The Journal of Bone and Joint Surgery (American). 2008;90:14-18.
doi:10.2106/JBJS.G.01109
© 2008 The Journal of Bone and Joint Surgery, Inc.
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BMP4 Is Dispensable for Skeletogenesis and Fracture-Healing in the Limb

Kunikazu Tsuji, PhD, Karen Cox, BA, Amitabha Bandyopadhyay, PhD, Brian D. Harfe, PhD, Clifford J. Tabin, PhD and Vicki Rosen, PhD

Corresponding author:
Vicki Rosen, PhD
Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115.
E-mail address: vicki_rosen{at}hsdm.harvard.edu

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the National Institutes of Health and the Musculoskeletal Transplant Foundation. Neither they nor a member of their immediate families 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, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

NOTE: This work was supported by a grant from the Musculoskeletal Transplant Foundation (to V.R.) and funds from Harvard School of Dental Medicine and the Forsyth Institute (to V.R.).

Bone morphogenetic proteins (BMPs) are potent bone-forming agents that show clinical efficacy when used in patients to augment fracture-healing. Molecular profiling of fracture tissues has confirmed that BMPs 2, 3, 4, 5, 6, and 7 are expressed during the healing process, and it has identified a specific temporal pattern of expression for each BMP. Mice engineered to express increased levels of BMP antagonists have fragile bones that are prone to fracture, suggesting that BMPs not only mediate bone formation in the context of repair, but may also have a role in maintaining adult bone. In this study, mice carrying floxed Bmp4 alleles were bred with Prx1-cre transgenic mice to establish limb-specific removal of Bmp4. We compared these mice to mice in which Bmp2 was specifically deleted from the limb, and we then assessed limb skeletogenesis and fracture-healing. Limb skeletogenesis occurs normally in the absence of BMP4, and postnatal skeletal growth was also unaffected when BMP4 was removed. When mice lacking BMP4 were challenged to repair fractures, they were able to mount a successful healing response. We concluded that BMP4 is not required for formation of the limb skeleton and that femur fracture-healing is unaffected by the absence of BMP4. This study demonstrates that BMP4 is not required for bone formation and function in the limb, giving us further insights into the utility of recombinant human BMPs as therapeutic agents.


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