title: Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities.
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.
authors.affiliation: Tissue Repair, Pfizer Research, Cambridge, MA 02140, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Berasi
authors.forename: Usha
authors.initials: U
authors.lastname: Varadarajan
authors.forename: Joanne
authors.initials: J
authors.lastname: Archambault
authors.forename: Michael
authors.initials: M
authors.lastname: Cain
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Souza
authors.forename: Abe
authors.initials: A
authors.lastname: Abouzeid
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Brown
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dorner
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Seeherman
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jelinsky
mesh_terms: D029404:Activin Receptors / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism* / Q000494:pharmacology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D055431:Growth Differentiation Factor 6 / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D055412:Growth Differentiation Factors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D010012:Osteogenesis / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013710:Tendons / Q000378:metabolism; D019699:Thrombospondins / Q000096:biosynthesis
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C525906:GDF6 protein, human; C499470:GDF7 protein, human; D055431:Growth Differentiation Factor 6; D055412:Growth Differentiation Factors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051785:Smad Proteins; D019699:Thrombospondins; C101864:thrombospondin 4; D015675:Osteocalcin; D029404:Activin Receptors; C498218:BMPR2 protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II