Non-endochondral bone formation (osteogenesis) occurs either as lamellar or woven bone. Lamellar bone forms during normal modeling and remodeling, whereas woven bone forms as part of an injury response (e.g., fracture healing, distraction osteogenesis, fatigue/stress fractures). Little is known about what leads the same cell type (the osteoblast) to directly produce lamellar bone in one case and woven bone in another. An advantage of woven bone is that it can quickly increase bone width and moment of inertia, leading to rapid restoration of whole-bone stiffness and strength. If the pathway(s) of non-endochondral woven bone formation could be better understood, it may lead to the discovery of novel strategies for treating disorders of low bone mass and strength. Recent work has demonstrated that a rapid woven bone response occurs after a single bout of damaging fatigue loading. In light of observations that new blood vessel formation (angiogenesis) also occurs after fatigue loading of bone, we hypothesize that the angiogenic response may influence the nature of the osteogenic response, i.e. woven versus lamellar. Our long-term goal is to determine the mechano-biological pathway that leads to rapid non-endochondral bone formation after mechanical loading. We hypothesize: (1) mechanical loading-induced woven bone formation is a response to structural damage rather than a response to cyclic deformation; and (2) the osteogenic response to damaging fatigue loading is dependent on the vigor of the angiogenic response. Using the rat ulnar loading model, in Specific Aim 1 we will: (A) determine the osteogenic response to fatigue (i.e., dynamic) loading as a function of the level of structural damage; (B) determine the osteogenic response to creep (i.e., static) loading as a function of the level of structural damage; and (C) correlate patterns of bone formation with finite element-predicted patterns of bone strain.
In Specific Aim 2, we will: (A) assess changes in bone vasculature following damaging fatigue loading; (B) assess the spatial pattern of expression of important osteogenic (e.g., BMP-2) and angiogenic factors (e.g., VEGF); and (C) assess the ability of anti-angiogenic compounds to block woven bone formation after damaging fatigue loading. Taken together, these studies will establish important mechanical and angiogenic factors that mediate the distinct processes of lamellar versus woven bone formation. They will extend our understanding of the osteogenic response to skeletal stress injuries (fatigue fractures) and will serve as a basis for future development of novel strategies for rapid bone formation to augment weak or damaged bones. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR050211-01
Application #
6676316
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
2003-07-25
Project End
2007-04-30
Budget Start
2003-07-25
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$359,550
Indirect Cost
Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Shi, Yu; He, Guangxu; Lee, Wen-Chih et al. (2017) Gli1 identifies osteogenic progenitors for bone formation and fracture repair. Nat Commun 8:2043
McKenzie, Jennifer A; Buettmann, Evan; Abraham, Adam C et al. (2017) Loss of scleraxis in mice leads to geometric and structural changes in cortical bone, as well as asymmetry in fracture healing. FASEB J 31:882-892
McBride-Gagyi, Sarah Howe; McKenzie, Jennifer A; Buettmann, Evan G et al. (2015) Bmp2 conditional knockout in osteoblasts and endothelial cells does not impair bone formation after injury or mechanical loading in adult mice. Bone 81:533-543
Tomlinson, Ryan E; Silva, Matthew J (2015) HIF-1? regulates bone formation after osteogenic mechanical loading. Bone 73:98-104
Izawa, Takashi; Rohatgi, Nidhi; Fukunaga, Tomohiro et al. (2015) ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis. Cell Rep 11:1625-37
Kazmers, Nikolas H; McKenzie, Jennifer A; Shen, Tony S et al. (2015) Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing. Bone 81:524-532
Tomlinson, Ryan E; Shoghi, Kooresh I; Silva, Matthew J (2014) Nitric oxide-mediated vasodilation increases blood flow during the early stages of stress fracture healing. J Appl Physiol (1985) 116:416-24
Tomlinson, Ryan E; Schmieder, Anne H; Quirk, James D et al. (2014) Antagonizing the ?v ?3 integrin inhibits angiogenesis and impairs woven but not lamellar bone formation induced by mechanical loading. J Bone Miner Res 29:1970-80
McBride, Sarah H; McKenzie, Jennifer A; Bedrick, Bronwyn S et al. (2014) Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells. PLoS One 9:e96862
Tomlinson, Ryan E; McKenzie, Jennifer A; Schmieder, Anne H et al. (2013) Angiogenesis is required for stress fracture healing in rats. Bone 52:212-9

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