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J. Biol. Chem., Vol. 276, Issue 24, 21351-21358, June 15, 2001
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From the Elevated levels of
[Ca2+]o in bone milieu as a result
of the resorptive action of osteoclasts are implicated in promoting proliferation and migration of osteoblasts during bone remodeling. However, mitogenic effects of [Ca2+]o have only
been shown in some, but not all, clonal osteoblast-like cells, and the
molecular mechanisms underlying [Ca2+]o-induced
mitogenic signaling are largely unknown. In this study we demonstrated
for the first time that [Ca2+]o stimulated
proliferation of primary human osteoblasts and selectively activated
extracellular signal-regulated kinases (ERKs). Neither p38
mitogen-activated protein (MAP) kinase nor stress-activated
protein kinase was activated by [Ca2+]o.
Treatment of human osteoblasts with a MAP kinase kinase inhibitor,
PD98059, impaired both basal and
[Ca2+]o-stimulated phosphorylation of ERKs and
also reduced both basal and [Ca2+]o-stimulated
proliferation. [Ca2+]o treatment resulted in two
distinctive phases of ERK activation: an acute phase and a sustained
phase. An inhibition time course revealed that it was the sustained
phase, not the acute phase, that was critical for
[Ca2+]o-stimulated osteoblast proliferation. Our
results demonstrate that mitogenic responsiveness to
[Ca2+]o is present in primary human
osteoblasts and is mediated via prolonged activation of the MAP kinase
kinase/ERK signal pathway.
Sustained Activation of the Extracellular Signal-regulated Kinase
Pathway Is Required for Extracellular Calcium Stimulation of Human
Osteoblast Proliferation*
§,
Renal Division and the ¶ Division of
Bone and Mineral Diseases, Department of Medicine, Washington
University, School of Medicine, St. Louis, Missouri 63110
*
This work was supported in part by NIDDK, National
Institutes of Health Grants DK-09976, DK-30178, and DK-07126 (to
E. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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