Pro-inflammatory cytokines: The link between obesity and osteoarthritis.

Osteoarthritis (OA), characterized by joint malfunction and chronic disability, is the most common form of arthritis. Clinical and animal experiments reveal that age-related OA is associated with many factors such as age, sex, trauma, and obesity. One of the most influential and modifiable risk factors is obesity. Obesity not only increases mechanical stress on the tibiofemoral cartilage, but also leads to a higher prevalence of OA in non-weight-bearing areas. There is a link between obesity and inflammation. Adipose tissues play a crucial role in this context because they are the major source of cytokines, chemokines, and metabolically-active mediators named adipokines. The adipokines, including adiponectin and leptin, have been demonstrated to regulate inflammatory immune responses in cartilage. Obese people and animals show a higher level of serum tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL)-1β and IL-6, all of which are produced by macrophages derived from adipose tissue. These pro-inflammatory cytokines regulate the proliferation and apoptosis of adipocytes, promote lipolysis, inhibit lipid synthesis and decrease blood lipids through autocrine and paracrine mechanisms. Elevated levels of TNF-α, IL-1 and IL-6 have been found in the synovial fluid, synovial membrane, subchondral bone and cartilage of OA patients, confirming their important roles in OA pathogenesis. TNF-α, IL-6 and IL-1 are the factors released by fat to negatively regulate cartilage directly. Moreover, TNF-α, IL-1 and IL-6 can induce the production of other cytokines, matrix metalloproteinases (MMPs) and prostaglandins and inhibit the synthesis of proteoglycans and type II collagen; thus, they play a pivotal role in cartilage matrix degradation and bone resorption in OA. Activated chondrocytes also produce MMP-1, MMP-3, MMP-13, and aggrecanase 1 and 2 (ADAMTS-4, ADAMTS-5). In addition, IL-1, TNF-α and IL-6 may cause OA indirectly by regulating release of adiponectin and leptin from adipocytes. In this review, we first summarize the relationship between obesity and inflammation. Then we summarize the roles of IL-1, TNF-α and IL-6 in OA. We further discuss how IL-1, TNF-α and IL-6 regulate the communication between fat and OA, and their pathological roles in obesity-related OA. Lastly, we discuss the possibility of using the pro-inflammatory signaling pathway as a therapeutic target to develop drugs for obesity-related OA.