Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities

Stephen P Berasi; Usha Varadarajan; Joanne Archambault; Michael Cain; Tatyana A Souza; Abe Abouzeid; Jian Li; Christopher T Brown; Andrew J Dorner; Howard J Seeherman; Scott A Jelinsky

doi:10.3109/08977194.2011.593178

Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities

Growth Factors. 2011 Aug;29(4):128-39. doi: 10.3109/08977194.2011.593178. Epub 2011 Jun 27.

Authors

Stephen P Berasi¹, Usha Varadarajan, Joanne Archambault, Michael Cain, Tatyana A Souza, Abe Abouzeid, Jian Li, Christopher T Brown, Andrew J Dorner, Howard J Seeherman, Scott A Jelinsky

Affiliation

¹ Tissue Repair, Pfizer Research, Cambridge, MA 02140, USA.

Abstract

Ectopic expression of recombinant human bone morphogenetic protein 2 (rhBMP2) induces osteogenesis, while ectopic expression of rhBMP12 and rhBMP13 induces the formation of tendon-like tissue. Despite their different in vivo activities, all three ligands bound to the type I bone morphogenic protein receptors (BMPRs), activin receptor-like kinase (ALK)-3 and ALK6, and to the type II BMPRs, activin receptor type-2A, activin receptor type-2B, and BMPR2, with similar affinities. Treatment of C3H10T1/2 cells with rhBMP2 activated SMAD signaling and induced expression of osteoblast markers including osteocalcin mRNA (Ocn). In contrast, treatment with rhBMP12 or rhBMP13 resulted in a dose-dependent induction of a tendon-specific gene (Thbs4) expression with no detectable activation of SMAD 1, 5, and 8. Differential regulation of Thbs4 and Ocn has potential utility as an in vitro biomarker for induction of tenogenic signaling. Such an assay also permits the ability to distinguish between the activities of different BMPs and may prove useful in studies on the molecular mechanisms of BMP tenogenic activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors / metabolism
Animals
Bone Morphogenetic Protein 2 / metabolism*
Bone Morphogenetic Protein 2 / pharmacology
Bone Morphogenetic Protein Receptors, Type I / metabolism*
Bone Morphogenetic Protein Receptors, Type II / metabolism*
Bone Morphogenetic Proteins / metabolism*
Bone Morphogenetic Proteins / pharmacology
Cell Differentiation / drug effects
Cell Line
Growth Differentiation Factor 6 / biosynthesis
Growth Differentiation Factor 6 / metabolism*
Growth Differentiation Factor 6 / pharmacology
Growth Differentiation Factors / metabolism*
Growth Differentiation Factors / pharmacology
Humans
Mice
Mice, Inbred C3H
Osteocalcin / biosynthesis
Osteocalcin / genetics
Osteogenesis / drug effects
Polymerase Chain Reaction
Protein Binding
RNA, Messenger / biosynthesis
Recombinant Proteins / biosynthesis
Recombinant Proteins / metabolism
Signal Transduction / drug effects
Smad Proteins / metabolism
Tendons / metabolism
Thrombospondins / biosynthesis

Substances

BMP2 protein, human
Bone Morphogenetic Protein 2
Bone Morphogenetic Proteins
GDF6 protein, human
GDF7 protein, human
Growth Differentiation Factor 6
Growth Differentiation Factors
RNA, Messenger
Recombinant Proteins
Smad Proteins
Thrombospondins
thrombospondin 4
Osteocalcin
Activin Receptors
BMPR2 protein, human
Bone Morphogenetic Protein Receptors, Type I
Bone Morphogenetic Protein Receptors, Type II