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

Hui Xie; Zhuang Cui; Long Wang; Zhuying Xia; Yin Hu; Lingling Xian; Changjun Li; Liang Xie; Janet Crane; Mei Wan; Gehua Zhen; Qin Bian; Bin Yu; Weizhong Chang; Tao Qiu; Maureen Pickarski; Le Thi Duong; Jolene J Windle; Xianghang Luo; Eryuan Liao; Xu Cao

doi:10.1038/nm.3668

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

Nat Med. 2014 Nov;20(11):1270-8. doi: 10.1038/nm.3668. Epub 2014 Oct 5.

Authors

Hui Xie¹, Zhuang Cui², Long Wang³, Zhuying Xia¹, Yin Hu¹, Lingling Xian⁴, Changjun Li⁴, Liang Xie⁴, Janet Crane⁴, Mei Wan⁴, Gehua Zhen⁴, Qin Bian⁴, Bin Yu⁵, Weizhong Chang⁴, Tao Qiu⁴, Maureen Pickarski⁶, Le Thi Duong⁶, Jolene J Windle⁷, Xianghang Luo⁸, Eryuan Liao⁸, Xu Cao⁴

Affiliations

¹ 1] Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Institute of Endocrinology and Metabolism, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
² 1] Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Orthopedics and Trauma, Nan Fang Hospital, Southern Medical University, Guangzhou, Cuangdong, China.
³ 1] Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁵ Department of Orthopedics and Trauma, Nan Fang Hospital, Southern Medical University, Guangzhou, Cuangdong, China.
⁶ Bone Biology, Merck Research Laboratories, West Point, Pennsylvania, USA.
⁷ Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
⁸ Institute of Endocrinology and Metabolism, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

PMID: 25282358
PMCID: PMC4224644
DOI: 10.1038/nm.3668

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding