Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro

I. R. Garrett, D. Chen, G. Gutierrez, M. Zhao, A. Escobedo, G. Rossini, Stephen E Harris, W. Gallwitz, K. B. Kim, S. Hu, C. M. Crews, G. R. Mundy

Research output: Contribution to journalArticle

253 Citations (Scopus)

Abstract

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic β subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and -4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation and that inhibition of specific components of this system may be useful therapeutically in common diseases of bone loss.

Original languageEnglish (US)
Pages (from-to)1771-1782
Number of pages12
JournalJournal of Clinical Investigation
Volume111
Issue number11
StatePublished - Jun 2003
Externally publishedYes

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Proteasome Inhibitors
Osteoblasts
Osteogenesis
Proteasome Endopeptidase Complex
Ubiquitin
Bone Morphogenetic Protein 6
Bone Morphogenetic Protein 4
Bone and Bones
Bone Morphogenetic Protein 2
Bone Diseases
Organ Culture Techniques
Drosophila
In Vitro Techniques
Rodentia
Catalytic Domain
Gene Expression
Messenger RNA
Genes
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Garrett, I. R., Chen, D., Gutierrez, G., Zhao, M., Escobedo, A., Rossini, G., ... Mundy, G. R. (2003). Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. Journal of Clinical Investigation, 111(11), 1771-1782.

Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. / Garrett, I. R.; Chen, D.; Gutierrez, G.; Zhao, M.; Escobedo, A.; Rossini, G.; Harris, Stephen E; Gallwitz, W.; Kim, K. B.; Hu, S.; Crews, C. M.; Mundy, G. R.

In: Journal of Clinical Investigation, Vol. 111, No. 11, 06.2003, p. 1771-1782.

Research output: Contribution to journalArticle

Garrett, IR, Chen, D, Gutierrez, G, Zhao, M, Escobedo, A, Rossini, G, Harris, SE, Gallwitz, W, Kim, KB, Hu, S, Crews, CM & Mundy, GR 2003, 'Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro', Journal of Clinical Investigation, vol. 111, no. 11, pp. 1771-1782.
Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. Journal of Clinical Investigation. 2003 Jun;111(11):1771-1782.
Garrett, I. R. ; Chen, D. ; Gutierrez, G. ; Zhao, M. ; Escobedo, A. ; Rossini, G. ; Harris, Stephen E ; Gallwitz, W. ; Kim, K. B. ; Hu, S. ; Crews, C. M. ; Mundy, G. R. / Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 11. pp. 1771-1782.
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