Inhibition of Sca-1-Positive Skeletal Stem Cell Recruitment by Alendronate Blunts the Anabolic Effects of Parathyroid Hormone on Bone Remodeling

SummaryThe 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.

► Effects of alendronate and PTH in bone formation are not additive ► Alendrondate inhibits PTH-induced recruitment of bone marrow stromal cells ► TGF-β1 is needed for PTH-induced bone formation ► TGF-β1 recruits bone marrow stromal cells, and alendronate inhibits its release