Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling.
The anabolic effects of parathyroid hormone (PTH) on bone formation are impaired by concurrent use of antiresorptive drugs. We found that the release of active transforming growth factor (TGF)-β1 during osteoclastic bone resorption is inhibited by alendronate. We showed that mouse Sca-1-positive (Sca-1(+)) bone marrow stromal cells are a skeletal stem cell subset, which are recruited to bone remodeling sites by active TGF-β1 in response to bone resorption. Alendronate inhibits the release of active TGF-β1 and the recruitment of Sca-1(+) skeletal stem cells for the bone formation. The observation was validated in a Tgfb1(-/-) mouse model, in which the anabolic effects of PTH on bone formation are diminished. The PTH-stimulated recruitment of injected mouse Sca-1(+) cells to the resorptive sites was inhibited by alendronate. Thus, inhibition of active TGF-β1 release by alendronate reduces the recruitment of Sca-1(+) skeletal stem cells and impairs the anabolic action of PTH in bone.
Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Xiangwei
X
Wu
Lijuan
L
Pang
Weiqi
W
Lei
William
W
Lu
Jun
J
Li
Zhaoyang
Z
Li
Frank J
FJ
Frassica
Xueling
X
Chen
Mei
M
Wan
Xu
X
Cao
D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D000950:Antigens, Ly; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones; D002454:Cell Differentiation; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D008565:Membrane Proteins; D008660:Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*
D000950:Antigens, Ly; D050071:Bone Density Conservation Agents; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D019386:Alendronate