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

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...

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Bibliographic Details
Published in:PloS one 2009-04, Vol.4 (4), p.e5275-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: Article
Language:English
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
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0005275