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Symposium Leatures


The Roles of Vascular Endothelial Growth Factor-A in Skeletal Development, Homeostasis and Disease


Plenary Lecture

The Roles of Vascular Endothelial Growth Factor-A in Skeletal Development, Homeostasis and Disease

Professor Bjorn Olsen, Harvard Medical School, USA


Based on an evolutionary history going back to the appearance of Eumetazoa, vascular endothelial growth factor-A (VEGF) has multiple functions in skeletal development, growth and repair [1]. During skeletal development, its expression in condensing mesenchymal cells and chondrocytes is required for organization of blood vessels around the skeletal elements. In intramembranous and endochondral bones it is expressed in osteoblastic progenitor cells, regulating their differentiation and stimulating angiogenesis. During endochondral ossification its expression in hypertrophic chondrocytes is also critical for invasion of hematopoietic cells, osteoclasts, osteoblasts and vascular endothelial cells into primary and secondary ossification centers.

These effects of VEGF are based on VEGF receptor-dependent paracrine signaling or on intracellular (intracrine) mechanisms. For example, in the perichondrium of developing limb bones, paracrine VEGF signaling in Osterix (Osx)-positive progenitor cells regulates osteoblast differentiation via stimulating angiogenesis and Indian Hedgehog (Ihh) and β-catenin expression [2]. In craniofacial development, VEGF produced by Osx-positive preosteoblasts stimulates mandibular bone formation, but this is likely via an intracellular mechanism [3]. Strong evidence in favor of an intracellular VEGF mechanism for osteoblast differentiation of bone marrow mesenchymal stromal cells (BMSCs) comes from studies of mice exhibiting postnatal decrease in trabecular bone and increased marrow fat as a result of VEGF deficiency in Osx-positive cells [4]. The balance between osteoblast and adipocyte differentiation of BMSCs is not affected by exogenous VEGF or neutralizing antibodies against VEGF.

VEGF functions are dose-dependent and control mechanisms exist to ensure that VEGF levels are maintained within optimal ranges. Functional changes in such mechanisms are associated with several diseases, from hemangioma in infants to common aging diseases of the eye and of synovial joints. VEGF-production is required for synovial joint development, but VEGF expression in synovial joints of aging individuals promotes the degenerative changes and the associated pain of osteoarthritis [5].

[1] Zelzer E, Olsen BR. Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, and repair. Curr Top Dev Biol 2005;65:169-87.

[2] Duan X, Murata Y, Liu Y, Nicolae C, Olsen BR, Berendsen AD. Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development. Development 2015;142:1984-91.

[3] Duan X, Bradbury SR, Olsen BR, Berendsen AD. VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol 2016, doi: 10.1016/j.matbio.2016.02.005. [Epub ahead of print].

[4] Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R, Ferrara N, Olsen BR. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest 2012;122:3101-13.

[5] Hamilton JL, Nagao M, Levine BR, Chen D, Olsen BR, Im H-J. Targeting VEGF and Its receptors for the treatment of osteoarthritis and associated pain. J Bone Miner Res 2016, 10.1002/jbmr.2828. [Epub ahead of print].


Biography of Professor Bjorn R. Olsen, MD, PhD

Dr. Olsen

Dr. Bjorn R. Olsen, Hersey Professor of Cell Biology at Harvard Medical School and Dean for Research and Professor of Developmental Biology at the Harvard School of Dental Medicine, has made fundamental contributions to extracellular matrix, skeletal and vascular biology. He has received many honors, including honorary degrees from Rutgers Robert Wood Johnson Medical School (New Jersey), University of Oslo (Norway) and Okayama University (Japan), numerous research prizes and awards, and he is a Fellow of the American Association for the Advancement of Science and the American Association of Anatomists.  

He received his MD and PhD degrees from the University of Oslo, Norway, in 1967, where he became a faculty member at the Anatomical lnstitute and conducted molecular studies on the structure of collagen.  In 1971, he came to the United States to work with Dr. Darwin Prockop and joined the faculty at Rutgers Medical School, now Rutgers Robert Wood Johnson Medical School, where he was Professor of Biochemistry from 1976 until he moved to Harvard Medical School in 1985 as Hersey Professor of Anatomy and Cell Biology.

Based on a combination of mouse and human genetics, biochemistry and cell biology, research in his laboratory has uncovered fundamental roles of collagens, transcription factors and receptors that affect not only skeletal development, but also angiogenesis and blood vessel morphogenesis.  Work aimed at understanding the roles of collagenous proteins in tissue development led to the discovery of several novel families of non-fibrillar collagens (known as FACIT collagens, Short-Chain collagens and Multiplexins) and uncovered disease mechanisms in many collagen-based genetic disorders. The discoveries include finding that collagen type X mutations cause dwarfism (Schmid metaphyseal chondrodysplasia) and demonstrating that mutations in collagen types IX and XI are associated with early-onset osteoarthritis in both mice and humans. Furthermore, Dr. Olsen’s research group demonstrated that loss-of-function mutations in collagen type VIII result in corneal dystrophy and showed that ocular defects, including retinal degeneration, are associated with collagen XVIII loss-of-function mutations in a mouse model of the human Knobloch syndrome. The Olsen group was the first to report mutations in the transcription factor HOXD13 in Polysyndactyly and loss-of-function mutations in the transcription factor RUNX2/CBFA1 in Cleidocranial Dysplasia. In mapping of the gene for Osteoporosis Pseudoglioma syndrome, the group also established the basis for subsequent finding of mutations in the Wnt-binding receptor LRP5. Likewise, mapping of the gene for the craniofacial disorder Cherubism led to the identification and characterization of the causative activating mutations in SH3BP2. Furthermore, mapping of the gene for excessive bone formation in Craniometaphyseal Dysplasia led to identification of mutations in the pyrophosphate transporter ANK, and mapping of hypodontia and oligodontia resulted in discovery of mutations in the transcription factors PAX9 and MSX1. In research aimed at uncovering pathogenetic mechanisms of vascular anomalies, the Olsen laboratory discovered that activating mutations in the receptor tyrosine kinase TIE2 in Venous Malformations and mutations/functional polymorphisms in TEM8 (Anthrax toxin receptor 1) and vascular endothelial growth factor receptor 2 (VEGFR2) are associated with the rapid growth of Infantile Hemangioma, the most common tumor of infancy.

By simultaneously addressing questions related to skeletal genetics and development and vascular disease the Olsen laboratory has been able to characterize complex developmental and disease mechanisms at the intersection between skeletal and vascular biology. This has recently led to exciting new insights into the process of endothelial-mesenchymal transition and its contribution to heterotopic bone formation in Fibrodysplasia Ossificans Progressiva, the role of vascular endothelial growth factor in the differentiation of mesenchymal stem cells to osteoblasts and adipocytes and the realization that mouse models of the TEM8-related mechanisms in Infantile Hemangioma are also models of a human syndrome (GAPO) with severe craniofacial (including dental), skeletal, and connective tissue anomalies.