Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways
Natalie A. Sims, … , Matthias Ernst, T. John Martin
Natalie A. Sims, … , Matthias Ernst, T. John Martin
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):379-389. https://doi.org/10.1172/JCI19872.
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Article Bone Biology

Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways

Abstract

The gp130-dependent cytokines, which signal through at least two intracellular pathways, regulate osteoclast and osteoblast formation. To define their roles in regulating bone mass, we analyzed mice in which gp130 signaling via either the signal transducer and activator of transcription (STAT) 1/3 (gp130ΔSTAT/ΔSTAT) or SHP2/ras/MAPK (gp130Y757F/Y757F) pathway was attenuated. In gp130ΔSTAT/ΔSTAT mice, trabecular bone volume (BV/TV) and turnover were normal, but bone length was reduced by premature growth plate closure, indicating an essential role for gp130-STAT1/3 signaling in chondrocyte differentiation. In contrast, while bone size was normal in gp130Y757F/Y757F mice, BV/TV was reduced due to high bone turnover, indicated by high osteoclast surface/bone surface (OcS/BS) and osteoblast surface/bone surface (ObS/BS). Furthermore, generation of functional osteoclasts from bone marrow of gp130Y757F/Y757F mice was elevated, revealing that while gp130 family cytokines stimulate osteoclastogenesis through the osteoblast lineage, gp130, via SHP2/Ras/MAPK, inhibits osteoclastogenesis in a cell lineage–autonomous manner. Genetic ablation of IL-6 in gp130Y757F/Y757F mice exacerbated this osteopenia by reducing ObS/BS without affecting OcS/BS. Thus, while IL-6 is critical for high bone formation in gp130Y757F/Y757F mice, it is not involved in the increased osteoclastogenesis. In conclusion, gp130 is essential for normal bone growth and trabecular bone mass, with balanced regulation depending on selective activation of STAT1/3 and SHP2/ras/MAPK, respectively. Furthermore, the latter pathway can directly inhibit osteoclastogenesis in vivo.

Authors

Natalie A. Sims, Brendan J. Jenkins, Julian M.W. Quinn, Akira Nakamura, Markus Glatt, Matthew T. Gillespie, Matthias Ernst, T. John Martin

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Increased bone formation in male and female gp130Y757F/Y757F mutant mice...
Increased bone formation in male and female gp130Y757F/Y757F mutant mice. Histomorphometric indices of bone formation including tibial ObS/BS, OV/BV, and MAR were significantly higher in male (a) and female (b) F/F mice compared with WT and Δ/Δ mice. All values are mean ± SEM from a minimum of eight mice per group at 12–16 weeks of age. *P < 0.05; **P < 0.01; ***P < 0.001 vs. WT of the same sex. (c) Ex vivo osteoblast differentiation from bone marrow cultured under osteoblastogenic conditions was not significantly altered in F/F mice (black bars) compared with WT mice (white bars). Shown are alkaline phosphatase–positive colony formation as a percentage of well area (%ALP+ area) and mineralization detected by a von Kossa stain for calcified matrix (%). Values are mean ± SEM from three experimental preparations at each time point using a minimum of three mice of mixed sexes per genotype for each experiment.