Gp130-mediated signaling is necessary for normal osteoblastic function in vivo and in vitro

Abstract

Previous studies have shown that mice missing gp130, the common receptor subunit for many cytokines, die at or before birth with multiple skeletal abnormalities. Furthermore, interactions between PTH and gp130 signaling have suggested that gp130 signaling might influence calcium homeostasis. We, therefore, examined the function of osteoblasts, osteoclasts, and calcium homeostasis in gp130(-/-) mice, both in vivo and in vitro. Osteoblasts from these mice exhibit widespread abnormalities, including decreased alkaline phosphatase mRNA and protein, both in vivo and in osteoblast cultures. Although osteoclast number is increased in gp130(-/-) fetuses, these osteoclasts exhibit abnormalities in the resorptive organelle and the ruffled border, and the mice are mildly hypocalcemic. Although the hypocalcemia is associated with secondary hyperparathyroidism, the increase in PTH does not explain the increase in osteoclast number because removal of the PTH gene in gp130(-/-) fetuses does not importantly change osteoclast number. Calvarial bone resorption in response to PTH is defective, as is the ability of osteoblastic cells from gp130(-/-) mice to stimulate osteoclastogenesis from normal precursors in vitro or to increase receptor activator of nuclear factor-kappa B ligand mRNA levels after exposure to PTH. These studies demonstrate the importance of gp130 signaling for osteoblast function and calcium homeostasis.