Excess Visceral Fat Generates Inflammatory Signaling that Harms Joint Health
Excess visceral fat generates inflammatory signaling through a range of mechanisms, including DNA debris from stressed and dying fat cells that triggers innate immune sensors, and an additional burden of senescent cells producing the senescence-associated secretory phenotype (SASP). Chronic inflammatory signaling is disruptive to cell and tissue function throughout the body, and, as illustrated here, joints are no exception.
Osteoarthritis (OA) is a major cause of disability and globally the most common musculoskeletal health issue with more than 30% of those over 45 years of age having sought treatment. In recent attempts to develop new treatments for patients it is now emerging that the multifaceted clinical pathology of OA is underpinned by particular molecular endotypes defined by distinct molecular mechanisms and signaling pathways, which may overlap. In OA these include 'low repair', 'bone cartilage', 'metabolic' and 'inflammatory' endotypes.
In attempting to understand the drivers of these endotypes, it is notable that obesity is a major risk factor for the development of OA. Excessive mechanical loading of the joint is often cited as the cause of the association between obesity and OA. However, studies also find that obesity increases the risk of developing OA in the hands, a non-load bearing joint, illustrating that the association is not solely due to pathological loading on the articular cartilage but may also be due to the chronic inflammatory metabolic effects of obesity.
Hand, hip, knee, and foot joint synovial tissue was obtained from OA patients (n = 32) classified as obese (BMI over 30) or normal weight (BMI 18.5-24.9). Targeted proteomic, metabolic, and transcriptomic analysis found the inflammatory landscape of OA synovial fibroblasts are independently impacted by obesity, joint loading, and anatomical site with significant heterogeneity between obese and normal weight patients, confirmed by bulk RNAseq. Further investigation by single cell RNAseq identified four functional molecular endotypes including obesity specific subsets defined by an inflammatory endotype related to immune cell regulation, fibroblast activation, and inflammatory signaling.
These cell types draw similarity to fibroblast subsets reported in rheumatoid arthritis (RA), suggesting OA pathogenesis in obese patients may be akin to the more inflammatory RA joint. Obese OA specific clusters are involved in the activation and recruitment of immune cells, which are reminiscent of 'immune-effector fibroblasts' reported in RA known to regulate and recruit immune cells. In conclusion, these findings demonstrate the significance of obesity in changing the inflammatory landscape of synovial fibroblasts in both load bearing and non-load bearing joints.