gp130, a subunit for several cytokine signal transducing receptors, mediates diverse activities including osteoclastogenesis. In vitro observations suggest that PTH also triggers the gp130-mediated signal for bone resorption by stimulating secretion of IL-6, IL-11 and LIF from osteoblast/stromal cells. Though this gp130 signaling is required for full activation of bone resorption by PTH in vitro, the relationship between PTH and gp130 signaling pathway in vivo is not yet clarified. To address the importance of gp130 as a mediator of PTH action in osteoclast activation, the blood ionized calcium and blood serum PTH level was investigated in gp130-/-and wild type mice at E18.5 using a CIBA/Corning 634 Ca+2/pH analyzer and rat intact PTH Kit, respectively. In addition, calcium transport efficiency was assessed from gp130 mice at E17.5. The resorptive activity of osteoclasts from intact calvariae by a 45Ca release assay and the osteoclastic developmental condition in tibiae were also analyzed, respectively. The gp130-/-mice revealed signigicantly lower ionized calcium level(1.44±0.03 vs 1.77±0.03 mmol/1, P<0.001)and significantly higher blood serum PTH(251.8±5.3 vs 20.5±5.3 pg/ml, P<0.001) compared to wild type littermates. There was no remarkable pathologic change of placenta in gp130-/-and the 45Ca transport through placenta was accelerated in gp130-/-compared to wild type littermates(% to Het 83% in-/-vs 148% un +/+). The gp130-/-embryos had small skeletons with bones containing little primary spongiosa, and large multinucleated TRAP+ cells along the lower border of the growth plate. Release of 45Ca from prelabeled calvarial bone(E18.5) in response to either 10-7 M hPTH(1-34) or 20 ng/ml sRANKL was lower in gp130-/-calvarial bone compared to gp130+/+ calvarial bone(PTH 1.83±0.6 fold over basal in-/-vs 2.79±0.6 in +/+ and sRANKL 1.3±0.4 in -/- vs 2.0±0.4 in +/+, P<0.5).
These results strongly support the hypothesis that PTH activates bone resorption, in part, by stimulating osteotrophic cytokine secretion from osteoblast/stromal cells, which triggers gp130-mediated signaling for osteoclastic activation.
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