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 (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) 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 CD31(hi)Emcn(hi) 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 CD31(hi)Emcn(hi) 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 CD31(hi)Emcn(hi) 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Phosphatase / metabolism
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Animals
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Becaplermin
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Cathepsin K / antagonists & inhibitors
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Cathepsin K / metabolism
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Cell Count
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Cell Movement / drug effects
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Culture Media, Conditioned / pharmacology
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Female
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Femur / diagnostic imaging
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Femur / drug effects
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Femur / metabolism
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Focal Adhesion Protein-Tyrosine Kinases / metabolism
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Isoenzymes / metabolism
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mice, Inbred C57BL
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Neovascularization, Physiologic* / drug effects
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Osteoclasts / drug effects
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Osteoclasts / enzymology
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Osteoclasts / metabolism*
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Osteogenesis* / drug effects
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Ovariectomy
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Phosphorylation / drug effects
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Protease Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-sis / metabolism*
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Tartrate-Resistant Acid Phosphatase
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X-Ray Microtomography
Substances
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Culture Media, Conditioned
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Isoenzymes
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Platelet Endothelial Cell Adhesion Molecule-1
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Protease Inhibitors
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Proto-Oncogene Proteins c-sis
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Becaplermin
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Focal Adhesion Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-akt
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Cathepsin K
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Ctsk protein, mouse