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Angiogenic factors in bone local environment

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Abstract

Angiogenesis plays an important role in physiological bone growth and remodeling, as well as in pathological bone disorders such as fracture repair, osteonecrosis, and tumor metastasis to bone. Vascularization is required for bone remodeling along the endosteal surface of trabecular bone or Haversian canals within the cortical bone, as well as the homeostasis of the cartilage-subchondral bone interface. Angiogenic factors, produced by cells from a basic multicellular unit (BMU) within the bone remodeling compartment (BRC) regulate local endothelial cells and pericytes. In this review, we discuss the expression and function of angiogenic factors produced by osteoclasts, osteoblasts and osteocytes in the BMU and in the cartilage-subchondral bone interface. These include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), BMP7, receptor activator of NF-κB ligand (RANKL) and epidermal growth factor (EGF)-like family members. In addition, the expression of EGFL2, EGFL3, EGFL5, EGFL6, EGFL7, EGFL8 and EGFL9 has been recently identified in the bone local environment, giving important clues to their possible roles in angiogenesis. Understanding the role of angiogenic factors in the bone microenvironment may help to develop novel therapeutic targets and diagnostic biomarkers for bone and joint diseases, such as osteoporosis, osteonecrosis, osteoarthritis, and delayed fracture healing.

Introduction

Bone is a connective tissue that is characterized by a mixture of organic collagen and inorganic hydroxyapatite. It continuously undergoes remodeling to maintain skeletal size, shape and structural integrity. Angiogenesis plays a pivotal role during bone remodeling. Vasculature that supplies oxygen, nutrients, hormones, cytokines, as well as osteoblast and osteoclast precursor cells, is important in bone remodeling. The bone remodeling compartment (BRC), an anatomical structure identified at the site of bone remodeling, is closely associated with blood vessels. The initiation of sprouting angiogenesis from existing bone vasculature toward the BRC and maintenance of newly formed vessels could be regulated by osteoclasts, osteoblasts, and osteocytes. Cumulative evidence shows that bone cells are capable of producing angiogenic factors, while the endothelium could contribute osteogenic factors, indicative of intercellular communication between bone cells and endothelial cells. In recent years, a role for EGF-like family members has been identified in bone biology, including factors such as EGF, heparin binding-EGF (HB-EGF), transforming growth factor-alpha (TGFα), betacellulin (BTC), and EGF-like protein 6 (EGFL6). Interestingly, the EGF-like family also plays an important role in angiogenesis. This review aims to provide a summary focusing on the expression of angiogenic factors in the bone microenvironment, and the complex inter-relationship between angiogenesis and osteogenesis.

Section snippets

Bone remodeling and angiogenesis

Bone is a living tissue and, in order to maintain mechanical integrity, it is continuously undergoing remodeling [1]. Bone remodeling is accomplished by two important steps, bone resorption followed by new bone formation. Osteoclasts are the principal cells in bone resorption. Osteoclasts remove old and damaged bone by attachment to the bone surface and degradation of bone matrix. The resorption area is then filled with osteoblasts, which play an important role in bone mineralization and

The bone remodeling compartment: a vascularized structure at the site of remodeling

Bone remodeling takes place in a specialized vascular structure called the BRC [51]. The BRC is a narrow sinus on the bone surface, which is formed between the bone marrow and the remodeling surface. When the bone remodeling process is initiated the lining cells of the endosteal membrane detach from the bone by disruption of the gap junctions to form the roof of the BRC [5], [52]. It is well accepted that capillaries are associated with the BRC. There are two hypothetical models of capillary

Angiogenic factors in bone remodeling compartment

Locally produced angiogenic factors in the bone mircoenvironment are critical for bone remodeling. Osteoclasts, osteoblasts, and osteocytes, three major cells in bone remodeling, could produce angiogenic factors which influence the directional angiogenesis and maintain the blood supply above BRC canopies during the entire remodeling cycle. Previous reviews identify a myriad of molecules produced by osteoblasts and osteoclasts that could regulate endothelial cell activities, including

Conclusion

Vasculature of bone is important for skeletal development during the embryonic stage, postnatal growth, and bone remodeling. However, the role of angiogenesis and local angiogenic factors produced in the BRC remain to be fully elucidated. Formation of blood vessels near the BRC canopy is necessary for the bone remodeling process. The directional sprouting of endothelial cells toward the BRC could be driven by angiogenic factors expressed within the BRC. Interestingly, evidence shows that

Disclosure

All authors state that they have no conflicts of interest.

