Editorial: Insulin Resistance: Releasing the Brakes on Synovial Inflammation and Osteoarthritis?

In studies of osteoarthritis (OA), evidence indicating a link between OA and type 2 diabetes mellitus (DM) has emerged (1,2). As both are closely related to aging and obesity, it is no surprise that as our population has grown older and more obese, the incidence of both OA and type 2 DM has increased markedly. Previously, the association between OA and type 2 DM was considered correlative, in that obesity was thought to lead to knee OA primarily through the alteration of joint biomechanical loading, and type 2 DM was largely attributed to an imbalance between nutrient supply and demand, leading to insulin resistance and pancreatic exhaustion. This perspective is changing, however, as the pathogenesis of obesity-associated OA is progressively considered more complex. For example, the increased incidence and severity of hand OA in obese individuals have long suggested the possibility of a systemic connection to obesity. Multiple pathways linking obesity to OA, including biomechanical, inflammatory, posttraumatic, genetic, and metabolic pathways (3), have now been proposed. In particular, there is growing evidence to indicate that diabetes increases the risk of OA even when the risk models are controlled for the presence of obesity. The diabetes–OA link arises from a number of key observations that highlight obesity-independent associations between OA and the metabolic syndrome (4). The metabolic syndrome, which has insulin resistance as its central feature, includes at least 3 of the following factors: hypertension, increased triglyceride levels, reduced high-density lipoprotein cholesterol levels, increased waist circumference, and elevated fasting glucose levels. Increasing numbers of components of the metabolic syndrome have been found to predict an increased occurrence and progression of radiographic knee OA (5). Furthermore, in a recent study using a meta-analytic approach, a positive association between OA and type 2 DM was observed, with an odds ratio (OR) of 1.46 (95% confidence interval [95% CI] 1.08– 1.96) for OA in type 2 DM populations (2). Interestingly, of those studies that adjusted for body mass index (BMI), a positive association between OA and type 2 DM was primarily observed in studies published since 2009. One potential explanation for this recent increase in BMI-adjusted odds is an increase in the prevalence of other metabolic syndrome factors that are associated with type 2 DM and that contribute to OA. In addition, a contribution of diabetes to inflammation in OA is supported by the observation that, in knee OA, individuals with diabetes have more joint effusions and synovitis, which are independent of BMI (1). In this issue of Arthritis & Rheumatology, Hamada and colleagues present compelling data linking both synovial tumor necrosis factor (TNF) production and insulin resistance to the pathogenesis of OA (6) (as summarized in Figure 1). Although anti-TNF therapies for OA have had limited success, the findings reported by Hamada et al suggest a causal role for TNF in OA, specifically in obesityand diabetes-associated OA. Using a mouse model of high-fat diet–induced obesity and glucose intolerance, the authors showed that Tnf gene expression and TNF protein levels were elevated in the synovium adjacent to osteophytes, an early pathogenic feature in this model. The authors further demonstrated the relevance of TNF to the development of osteophytes in this model, by replicating the experiments in TNFknockout mice. The ablation of TNF greatly diminished The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R03-AR-066828 and National Institute on Aging grant R01-AG-049058 to Dr. Griffin). Timothy M. Griffin, PhD: Oklahoma Medical Research Foundation and the University of Oklahoma Health Sciences Center, Oklahoma City; Kim M. Huffman, MD, PhD: Duke University Medical Center and Durham VA Medical Center, Durham, North Carolina. Address correspondence to Timothy M. Griffin, PhD, Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, MS 21, 825 NE 13th Street, Oklahoma City, OK 73104. E-mail: tim-griffin@omrf.org. Submitted for publication December 2, 2015; accepted in revised form January 5, 2016.