Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis

Interleukin-6 (IL-6) plays a key role in the local and systemic manifestations of rheumatoid arthritis (RA). IL-6 is not only a proinflammatory cytokine, but also interacts in complex ways with the cells involved in bone remodeling. In RA, IL-6 may indirectly promote osteoclastogenesis by increasing the release of RANK-L by osteoblasts and synovial cells. However, IL-6 inhibits osteoclastogenesis in vitro, via a direct mechanism. The effects of IL-6 on osteoblasts may vary with the cell differentiation stage: thus, IL-6 may promote the differentiation of pre-osteoblasts to mature osteoblasts while also diminishing the proliferation of osteoblasts at late differentiation stages. Thus, the effects of IL-6 on bone remodeling are complex and may occur in opposite directions depending on the model or experimental conditions. Nevertheless, results from studies in animal models and humans support a negative effect of IL-6 on bone. Thus, in patients with RA, blocking IL-6 may be effective both in diminishing the inflammatory manifestations and in preventing the bone complications of the disease.