Acknowledgments

This work was funded in part by National Health and Medical Research Council of Australia, Western Australia Medical & Health Research Infrastructure Fund, and a grant from the National Natural Science Foundation of China (NSFC, no. 81228013). Professor Vicki Rosen was an Australia-Harvard Fellow to the School of Pathology and Laboratory Medicine, the University of Western Australia in 2012.

Dr. Shek Man Chim is a research associate in Molecular Laboratory, School of Pathology and Laboratory Medicine at The University of Western Australia. He received his BSc (Hons) in Biology from the Hong Kong University of Science and Technology in 2004, and PhD from the University of Western Australia in 2009. His research interest is to understand the intercellular communication between bone cells and endothelial cells, which will aid in advancing our knowledge of bone remodeling and

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    Dr. Shek Man Chim is a research associate in Molecular Laboratory, School of Pathology and Laboratory Medicine at The University of Western Australia. He received his BSc (Hons) in Biology from the Hong Kong University of Science and Technology in 2004, and PhD from the University of Western Australia in 2009. His research interest is to understand the intercellular communication between bone cells and endothelial cells, which will aid in advancing our knowledge of bone remodeling and angiogenesis, and may facilitate to design novel therapeutic strategies for the treatment of disease.

    Dr. Jennifer Tickner is a Postdoctoral Research Associate in the Cell Signalling Group, based at the University of Western Australia. She graduated from the University of Western Australia with 1st class honours in microbiology and subsequently obtained her PhD in Anatomy and Developmental Biology from University College London in 2006. Her doctoral work was completed in the research group of Prof. Tim Arnett, studying the effects of oxygen tension on bone cells. She has published several papers on the effects of physiological factors on bone cell formation and activity, and a review on signalling pathways in osteoclasts. She is currently working on phenotypic and mechanistic analysis of ENU-mutagenised mouse models to identify novel regulators of bone homeostasis.

    Siu To Chow received his BSc in Molecular Medicine and Biochemistry and Master of Infectious Disease in School of Pathology and Laboratory Medicine at the University of Western Australia. He was involved in research projects investigating novel molecules secreted by osteoblasts and osteoclasts which have potential to regulate angiogenesis and bone homeostasis via paracrine/autocrine mechanism.

    Vincent Kuek is a PhD student in Molecular Laboratory, School of Pathology and Laboratory Medicine at The University of Western Australia (UWA). He completed his Bsc (Hons) in Microbiology at UWA. His research project focuses on the discovery of genes and their mechanisms involved in the intercellular crosstalk between osteoblasts, osteoclasts and endothelial cells, which may potentially lead to the development of new therapeutic treatments and improved treatments for bone diseases.

    Dr. Baosheng Guo is the Postdoctoral Research Fellow of the Hong Kong Baptist University. He was graduated from the Hebei North University, Hebei, China and perused his Bachelor Degree of Medicine in 2005. Then, he began his postgraduate research project of Master Degree at the Shanghai University of Chinese Medicine, Shanghai, China and the Hong Kong Polytechnic University, Hong Kong. He finished his PhD study at Department of Orthopaedics & Traumatology of the Chinese University of Hong Kong in 2012. He previously worked as resident at the Luo Yang Orthopeadic & Traumatology Hospital in 2006 and research assistant at Department of Rehabilitation Sciences of the Hong Kong Polytechnic University, Hong Kong from 2008 to 2009. Dr. Baosheng Guo has the technical expertise on bone biomechanics, bone bioimaging and bone biology and focused research study on muscle atrophy as well as RNAi-based or phytotherapy-based translational research in osteoporosis. Relate research work has been published on PloS One, Nature Medicine and Bone.

