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Osteogenic Activity of the Fourteen Types of Human Bone Morphogenetic Proteins (BMPs)

Investigation performed at The University of Chicago Medical Center, Chicago, Illinois

Hongwei Cheng, MD, PhD
Wei Jiang, BA
Rex C. Haydon, MD, PhD
Ying Peng, MD
Lan Zhou, MD, PhD
Hue H. Luu, MD
Naili An, MD
Benjamin Breyer, MD
Pantila Vanichakarn, BS
Jan Paul Szatkowski, BS
Jae Yoon Park, BS
Tong-Chuan He, MD, PhD
Department of Surgery, Section of Orthopaedic Surgery, Molecular Oncology Laboratory (H.C., W.J., F.M.P., R.C.H., Y.P., L.Z., H.H.L., N.A., B.B., P.V., J.P.S., J.Y.P. and T.-C.H), Committee on Genetics (Y.P. and T.-C.H.), Committee on Cancer Biology (N.A. and T.-C.H.), The University of Chicago Medical Center, 5841 South Maryland Avenue, MC3079, Chicago, IL 60637. E-mail address for T.-C. He: tche{at}surgery.bsd.uchicago.edu

Frank M. Phillips, MD
The Rush Arthritis and Orthopaedics Institute, 1725 West Harrison Street, Suite 1063, Chicago, IL 60612. E-mail address: frank.phillips@midwestortho.com

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Schweppe Foundation (T.-C.H.), the Orthopaedic Research and Education Foundation (T.-C.H. and R.C.H.), the North American Spine Society (F.M.P. and T.-C.H.), and the Aircast Foundation (T.-C.H.). None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. 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. Human BMP cDNAs were provided by Genetics Institute (Cambridge, Massachusetts).

A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

Background: Bone morphogenic proteins (BMPs) are known to promote osteogenesis, and clinical trials are currently underway to evaluate the ability of certain BMPs to promote fracture-healing and spinal fusion. The optimal BMPs to be used in different clinical applications have not been elucidated, and a comprehensive evaluation of the relative osteogenic activity of different BMPs is lacking.

Methods: To identify the BMPs that may possess the most osteoinductive activity, we analyzed the osteogenic activity of BMPs in mesenchymal progenitor and osteoblastic cells. Recombinant adenoviruses expressing fourteen human BMPs (BMP-2 to BMP-15) were constructed to infect pluripotent mesenchymal progenitor C3H10T1/2 cells, preosteoblastic C2C12 cells, and osteoblastic TE-85 cells. Osteogenic activity was determined by measuring the induction of alkaline phosphatase, osteocalcin, and matrix mineralization upon BMP stimulation.

Results: BMP-2, 6, and 9 significantly induced alkaline phosphatase activity in pluripotential C3H10T1/2 cells, while BMP-2, 4, 6, 7, and 9 significantly induced alkaline phosphatase activity in preosteoblastic C2C12 cells. In TE-85 osteoblastic cells, most BMPs (except BMP-3 and 12) were able to induce alkaline phosphatase activity. The results of alkaline phosphatase histochemical staining assays were consistent with those of alkaline phosphatase colorimetric assays. Furthermore, BMP-2, 6, and 9 (as well as BMP-4 and, to a lesser extent, BMP-7) significantly induced osteocalcin expression in C3H10T1/2 cells. In C2C12 cells, osteocalcin expression was strongly induced by BMP-2, 4, 6, 7, and 9. Mineralized nodules were readily detected in C3H10T1/2 cells infected with BMP-2, 6, and 9 (and, to a lesser extent, those infected with BMP-4 and 7).

Conclusions: A comprehensive analysis of the osteogenic activity of fourteen types of BMPs in osteoblastic progenitor cells was conducted. Our results suggest an osteogenic hierarchical model in which BMP-2, 6, and 9 may play an important role in inducing osteoblast differentiation of mesenchymal stem cells. In contrast, most BMPs are able to stimulate osteogenesis in mature osteoblasts.

Clinical Relevance: These findings have implications for the development of effective formulas for bone-healing and spinal fusion. The efficacy of osteogenesis may depend not only on the type of BMP or the combination of BMPs that is used but also on the cell types that are present.

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