gp130 signaling in bone cell biology: multiple roles revealed by analysis of genetically altered mice.

The receptor subunit gp130 is utilized by a wide range of cytokines, many of which have critical functions in regulating the actions of osteoclasts and osteoblasts. In vitro studies have revealed remarkably consistent effects of many of these family members, specifically, actions on receptors in the osteoblast lineage that stimulate osteoblast differentiation and stimulate production of RANKL, thereby increasing the formation of osteoclasts. In contrast to this simple model of gp130 action on bone, deletion of cytokines or receptors that interact with gp130 reveal a range of bone phenotypes implicating critical roles for gp130 signaling in longitudinal bone growth, bone resorption and bone formation. In most cases, deletion of gp130, ligands or ligand-specific receptors interacting with gp130 causes a low level of bone formation; a high level of bone formation was only observed in gp130(Y757F/Y757F) mice, gp130 signaling mutants, where it is caused by a cell-lineage autonomous increase in osteoclast formation and an IL-6-dependent coupling pathway. On the other hand, the range of gene knockouts may cause either a reduction or an increase in osteoclast formation, and in many cases alterations in osteoclast size and ability to resorb bone. Since some knockouts are neonatal lethal, interpretation of ex vivo analyses and the contribution of each component to bone remodeling are not clearly defined, and there is still much work to be done before these questions can be resolved. Taken together these results indicate multiple roles for gp130 cytokines in controlling osteoblasts and osteoclast function, including paracrine roles to mediate signaling between these two cell types.