    Prof. Ge Zhang is the associate professor of the Hong Kong Baptist University and the author of over 106 peer-reviewed papers on RNAi-based or phytotherapy-based translational research, targeted delivery in osteoporosis, osteonecrosis, osteoarthritis, rheumatoid arthritis and facture repair. He was educated at the Shanghai University of Chinese Medicine, Shanghai, China and got the Doctor Degree of Medicine in 1995. Then, he started his research career at the Institute of Orthopaedics & Traumatology, Shanghai University of Chinese Medicine, China in 1997 and finished his PhD project from 2000 to 2003. Then, he worked as Postdoctoral Research Fellow at Department of Orthopaedics & Traumatology of the Chinese University of Hong Kong from 2004 to 2007. In 2007, he was the Research Assistant Professor of the Chinese University of Hong Kong. In 2012, Prof. Ge Zhang was appointed as Associate Professor of the Hong Kong Baptist University. Prof. Ge Zhang has comprehensive expertise on bone bioimaging, bone biology and bone biomechanics and interested in RNAi-based or phytotherapy-based translational research on joint and musculoskeletal diseases. The research work was published on over 106 peer-reviewed journals, such as Nature Medicine, Arthritis & Rheumatism, Journal of Bone and Mineral Research and Bone.

    Prof. Vicki Rosen arrived at Harvard School of Dental Medicine (HSDM) by way of industry, having spent the majority of her research career as a scientist at Genetics Institute, a biotechnology company, where she was part of a research team that identified the bone morphogenetic protein (BMP) genes in 1988. She became a professor in the Faculty of Medicine in 2001, and chair of the Department of Developmental Biology at HSDM in 2005. Prof. Rosen's lab studies the physiological roles that BMPs play in the development, maintenance, and repair of musculoskeletal tissues (bone, cartilage, tendon, ligament, meniscus, muscle) using molecular, cellular, and genetic approaches in a variety of model systems. Prof. Rosen believes that enhancing our current understanding of BMP biology will lead to the development of novel strategies for repair and regeneration of individual components of the musculoskeletal system, and also will provide new models for examining the complex tissue interactions that are required for its function.

    Prof. Erber graduated in Medicine with 1st class honours from the University of Sydney. She undertook her Haematology training at the Royal North Shore Hospital of Sydney and the University of Oxford (as a Rhodes Scholar) where she undertook research leading to Doctorate of Philosophy. She has held Haematologist posts at Royal Perth Hospital, PathCentre, and most recently Addenbrooke's Hospital in Cambridge. She took up her current appointment as Chair and Head of the School of Pathology and Laboratory Medicine at the University of Western Australia in May 2011. Throughout her professional career Prof. Erber's major interest has been the adoption of new cutting-edge technologies, translating these into diagnostic pathology practice, especially in the field of haematological malignancies. She has more than 140 publications in peer-reviewed journals and published 3 books.

    Prof. Jiake Xu is Winthrop Professor and Head of Molecular Laboratory in the School of Pathology and Laboratory Medicine at the University of Western Australia (UWA). He is also a founding Fellow, Faculty of Science, the Royal College of Pathologists of Australia, and has been appointed the President-elect of the Australian and New Zealand Orthopaedic Research Society (ANZORS). He finished his medical training in Guangzhou Medical College in China in 1985. After completing his PhD studies at UWA in 1994, he carried out his postdoctoral research at Stanford University from 1994 to 1998. He returned to UWA in 1998, and has since undertaken research and teaching in the Schools of Surgery and Pathology and Laboratory Medicine. His current research activities are focused on gene discovery, molecular mechanisms of osteoclast functions and the intercellular communication between osteoclasts and osteoblasts, which have significant implication in bone diseases; including osteoporosis, Paget's disease of bone and malignancy-related osteolysis.

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