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This version published online on August 28, 2003
Endocrinology, doi:10.1210/en.2003-0273
A more recent version of this article appeared on December 1, 2003
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Submitted on March 3, 2003
Accepted on August 20, 2003

Parathyroid Hormone Related Peptide Interacts with Bone Morphogenetic Protein 2 to increase Osteoblastogenesis and decrease Adipogenesis in Pluripotent C3H10T1/2 Mesenchymal Cells

George K. Chan1, Dengshun Miao1, Ron Deckelbaum1, Isabel Bolivar1, Andrew Karaplis1, and David Goltzman1*

1 The Calcium Research Laboratory, McGill University Health Centre, The Lady Davis Research Institute-Jewish General Hospitaland the Department of Medicine, McGill University, Montreal, Quebec, Canada

* To whom correspondence should be addressed. E-mail: david.goltzman{at}mcgill.ca.

We examined the effect of PTHrP on modulating adipogenesis and osteoblastogenesis in the pluripotent mesenchymal cell line C3H10T1/2. These cells express the type 1 PTH/PTHrP receptor thereby allowing PTHrP to inhibit Bone Morphogenetic Protein 2 (BMP2) from enhancing gene expression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and the adipocyte specific protein aP2, and from augmenting the accumulation of lipid. In the presence of BMP2, PTHrP or a protein kinase C (PKC) stimulator (phorbol ester), increased expression of indices of the osteoblast phenotype including alkaline phosphatase, type I collagen and osteocalcin, whereas a PKC inhibitor (chelerythrin chloride) inhibited PTHrP action. PTHrP and a phorbol ester increased gene expression of the BMP IA receptor and both enhanced BMP2 dependent increases in SMAD6 promoter activity. Overexpression of the BMP IA receptor facilitated the capacity of BMP2 to increase osteoblastogenesis in the absence of PTHrP and a dominant negative BMP IA receptor variant inhibited this effect of BMP2. These results demonstrate that PTHrP can direct osteoblastic rather then adipogenic commitment of mesenchymal cells, implicates PKC signaling in this activity and shows that PTHrP action involves enhanced gene expression of the BMP IA receptor which facilitates BMP2 action in enhancing osteoblastogenesis in pluripotent mesenchymal cells.
Key words: Parathyroid Hormone related Peptide • Bone Morphogenetic Protein • Osteoblasts • Mesenchymal Stem Cells






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