This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhao, M.
Right arrow Articles by Mundy, G. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhao, M.
Right arrow Articles by Mundy, G. R.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2009, p. 1291-1305, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01566-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Inhibition of Microtubule Assembly in Osteoblasts Stimulates Bone Morphogenetic Protein 2 Expression and Bone Formation through Transcription Factor Gli2{triangledown}

Ming Zhao,1* Seon-Yle Ko,1 Jin-Hua Liu,1 Di Chen,2 Jianghong Zhang,1 Baolin Wang,5 Stephen E. Harris,3 Babatunde O. Oyajobi,4 and Gregory R. Mundy1

Vanderbilt Center for Bone Biology, Department of Medicine/Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232,1 Department of Orthopedics, University of Rochester Medical Center, Rochester, New York 14642,2 Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229,3 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229,4 Departments of Genetic Medicine and Cell & Developmental Biology, Weill Medical College of Cornell University, New York, New York 100215

Received 7 October 2008/ Accepted 14 December 2008

Bone morphogenetic protein 2 (BMP-2) is essential for postnatal bone formation and fracture repair. By screening chemical libraries for BMP-2 mimics using a cell-based assay, we identified inhibitors of microtubule assembly as stimulators of BMP-2 transcription. These microtubule inhibitors increased osteoblast differentiation in vitro, stimulated periosteal bone formation when injected locally over murine calvaria, and enhanced trabecular bone formation when administered systemically in vivo. To explore molecular mechanisms mediating these responses, we examined effects of microtubule inhibitors on the hedgehog (Hh) pathway, since this pathway is known to regulate BMP-2 transcription in osteoblasts and microtubules have been shown to be involved in Hh signaling in Drosophila. Here we show that in osteoblasts, inhibition of microtubule assembly increased cytoplasmic levels and transcriptional activity of Gli2, a transcriptional mediator of Hh signaling that we have previously shown to enhance BMP-2 expression in osteoblasts (M. Zhao et al., Mol. Cell. Biol. 26:6197-6208, 2006). Microtubule inhibition blocked β-TrCP-mediated proteasomal processing of Gli2 in osteoblasts. In summary, inhibition of microtubule assembly enhances BMP-2 gene transcription and subsequent bone formation, in part, through inhibiting proteasomal processing of Gli2 and increasing intracellular Gli2 concentrations.

* Corresponding author. Present address: Department of Basic Medical Sciences, School of Medicine, University of Missouri—Kansas City, 2411 Holmes St., Rm. M3-121, Kansas City, MO 64108. Phone: (816) 235-5712. Fax: (816) 235-6517. E-mail: zhaomin{at}umkc.edu

{triangledown} Published ahead of print on 22 December 2008.

Molecular and Cellular Biology, March 2009, p. 1291-1305, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01566-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»