The long-term goal of these studies is to understand cellular and molecular mechanisms that control bone development and homeostasis. Previous accomplishments range from identification of extracellular matrix molecules, transcription factors and receptors/signaling molecules with critical functions in skeletal tissues to discovery of diseases caused by mutations in their genes. During the past funding period, mice with reduced expression of vascular endothelial growth factor (VEGF) in osteoblast precursor cells were found to have osteoporosis-like skeletons with reduced bone mass and increased bone marrow fat. To characterize the mechanisms by which VEGF regulates osteoblast and adipocyte fates in mesenchymal stem cells during bone homeostasis, extensive analyses of VEGF-dependent processes in vivo and in cultures of mesenchymal stem cells are now proposed. The experiments, based on data suggesting that VEGF controls osteoblast and adipocyte formation via unconventional, intracrine, mechanisms, address innovative hypotheses concerning the role of VEGF in mesenchymal stem cell differentiation to osteoblasts and adipocytes. Finally, based on the discovery that vascular endothelial cells can be converted to multipotent mesenchymal stem-like cells (EndMT), by mechanisms that are inhibited by VEGF, experiments are designed to explore the possibility of inducing EndMT as a way of promoting bone formation during surgical bone repair and to understand the roles of VEGF in this process.

Public Health Relevance

Osteoporosis is characterized by loss of bone mass and increased bone marrow fat, raising questions about how the balance between bone-forming cells and fat is regulated. This project addresses these questions in a mouse model of osteoporosis. In addition, based on the discovery that blood vessel-lining cells can be converted to bone- forming stem cells, ways of inducing such conversion during bone repair will be studied.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AR036819-30
Application #
8703608
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
30
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Hu, Kai; Olsen, Bjorn R (2016) The roles of vascular endothelial growth factor in bone repair and regeneration. Bone 91:30-8
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
Huang, Wei; Li, Qing; Amiry-Moghaddam, Mahmood et al. (2016) Critical Endothelial Regulation by LRP5 during Retinal Vascular Development. PLoS One 11:e0152833
Hu, Kai; Olsen, Bjorn R (2016) Vascular Endothelial Growth Factor Control Mechanisms in Skeletal Growth and Repair. Dev Dyn :
Olsen, Bjorn R; Berendsen, Agnes D; Besschetnova, Tatiana Y et al. (2016) Regulatory mechanisms of skeletal and connective tissue development and homeostasis - lessons from studies of human disorders. Int J Exp Pathol 97:296-302
Hamilton, John L; Nagao, Masashi; Levine, Brett R et al. (2016) Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain. J Bone Miner Res 31:911-24
Hu, Kai; Olsen, Bjorn R (2016) Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest 126:509-26
Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R et al. (2016) VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol 52-54:127-40
Yalak, Garif; Olsen, Bjorn R (2015) Proteomic database mining opens up avenues utilizing extracellular protein phosphorylation for novel therapeutic applications. J Transl Med 13:125
Berendsen, Agnes D; Olsen, Bjorn R (2015) Bone development. Bone 80:14-8

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