Obesity remains the most important risk factor for the incidence and progression of osteoarthritis (OA). The leading cause of OA was believed to be overloading the joints due to excess weight which in turn leads to the destruction of articular cartilage. However, recent studies have proved otherwise, various other factors like adipose deposition, insulin resistance, and especially the improper coordination of innate and adaptive immune responses may lead to the initiation and progression of obesity-associated OA. It is becoming increasingly evident that multiple inflammatory cells are recruited into the synovial joint that serves an important role in pathological changes in the synovial joint. Polarization of macrophages and macrophage-produced mediators are extensively studied and linked to the inflammatory and destructive responses in the OA synovium and cartilage. However, the role of other major innate immune cells such as neutrophils, eosinophils, and dendritic cells in the pathogenesis of OA has not been fully evaluated. Although cells of the adaptive immune system contribute to the pathogenesis of obesity-induced OA is still under exploration, a quantity of literature indicates OA synovium has an enriched population of T cells and B cells compared with healthy control. The interplay between a variety of immune cells and other cells that reside in the articular joints may constitute a vicious cycle, leading to pathological changes of the articular joint in obese individuals. This review addresses obesity and the role of all the immune cells that are involved in OA and summarised animal studies and human trials and knowledge gaps between the studies have been highlighted. The review also touches base on the interventions currently in clinical trials, different stages of the testing, and their shortcomings are also discussed to understand the future direction which could help in understanding the multifactorial aspects of OA where inflammation has a significant function.

Epidemiological and experimental studies have established obesity to be an important risk factor for osteoarthritis (OA), however, the mechanisms underlying this link remains largely unknown. Here, we studied local inflammatory responses in metabolic-OA. Wistar rats were fed with control diet (CD) and high-carbohydrate, high-fat diet (HCHF) for period of 8 and 16 weeks. After euthanasia, the knees were examined to assess the articular cartilage changes and inflammation in synovial membrane. Further IHC was conducted to determine the macrophage-polarization status of the synovium. In addition, CD and HCHF synovial fluid was co-cultured with bone marrow-derived macrophages to assess the effect of synovial fluid inflammation on macrophage polarisation. Our study showed that, obesity induced by a high-carbohydrate, high-fat (HCHF) diet is associated with spontaneous and local inflammation of the synovial membranes in rats even before the cartilage degradation. This was followed by increased synovitis and increased macrophage infiltration into the synovium and a predominant elevation of pro-inflammatory M1 macrophages. In addition, bone marrow derived macrophages, cultured with synovial fluid collected from the knees of obese rats exhibited a pro-inflammatory M1 macrophage phenotype. Our study demonstrate a strong association between obesity and a dynamic immune response locally within synovial tissues. Furthermore, we have also identified synovial resident macrophages to play a vital role in the inflammation caused by the HCHF diet. Therefore, future therapeutic strategies targeted at the synovial macrophage phenotype may be the key to break the link between obesity and OA.

Objective.: Degradative enzymes, such as A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinases (MMP), play key roles in development of osteoarthritis (OA). We investigated if crosstalk between subchondral bone osteoblasts (SBO) and articular cartilage chondrocytes (ACC) in OA alters the expression and regulation of ADAMTS5, ADAMTS4, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-13, and also tested the possible involvement of mitogen-activated protein kinase (MAPK) signaling pathway during this process.Methods.: ACC and SBO were isolated from normal and OA patients. An in vitro coculture model was developed to study the regulation of ADAMTS and MMP under normal and OA joint crosstalk conditions. The MAPK-ERK inhibitor PD98059 was applied to delineate the involvement of specific pathways during this interaction process.Results.: Indirect coculture of OA SBO with normal ACC resulted in significantly increased expression of ADAMTS5, ADAMTS4, MMP-2, MMP-3, and MMP-9 in ACC, whereas coculture of OA ACC led to increased MMP-1 and MMP-2 expression in normal SBO. Upregulation of ADAMTS and MMP under these conditions was correlated with activation of the MAPK-ERK1/2 signaling pathway, and addition of the MAPK-ERK inhibitor PD98059 reversed the overexpression of ADAMTS and MMP in cocultures.Conclusion.: These results add to the evidence that in human OA, altered bidirectional signals between SBO and ACC significantly influence the critical features of both cartilage and bone by producing abnormal levels of ADAMTS and MMP. We have demonstrated for the first time that this altered crosstalk was mediated by the phosphorylation of MAPK-ERK1/2 signaling pathway.