The Role of the Interleukin-6/gp130 Signaling Pathway in Bone Metabolism

There is increasing evidence that the IL-6 family of cytokines and signaling pathways downstream of the common gp130 receptor subunit play critical roles in the processes of bone homeostasis and remodeling. The binding of IL-6 to sIL-6R is a prerequisite step for the activation of gp130/STAT3 signaling. Once gp130 is activated, there are at least two intracellular signaling cascades that can transmit divergent signals to bone cells. Although there is some conflicting data regarding the effects of IL-6 on bone, it is generally accepted that the primary effect of this cytokine group is the stimulation of osteoclastic bone resorption. In addition, IL-6 effects on osteoclasts appear to be predominantly indirect via modulation of osteoblasts and the OPG/RANKL/RANK system that coordinates the functions and activities of osteoblasts and osteoclasts. IL-6 alone has minimal effects on osteoclast differentiation and activation. However, IL-6 acts synergistically with growth factors, steroid hormones, inflammatory cytokines, and prostaglandins in bone cells. Reciprocal interactions between IL-6 and PGE₂ are particularly relevant to bone metabolism. IL-6 enhances the expression of two subtypes of EP receptor and mediates PGE₂-induced suppression of OPG secretion. A better understanding of the complex, cell-specific, interactive effects of IL-6 and various bone modulators may uncover new paradigms for the treatment of bone diseases.