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PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis

Abstract

Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31hiEmcnhi vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase–positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31hiEmcnhi vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31hiEmcnhi vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31hiEmcnhi vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.

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Figure 1: TRAP+ cell deficient mice exhibit reduced cortical bone.
Figure 2: Preosteoclasts secrete PDGF-BB to induce migration of MSCs and EPCs.
Figure 3: Depletion of PDGF-BB in preosteoclasts reduces CD31hiEmcnhi cell numbers and bone formation.
Figure 4: CTSK inhibitor increases TRAP+ cell PDGF-BB secretion to couple CD31hiEmcnhi vessel formation with bone formation.
Figure 5: Preosteoclast-conditioned medium induces tube formation by MSCs and EPCs via Akt-dependent phosphorylation of FAK.
Figure 6: Increasing PDGF-BB stimulates CD31hiEmcnhi vessel formation and bone formation in ovariectomized mice.

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Acknowledgements

This research was supported by US National Institutes of Health grants DK 057501 and AR 063943 (to X.C.), China National Funds for Distinguished Young Scientists grant 81125006 (to X.L.) and the Merck Investigator-Initiated Studies Program.

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H.X. conceived the ideas for experimental designs, conducted the majority of the experiments, analyzed data and prepared the manuscript. Z.C., L.W., Z.X. and Y.H. maintained mice and collected tissue samples, performed microcomputed tomography analyses, conducted immunohistochemistry and immunofluorescence, conducted cell culture and western blot experiments, and helped with manuscript preparation. L. Xian, C.L., L. Xie and W.C. maintained mice and helped with flow cytometry, cell culture and transwell migration assay. J.C., M.W., G.Z., Q.B., B.Y. and M.P. provided suggestions for the project and critically reviewed the manuscript. T.Q. performed confocal imaging. L.T.D. and J.J.W. provided mouse models. X.L. and E.L. participated in experimental design and helped compose the manuscript. X.C. developed the concept, supervised the project, conceived the experiments and wrote most of the manuscript.

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Correspondence to Xianghang Luo, Eryuan Liao or Xu Cao.

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M.P. and L.T.D. are employees of Merck & Co. They own stocks and stock options from this company.

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Xie, H., Cui, Z., Wang, L. et al. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 20, 1270–1278 (2014). https://doi.org/10.1038/nm.3668

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