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J. Biol. Chem., Vol. 282, Issue 36, 26450-26459, September 7, 2007

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Noggin Suppression Enhances in Vitro Osteogenesis and Accelerates in Vivo Bone Formation^*

Derrick C. Wan, Jason H. Pomerantz, Lisa J. Brunet^¶, Jae-Beom Kim, Yu-Fen Chou^||, Benjamin M. Wu^||, Richard Harland^¶, Helen M. Blau^¶, and Michael T. Longaker¹

From the Department of Surgery and the Baxter Laboratory in Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, the ^¶Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, California 94720, and the ^||Departments of Bioengineering and Materials Science and Engineering, University of California, Los Angeles, Los Angeles, California 90095

Several investigations have demonstrated a precise balance to exist between bone morphogenetic protein (BMP) agonists and antagonists, dictating BMP signaling and osteogenesis. We report a novel approach to manipulate BMP activity through a down-regulation of the potent BMP antagonist Noggin, and examined the effects on the bone forming capacity of osteoblasts. Reduction of noggin enhanced BMP signaling and in vitro osteoblast bone formation, as demonstrated by both gene expression profiles and histological staining. The effects of noggin suppression on in vivo bone formation were also investigated using critical-sized calvarial defects in mice repaired with noggin-suppressed osteoblasts. Radiographic and histological analyses revealed significantly more bone regeneration at 2 and 4 weeks post-injury. These findings strongly support the concept of enhanced osteogenesis through a down-regulation in Noggin and suggest a novel approach to clinically accelerate bone formation, potentially allowing for earlier mobilization of patients following skeletal injury or surgical resection.

Received for publication, April 18, 2007 , and in revised form, July 2, 2007.

^* This work was supported by National Institutes of Health Grants R01 DE14526 and R01 DE13194 and the Oak Foundation (to M. T. L.), National Institutes of Health Grant R01 GM49346 (to R. M. H.), an NRSA Grant (to J. H. P.), and the Ethicon-SUS Research Fellowship (to D. C. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: 257 Campus Dr., Stanford, CA 94305-5148. Fax: 650-736-1705; E-mail: longaker{at}stanford.edu.

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