high-fat diet (HFD), which leads to obesity, hyperglycaemia and dyslipidaemia, and OA. HFD can also exacerbate post-traumatic OA in mice.[10] Wheel-running exercise, and hence increased biomechanical forces exerted on joints, protected from HFD-induced OA, and this was associated with improved glucose tolerance without reducing body fat.[11] This indicates that biomechanics alone cannot account for the worsening of OA, at least in rodents, and that exercise may be joint protective through improving metabolic function. In addition, HFD-induced OA is associated with systemic elevations in pro-inflammatory cytokines.[11] Local adipose tissue such as the infrapatellar fat pad (IFP) in the knee may also produce inflammatory and catabolic mediators that contribute to OA pathogenesis and has been implicated as a source of inflammatory cytokines in both murine HFD-induced OA[12] and in human rheumatoid arthritis and OA.[13] Indeed, the IFP from OA patients was shown to have significantly increased levels of IL-6, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leptin, whilst also showing increased levels of fibrosis compared to healthy controls.[14] Furthermore, when compared to autologous subcutaneous fat, intra-articular adipose tissue within the infrapatellar and suprapatellar and acetabular fat pads all showed significantly increased levels of vascularity, fibrosis, and inflammatory mediators in OA patient samples.[15] It must be noted that OA changes within the intra-articular adipose tissues were unaffected by the presence of obesity. Similarly, other studies have disputed whether HFD leads to changes within the IFP, with no evidence found for an increase in inflammation nor adipocyte hypertrophy in the IFP in response to HFD, as had been observed in epididymal fat.[16] This suggests that the IFP may not undergo similar inflammatory changes in response to HFD as abdominal adipose tissue. It is increasingly recognised that differences in cellular composition and metabolic function exist between adipose depots. This is potentially a result of adipocyte populations arising from differing embryological sources[17] and the heterogeneous nature of the progenitor cell populations found within individual depots.[18] Intriguingly, these populations undergo significant alterations in the presence of diabetes.[18] Whilst research into the diverse nature of adipocyte biology is ongoing, our knowledge regarding intra-articular adipose tissue is particularly limited in relation to its insulin responsiveness, lipid handling properties, and response to inflammation. Thus, the relative importance of local versus systemic adipose inflammation, and of metabolic dysregulation, in the MetS-associated OA remains to be clarified.