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
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Acid Phosphatase / metabolism
- Animals
- Becaplermin
- Cathepsin K / antagonists & inhibitors
- Cathepsin K / metabolism
- Cell Count
- Cell Movement / drug effects
- Culture Media, Conditioned / pharmacology
- Endothelial Cells / cytology
- Endothelial Cells / drug effects
- Endothelial Cells / metabolism
- Female
- Femur / diagnostic imaging
- Femur / drug effects
- Femur / metabolism
- Focal Adhesion Protein-Tyrosine Kinases / metabolism
- Isoenzymes / metabolism
- Mesenchymal Stem Cells / cytology
- Mesenchymal Stem Cells / drug effects
- Mesenchymal Stem Cells / metabolism
- Mice, Inbred C57BL
- Neovascularization, Physiologic* / drug effects
- Osteoclasts / drug effects
- Osteoclasts / enzymology
- Osteoclasts / metabolism*
- Osteogenesis* / drug effects
- Ovariectomy
- Phosphorylation / drug effects
- Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
- Protease Inhibitors / pharmacology
- Proto-Oncogene Proteins c-akt / metabolism
- Proto-Oncogene Proteins c-sis / metabolism*
- Tartrate-Resistant Acid Phosphatase
- X-Ray Microtomography
Substances
- Culture Media, Conditioned
- Isoenzymes
- Platelet Endothelial Cell Adhesion Molecule-1
- Protease Inhibitors
- Proto-Oncogene Proteins c-sis
- Becaplermin
- Focal Adhesion Protein-Tyrosine Kinases
- Proto-Oncogene Proteins c-akt
- Acid Phosphatase
- Tartrate-Resistant Acid Phosphatase
- Cathepsin K
- Ctsk protein, mouse