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Scientific Article   |    
Bone Morphogenetic Protein-7 Modulates Genes that Maintain the Vascular Smooth Muscle Cell Phenotype in Culture
Haimanti Dorai, PhD; T Kuber Sampath, PhD
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Investigation performed at Creative BioMolecules Inc., Hopkinton, Massachusetts
Haimanti Dorai, PhD T. Kuber Sampath, PhD Curis Inc, 21 Erie Street, Cambridge, MA 02139. E-mail adddress for H. Dorai: hdorai@curis.comThe authors did not receive grants or outside funding in support of their research or preparation of this manuscript. One or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (Creative Biomolecule) No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

J Bone Joint Surg Am, 2001 Mar 01;83(1 suppl 1):S70-S78
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Abstract

Background: The vasculature is an important component in the musculoskeletal system, and vascularization is a key event in the development of normal cartilage and bone formation. Blood vessels deliver nutrients, oxygen, and precursor cells to maintain the structural and functional integrity of joints and soft and hard tissues. Therefore, agents that help to inhibit proliferation and retain the phenotype of vascular smooth muscle cells (SMCs) are of critical importance. In this study, we examined the capacity of bone morphogenetic protein-7 (BMP-7) to inhibit the proliferation of SMCs and maintain their phenotype.

Methods: A thymidine-incorporation assay was used to monitor the proliferative activity of SMCs on stimulation with platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-ß), agents known to be stimulatory for these cells. Reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot analysis, and enzyme-linked immunosorbent assay (ELISA) were used to monitor the modulation of various genes and gene products. Immunolocalization of SMC specific markers was also performed.

Results: BMP-7 inhibited both serum-stimulated and growth factor-induced (PDGF-BB and TGF-ß1) SMC growth, as measured by 3 H-thymidine uptake and cell number, in primary human aortic smooth muscle (HASM) cell cultures. The addition of BMP-7 stimulated the expression of developmentally regulated as well as SMC-specific markers, namely, Id-1 and Id-2, a-actin, and SMC-specific heavy-chain myosin, as examined by semiquantitative and quantitative RT-PCR and by Northern blot analysis. Additionally, BMP-7 exhibited anti-inflammatory activity by downregulating intercellular adhesion molecule-1 (ICAM-1) expression. The collagen type III/I ratio that becomes lower with the transdifferentiation of SMCs into myofibroblasts is maintained in BMP-7-treated cultures compared with untreated controls. Studies on the mechanism of action indicate that BMP-7 treatment induces cyclin-dependent kinase-2 inhibitor, p21, which was inhibited during PDGF-BB-induced proliferation of SMCs. Finally, BMP-7 upregulates the expression of the inhibitory Smads, Smad6 and Smad7, which are known to inhibit TGF-ß superfamily signaling.

Conclusions: These results suggest that BMP-7 maintains the expression of the vascular SMC phenotype. Thus, BMP-7 may prevent vascular proliferative disorders and potentially could act as a palliative agent following damage to the vasculature.

Clinical Relevance: In musculoskeletal disorders in which the vasculature plays an important role, BMP-7 may be of benefit as an anti-inflammatory and anti-proliferative agent for vascular endothelium and help maintain vascular integrity.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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