Is RANKL a potential molecular target in osteoarthritis?

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.) 2009 Massachusetts Medical Society

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.

The purpose of this review is to highlight recent studies of osteoarthritis epidemiology, including research on prevalence, disease impact, and potential risk factors.