Angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. Mesenchymal cells in the developing stroma elicit angiogenic signals to attract new blood vessels to bone rudiments or regenerates. Other signals, likely emanating from the incoming vasculature, stimulate bone cell specification through interactions with cells within the vascular stem cell niche. The long-term goal of this project is to understand the cellular and molecular mechanisms that control interactions between bone cells and vascular elements. During the past funding period, we have identified the hypoxia inducible factor alpha (HIF-11) pathway as a key component in this process. Using a genetic approach, we have demonstrated that overexpression of HIF1 in mouse osteoblasts through disruption of Vhl profoundly increases angiogenesis and osteogenesis;these processes appear to be coupled by cell non-autonomous mechanisms involving VEGF. Preliminary studies described below suggest that endothelial cells are one source of bone morphogenic signal which couples angiogenesis to bone formation. Angiogenesis also appears to drive osteogenesis when long bones from the mutant and wild type mice are subjected to injury (distraction osteogenesis). Surprisingly however, manipulation of HIF1 levels in mature osteoblasts does not influence the formation of the flat bones of the skull. These results suggest that the mechanisms which couple angiogenesis to osteogenesis are context (skeletal site) specific. In this renewal application, we propose studies to characterize cellular and molecular mechanisms responsible for coupling angiogenesis to osteogenesis in three different skeletal contexts. This renewal grant has three aims:
Specific Aim 1 : Angiogenic-osteogenic coupling in developing long bones.
Specific Aim 2 : Angiogenic-osteogenic coupling following bone injury.
Specific Aim 3 : Angiogenic-osteogenic coupling in the developing cranium. The ultimate goal of this project is to elucidate the functional mechanisms underlying HIF-1/VEGF stimulated angiogenesis and osteogenesis. These findings should lead to better understanding of precise communication between angiogenesis and osteogenesis and aid in the design of new therapies to accelerate bone healing following injury

Public Health Relevance

Our studies conducted over the last few years have identified a signaling molecule called the hypoxia-inducible factor that controls these processes. The goal of our research is to understand the cellular and molecular mechanisms, which couple angiogenesis in bone formation. Successful completion of this work should lead to novel approaches for the treatment of bone development and regeneration.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Sharrock, William J
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Johns Hopkins University
Schools of Medicine
United States
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Dirckx, Naomi; Tower, Robert J; Mercken, Evi M et al. (2018) Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. J Clin Invest 128:1087-1105
Dewan, Ashvin K; Tomlinson, Ryan E; Mitchell, Stuart et al. (2015) Dysregulated TGF-? signaling alters bone microstructure in a mouse model of Loeys-Dietz syndrome. J Orthop Res 33:1447-54
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Riddle, Ryan C; Leslie, Julie M; Gross, Ted S et al. (2011) Hypoxia-inducible factor-1? protein negatively regulates load-induced bone formation. J Biol Chem 286:44449-56
Wan, Chao; Shao, Jin; Gilbert, Shawn R et al. (2010) Role of HIF-1alpha in skeletal development. Ann N Y Acad Sci 1192:322-6
Shomento, Stacy H; Wan, Chao; Cao, Xuemei et al. (2010) Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development. J Cell Biochem 109:196-204
Weinstein, Robert S; Wan, Chao; Liu, Qinglan et al. (2010) Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 9:147-61
Zhang, Fengjie; Qiu, Tao; Wu, Xiangwei et al. (2009) Sustained BMP signaling in osteoblasts stimulates bone formation by promoting angiogenesis and osteoblast differentiation. J Bone Miner Res 24:1224-33
Riddle, Ryan C; Khatri, Richa; Schipani, Ernestina et al. (2009) Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling. J Mol Med (Berl) 87:583-90

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