TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation.
Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-beta1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-beta1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-beta1 in the bone marrow. Treatment with a TGF-beta type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-beta1 functions to couple bone resorption and formation, modulation of TGF-beta1 activity could be an effective treatment for bone remodeling diseases.
Tang
Yi
Y
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Wu
Xiangwei
X
Lei
Weiqi
W
Pang
Lijuan
L
Wan
Chao
C
Shi
Zhenqi
Z
Zhao
Ling
L
Nagy
Timothy R
TR
Peng
Xinyu
X
Hu
Junbo
J
Feng
Xu
X
Van Hul
Wim
W
Wan
Mei
M
Cao
Xu
X
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016723:Bone Remodeling / Q000502:physiology; D001862:Bone Resorption / Q000503:physiopathology*; D003966:Camurati-Engelmann Syndrome / Q000209:etiology; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I