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Scientific Article   |    
Osteogenic Activity of the Fourteen Types of Human Bone Morphogenetic Proteins (BMPs)
Hongwei Cheng, MD, PhD; Wei Jiang, BA; Frank M. Phillips, MD; 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
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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@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).

J Bone Joint Surg Am, 2003 Aug 01;85(8):1544-1552
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Abstract

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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    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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    Tong-Chuan He, M.D., Ph.D.
    Posted on November 24, 2003
    Dr He, et al, respond to Dr Trieb
    University of Chicago Medical Center, Chicago, IL

    We thank Dr. Trieb for identifying this error. The correct statement should read “However, all BMPs except BMP-3 and 12 were shown to induce alkaline phosphatase activity in TE-85 cells”. In several independent experiments, we found that the TE-85 cells exhibited a base line alkaline phosphatase activity, and the BMP-mediated induction of alkaline phosphatase activity was at least one order of magnitude lower than that in C2C12 and C3H10T1/2 cells.

    In further reviewing our paper, we found an additional error in Fig. 2 (p.1547). According to our data, BMP-2, 4, 6, 7, and 9 were shown to induce the osteogenic differentiation of C2C12 cells. In the publication, BMP-6 was accidentally omitted.

    Hongwei Cheng, MD, PhD Wei Jiang, BA Frank M. Phillips, MD 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.

    Klemens Trieb
    Posted on October 27, 2003
    Osteogenic Activity of Human BMP's
    NULL

    TO THE EDITOR:

    The paper, "Osteogenic activity of the fourteen types of human bone morphogenetic proteins", by Cheng et al. provides important information about the osteogenic potential of different BMPs.

    On page 1548 (Line 9 from the bottom, left column) the authors write that BMP 3 and 10 do not stimulate alkaline phosphatase activity in TE-85 cells, but in Figure 1C, this seems to be true for BMP-3 and 12. Could the authors clarify this detail of their excellent paper?

    Klemens Trieb, M.D.: Department of Orthopaedic Surgery, University of Vienna, 1090 Vienna, Austria

    Univ.Prof. Dr. Klemens Trieb Department of Orthopedics University Vienna Währingergürtel 18-20 A-1090 Vienna, Austria Tel.: +43-1-40400-4070 FAX: +43-1-40400-4077 E-mail: Klemens.Trieb@akh-wien.ac.at

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