Pharmacologic Inhibition of the TGF-β Type I Receptor Kinase Has Anabolic and Anti-Catabolic Effects on Bone

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

doi:10.1371/journal.pone.0005275

Pharmacologic Inhibition of the TGF-β Type I Receptor Kinase Has Anabolic and Anti-Catabolic Effects on Bone

Journal Article · Thu Apr 16 00:00:00 EDT 2009 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0005275· OSTI ID:1627370

Mohammad, Khalid S. ^[1]; Chen, Carol G. ^[2]; Balooch, Guive ^[3]; Stebbins, Elizabeth ^[4]; McKenna, C. Ryan ^[5]; Davis, Holly ^[5]; Niewolna, Maria ^[5]; Peng, Xiang Hong ^[5]; Nguyen, Daniel H. N. ^[2]; Ionova-Martin, Sophi S. ^[4]; Bracey, John W. ^[6]; Hogue, William R. ^[6]; Wong, Darren H. ^[7]; Ritchie, Robert O. ^[3]; Suva, Larry J. ^[6]; Derynck, Rik ^[2]; Guise, Theresa A. ^[5]; Alliston, Tamara ^[2]

University of Virginia, Charlottesville, VA (United States); DOE/OSTI
University of California, San Francisco, CA (United States)
University of California, Berkeley, CA (United States)
Scios, Inc, Fremont, CA (United States)
University of Virginia, Charlottesville, VA (United States)
University of Arkansas, Little Rock, AR (United States)
Scios, Inc, Fremont, CA (United States); Pfizer RTC, Cambridge, MA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health(NIH); Arthritis Foundation; Sandler Family Foundation; Carl Nelson Chair; Stugis Foundation; Aurbach Endowment

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1627370

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 4 Vol. 4; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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