Exp Mol Med.  2010 Feb;42(2):87-98. 10.3858/emm.2010.42.2.010.

The N- and C-terminal domains of parathyroid hormone-related protein affect differently the osteogenic and adipogenic potential of human mesenchymal stem cells

• Casado-Diaz A
• Santiago-Mora R
• Quesada JM

• KMID: 983981
• DOI: http://doi.org/10.3858/emm.2010.42.2.010

Abstract

Parathyroid hormone-related protein (PTHrP) is synthesized by diverse tissues, and its processing produces several fragments, each with apparently distinct autocrine and paracrine bioactivities. In bone, PTHrP appears to modulate bone formation in part through promoting osteoblast differentiation. The putative effect of PTH-like and PTH-unrelated fragments of PTHrP on human mesenchymal stem cell (MSCs) is not well known. Human MSCs were treated with PTHrP (1-36) or PTHrP (107-139) or both (each at 10 nM) in osteogenic or adipogenic medium, from the start or after 6 days of exposure to the corresponding medium, and the expression of several osteoblastogenic and adipogenic markers was analyzed. PTHrP (1-36) inhibited adipogenesis in MSCs and favoured the expression of osteogenic early markers. The opposite was observed with treatment of MSCs with PTHrP (107-139). Moreover, inhibition of the adipogenic differentiation by PTHrP (1-36) prevailed in the presence of PTHrP (107-139). The PTH/PTHrP type 1 receptor (PTH1R) gene expression was maximum in the earlier and later stages of osteogenesis and adipogenesis, respectively. While PTHrP (107-139) did not modify the PTH1R overexpression during adipogenesis, PTHrP (1-36) did inhibit it; an effect which was partially affected by PTHrP (7-34), a PTH1R antagonist, at 1 microM. These findings demonstrate that both PTHrP domains can exert varying effects on human MSCs differentiation. PTHrP (107-139) showed a tendency to favor adipogenesis, while PTHrP (1-36) induced a mild osteogenic effect in these cells, and inhibited their adipocytic commitment. This further supports the potential anabolic action of the latter peptide in humans.

Keyword

adipogenesis; bone; mesenchymal stem cells; osteogenesis; parathyroid hormone-related protein

MeSH Terms

Adipogenesis/drug effects
Alkaline Phosphatase/biosynthesis/genetics
Antigens, Differentiation/biosynthesis/genetics
Bone Marrow/pathology
Cell Differentiation/drug effects
Cells, Cultured
Core Binding Factor Alpha 1 Subunit/biosynthesis/genetics
Culture Media
Gene Expression Regulation
Humans
Lipoprotein Lipase/biosynthesis/genetics
Mesenchymal Stem Cells/*drug effects/metabolism/pathology
Osteoblasts/drug effects/*metabolism/pathology
Osteogenesis/drug effects
PPAR gamma/biosynthesis/genetics
Parathyroid Hormone/*pharmacology
Peptide Fragments/*pharmacology
Receptor, Parathyroid Hormone, Type 1/antagonists & inhibitors