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J. Biol. Chem., Vol. 277, Issue 22, 19374-19381, May 31, 2002
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From the During bone formation, multipotential mesenchymal
cells proliferate and differentiate into osteoblasts, and subsequently
many die because of apoptosis. Evidence suggests that the receptor for parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), the PTH-1 receptor (PTH-1R), plays an important role in this process. Multipotential mesenchymal cells (C3H10T1/2) transfected with normal or mutant PTH-1Rs and MC3T3-E1 osteoblastic cells were used to explore the roles of PTH, PTHrP, and the PTH-1R in
cell viability relative to osteoblastic differentiation. Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors.
Furthermore, the effects of PTH and PTHrP on apoptosis were
dramatically dependent on cell status. In preconfluent C3H10T1/2 and
MC3T3-E1 cells, PTH and PTHrP protected against dexamethasone-induced
reduction in cell viability, which was dependent on cAMP activation.
Conversely, PTH and PTHrP resulted in reduced cell viability in
postconfluent cells, which was also dependent on cAMP activation.
Further, the proapoptotic-like effects were associated with an
inhibition of Akt phosphorylation. These data suggest that parathyroid
hormones accelerate turnover of osteoblasts by promoting cell viability early and promoting cell departure from the differentiation program later in their developmental scheme. Both of these actions occur at
least in part via the protein kinase A pathway.
Parathyroid Hormone and Parathyroid Hormone-related Protein Exert
Both Pro- and Anti-apoptotic Effects in Mesenchymal Cells*
,§,,,
, and**
Department of Periodontics, Prevention, and
Geriatrics, the Department of Biologic and Materials Sciences,
and the ** Department of Pathology, University of Michigan,
Ann Arbor, Michigan 48109, the § Department of
Periodontology, Faculty of Dentistry, Hacettepe University, 06100 Ankara, Turkey, and ¶ INSERM U426, Faculty de Medicine Xavier
Bichat, 75870 Paris, France
*
This work was supported by National Institutes of Health
Grants DK53904 (to L. K. M.) and DE13788 (to C. W.) and
The Scientific and Technical Research Council of Turkey
(NATO-A2) grant (to B. D.).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.
To whom correspondence should be addressed: Dept. of
Periodontics/Prevention/Geriatrics, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078. Tel.: 734-647-3206;
Fax: 734-763-5503; E-mail: mccauley@umich.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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