Pharmacologic inhibition of the TGF-β type I receptor kinase has anabolic and anti-catabolic effects on bone

Khalid S. Mohammad, Carol G. Chen, Guive Balooch, Elizabeth Stebbins, C. Ryan McKenna, Holly Davis, Maria Niewolna, Xiang Hong Peng, Daniel H.N. Nguyen, Sophi S. Ionova-Martin, John W. Bracey, William R. Hogue, Darren H. Wong, Robert O. Ritchie, Larry J. Suva, Rik Derynck, Theresa A. Guise, Tamara Alliston

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-β has been shown to developmentally regulate bone mass and bone matrix properties. However, the mechanisms that control postnatal skeletal integrity in a dynamic biological and mechanical environment are distinct from those that regulate bone development. In addition, despite advances in understanding the roles of TGF-β signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-β signaling on bone remain unclear. To examine the role of TGF-β in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-β type I receptor (TβRI) kinase on bone mass, architecture and material properties. Inhibition of TβRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TβRI inhibitors achieved these effects by increasing osteoblast differentiation and bone formation, while reducing osteoclast differentiation and bone resorption. Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation. Through these anabolic and anti-catabolic effects, TβRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TβRI inhibitors may be effective in treating conditions of skeletal fragility.

Original languageEnglish (US)
Article numbere5275
JournalPLoS ONE
Volume4
Issue number4
DOIs
StatePublished - Apr 16 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Mohammad, K. S., Chen, C. G., Balooch, G., Stebbins, E., McKenna, C. R., Davis, H., Niewolna, M., Peng, X. H., Nguyen, D. H. N., Ionova-Martin, S. S., Bracey, J. W., Hogue, W. R., Wong, D. H., Ritchie, R. O., Suva, L. J., Derynck, R., Guise, T. A., & Alliston, T. (2009). Pharmacologic inhibition of the TGF-β type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS ONE, 4(4), [e5275]. https://doi.org/10.1371/journal.pone.0005275