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 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.
Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, USA.
Khalid S
KS
Mohammad
Carol G
CG
Chen
Guive
G
Balooch
Elizabeth
E
Stebbins
C Ryan
CR
McKenna
Holly
H
Davis
Maria
M
Niewolna
Xiang Hong
XH
Peng
Daniel H N
DH
Nguyen
Sophi S
SS
Ionova-Martin
John W
JW
Bracey
William R
WR
Hogue
Darren H
DH
Wong
Robert O
RO
Ritchie
Larry J
LJ
Suva
Rik
R
Derynck
Theresa A
TA
Guise
Tamara
T
Alliston
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D001857:Bone Matrix / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D036224:Receptor, EphB4 / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D050659:Core Binding Factor Alpha 1 Subunit; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C493716:Runx2 protein, mouse; D016212:Transforming Growth Factor beta; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I