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gp130 signaling in bone cell biology: multiple roles revealed by analysis of genetically altered mice
1St. Vincent's Institute, Fitzroy, Melbourne, Victoria, Australia. nsims@svi.edu.au
Abstract:
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.
Insights
gp130 cytokines critically regulate bone remodeling by influencing osteoblasts and osteoclasts. Genetic alterations reveal complex roles in bone growth, formation, and resorption, highlighting paracrine signaling between these cell types.
Area of Science:
- Bone Biology and Endocrinology
- Cell Signaling Pathways
- Cytokine Receptor Interactions
Background:
- The gp130 receptor subunit is central to signaling by numerous cytokines involved in bone metabolism.
- In vitro studies suggest gp130 signaling promotes osteoblast differentiation and RANKL production, increasing osteoclast formation.
- However, in vivo studies reveal complex roles for gp130 signaling in bone remodeling.
Purpose of the Study:
- To investigate the multifaceted roles of gp130 cytokines in regulating osteoblast and osteoclast function.
- To elucidate the impact of gp130 signaling on bone growth, resorption, and formation.
- To understand the contribution of gp130 signaling components to bone remodeling.
Main Methods:
- Analysis of bone phenotypes in genetically modified mouse models with deletions of gp130, its ligands, or associated receptors.
- Evaluation of osteoblast differentiation, RANKL production, and osteoclast formation and function.
- Assessment of longitudinal bone growth and bone remodeling parameters.
Main Results:
- Deletion of gp130 components typically leads to reduced bone formation, except in specific signaling mutants (gp130(Y757F/Y757F) mice) which show increased bone formation due to enhanced osteoclastogenesis.
- Gene knockouts result in variable effects on osteoclast formation, size, and resorptive capacity.
- Neonatal lethality in some models complicates ex vivo analysis and precise determination of individual component contributions.
Conclusions:
- gp130 cytokines play diverse and critical roles in controlling osteoblast and osteoclast activity.
- gp130 signaling is essential for normal bone growth, formation, and resorption.
- Paracrine signaling mediated by gp130 cytokines between osteoblasts and osteoclasts is a key feature of bone remodeling.
