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      PDGF-BB secreted by preosteoclasts induces CD31 hiEmcn hi vessel subtype in coupling osteogenesis

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          Abstract

          Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study shows that the specific vessel subtype, strongly positive for CD31 and Endomucin (CD31 hiEmcn hi), couples angiogenesis and osteogenesis. We found that preosteoclasts secrete platelet derived growth factor-BB (PDGF-BB), inducing CD31 hiEmcn hi vessels during bone modeling and remodeling. Mice with depletion of PDGF-BB in tartrate-resistant acid phosphatase positive (TRAP +) cell lineage ( Pdgfb –/–) show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and CD31 hiEmcn hi vessels compared to wild-type mice. In the ovariectomized (OVX) osteoporotic mouse model, concentrations of serum and bone marrow PDGF-BB and CD31 hiEmcn hi vessels are significantly decreased. Inhibition of cathepsin K (CTSK) increases preosteoclast numbers, resulting in higher levels of PDGF-BB to stimulate CD31 hiEmcn hi vessels and bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a novel therapeutic target for osteoporosis to promote angiogenesis for bone formation.

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          Most cited references 74

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          Molecular mechanisms and clinical applications of angiogenesis.

          Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
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            Bone quality--the material and structural basis of bone strength and fragility.

             Ego Seeman,  D Delmas (2006)
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              Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone.

              The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                25 July 2014
                05 October 2014
                November 2014
                01 May 2015
                : 20
                : 11
                : 1270-1278
                Affiliations
                [1 ]Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
                [2 ]Institute of Endocrinology and Metabolism, Second Xiangya Hospital
                [3 ]Department of Orthopedics and Trauma, Nan Fang Hospital, Southern Medical University, Guangzhou, Cuangdong, China
                [4 ]Xiangya Hospital, Central South University, Changsha, Hunan, China
                [5 ]Bone Biology, Merck Research Laboratories, West Point, PA, USA
                [6 ]Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
                Author notes
                [* ]Corresponding authors: Xu Cao Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 231, Baltimore, Maryland 21205, USA. xcao11@ 123456jhmi.edu Tel.: 410-502-6440. Fax: 410-502-6414 Or Eryuan Liao ( eyliao@ 12345621cn.com ) or Xianghang Luo ( xianghangluo@ 123456hotmail.com ) Institute of Endocrinology and Metabolism, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China
                Article
                NIHMS614938
                10.1038/nm.3668
                4224644
                25282358
                Categories
                Article

                Medicine

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