The long-term goal of these studies is to understand the cellular and molecular mechanisms that control bone development and homeostasis. During the past funding period, significant progress has been made in identifying the multiple roles of vascular endothelial growth factor (VEGF) in skeletal development. These roles include serving as chemotactic factor for vascular invasion into cartilage models of future bones, serving as survival factor for chondrocytes in hypoxic regions, promoting matrix production by osteoblasts and chondrocytes and stimulating osteoclast formation and migration. Through the use of conditional targeting techniques for cell-specific inactivation of VEGF and VEGF receptor genes in mice (Aims 1 and 2), the work proposed is aimed at identifying the cellular mechanisms by which VEGF exerts its skeletal functions. Experiments using inducible, conditional targeting strategies to inactivate both VEGF and VEGF receptors are also planned to find out whether VEGF is required for postnatal skeletal growth and homeostasis. In studies of a mouse model for cherubism, a genetic disorder in humans, the investigators seek to identify mechanisms in myeloid cells that are important for regulation of macrophage/osteoclast differentiation. Based on extensive studies of mice in which the most common mutation in cherubism families has been knocked into the mouse gene, the investigators believe that cherubism is a hematopoietic disorder and that mutant myeloid progenitor cells are hyper-responsive to cytokines that stimulate differentiation to macrophages and osteoclasts. Through a combination of in vitro and in vivo studies (Aim 3) the signaling pathways that are affected by the cherubism mutations will be identified. Bone marrow cells from control and cherubism mutant mice will be compared in cell signaling studies of osteoclast formation in vitro. In vivo studies of the mutant mice will test the hypothesis that the mutations in cherubism cause a combination of molecular gain-of-function and loss-of-function effects. The outcomes of the proposed work will provide insights into cellular mechanisms of bone formation and resorption that are altered in skeletal disorders of excess bone formation and inflammatory bone loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR036819-26
Application #
7792325
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tseng, Hung H
Project Start
1985-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
26
Fiscal Year
2010
Total Cost
$585,519
Indirect Cost
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Hu, Kai; Olsen, Bjorn R (2017) Vascular endothelial growth factor control mechanisms in skeletal growth and repair. Dev Dyn 246:227-234
Nagao, Masashi; Hamilton, John L; Kc, Ranjan et al. (2017) Vascular Endothelial Growth Factor in Cartilage Development and Osteoarthritis. Sci Rep 7:13027
Hu, Kai; Olsen, Bjorn R; Besschetnova, Tatiana Y (2017) Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts. Matrix Biol 62:105-114
Hu, Kai; Besschetnova, Tatiana Y; Olsen, Bjorn R (2017) Soluble VEGFR1 reverses BMP2 inhibition of intramembranous ossification during healing of cortical bone defects. J Orthop Res 35:1461-1469
Hu, Kai; Olsen, Bjorn R (2016) The roles of vascular endothelial growth factor in bone repair and regeneration. Bone 91:30-8
Olsen, Bjorn R; Berendsen, Agnes D; Besschetnova, Tatiana Y et al. (2016) Fell-Muir Lecture: Regulatory mechanisms of skeletal and connective tissue development and homeostasis - lessons from studies of human disorders. Int J Exp Pathol 97:296-302
Huang, Wei; Li, Qing; Amiry-Moghaddam, Mahmood et al. (2016) Critical Endothelial Regulation by LRP5 during Retinal Vascular Development. PLoS One 11:e0152833
Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R et al. (2016) VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol 52-54:127-140
Nagao, M; Cheong, C W; Olsen, B R (2016) Col2-Cre and tamoxifen-inducible Col2-CreER target different cell populations in the knee joint. Osteoarthritis Cartilage 24:188-91
Hu, Kai; Olsen, Bjorn R (2016) Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest 126:509-26

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