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

• Published in: PloS one Vol. 4; no. 4; p. e5275
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.04.2009; Public Library of Science (PLoS)
• Subjects: Animals; Architecture; BASIC BIOLOGICAL SCIENCES; Biocompatibility; Biomedical materials; Bone (trabecular); Bone and Bones - anatomy & histology; Bone and Bones - cytology; Bone and Bones - metabolism; Bone Density - drug effects; Bone Development - drug effects; bone fracture; Bone growth; Bone marrow; Bone mass; Bone matrix; Bone Matrix - metabolism; Bone resorption; Bone Resorption - metabolism; Bone strength; Bones; Calcification, Physiologic - drug effects; Cancellous bone; Cbfa-1 protein; Cell Biology/Cell Signaling; Cell Differentiation - drug effects; Core Binding Factor Alpha 1 Subunit - metabolism; Diabetes and Endocrinology/Bone and Mineral Metabolism; Differentiation; Electric power; Endocrinology; Extracellular matrix; Female; femur; Fracture toughness; Fragility; Genetic engineering; Growth factors; Hormones; Inhibition; Inhibitors; Internal medicine; Laboratories; Male; Materials science; Mechanical properties; Medicine; Mice; Mice, Inbred C57BL; osteoblast differentiation; Osteoblastogenesis; Osteoblasts; Osteoblasts - metabolism; Osteoclastogenesis; Osteoclasts; Osteoclasts - metabolism; Osteogenesis; Pharmacology; Physiology/Muscle and Connective Tissue; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Receptor, EphB4 - metabolism; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; signal inhibition; Skeleton; Studies; Surgery; Test methods; Transforming Growth Factor beta - metabolism; Vertebrae; San Francisco California; California; United States > US; Arkansas; Virginia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005275

During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-beta 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-beta signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-beta signaling on bone remain unclear. To examine the role of TGF-beta in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-beta type I receptor (TbetaRI) kinase on bone mass, architecture and material properties. Inhibition of TbetaRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TbetaRI 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, TbetaRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.