Fractures account for 25% of all musculoskeletal injuries in the U.S., leading to 8 million treatment visits per year and 60 million lost work days. Rates of healing complication (delayed or non-union) range from 1-10%, affecting more than 100,000 patients annually. Stress fractures are a repetitive use injury affecting 500,000 people each year, mostly athletes and military recruits. Recently, a rare but devastating type of stress fracture - the atypical femur fracture - has been described, linked to bisphosphonate treatment. Although the methods by which full fractures and stress fractures heal are distinct, in both cases the key to achieving a functional repair is robust, periosteal bone formation (osteogenesis). The long-term goal of this project is to understand the mechanobiological pathways that regulate osteogenesis in the context of bone repair of the adult skeleton. Angiogenesis and inflammation are two processes integral to osteogenesis during bone repair, and recent evidence from the past funding period suggests that the osteocyte may play a role in initiating or regulating these processes. The overall hypothesis of this proposal is that the osteocyte contributes angiogenic and inflammatory factors critical to bone repair. Murine models for full fracture (closed, stabilizd femoral shaft fracture) and stress fracture (ulnar fatigue loading) will be used to create reproducible bone injuries. Histology, microCT and qPCR gene expression will be used to assess inflammatory, angiogenic and osteogenic outcomes.
In Aim 1, the role of the prototypic pro-angiogenic factor VEGFA (vascular endothelial growth factor) will be examined in different cell types (osteocyte, osteoblast, endothelial cell) using Cre-loxP methods. The recent availability of inducible Cre drivers makes this aim feasible in adult mice.
In Aim 2, the role of factors classically related to inflammation, but also relevant to vascular responses and angiogenesis, will be evaluated. Interleukin 6 (IL-6) and inducible nitric oxide synthase (iNOS) are expressed by bone cells and immune cells. In the past funding period iNOS was shown to mediate increased blood flow and osteogenesis after stress fracture. Using Cre-loxP methods and radiation chimera, the relative importance of osteocytes and immune cells in producing these two factors will be examined. In summary, the project will determine whether the osteocyte, already recognized as a master regulator of bone homeostasis and remodeling, plays an important role in bone repair. Better understanding of endogenous repair mechanisms may inform future treatment strategies to augment bone healing.

Public Health Relevance

Bone fractures account for 25% of all musculoskeletal injuries in the U.S., leading to 60 million lost work days, while stress fracture affect 500,000 people each year. A better understanding of the processes by which bones heal is critical to developing strategies to treat fractures that heal poorly (at least 100,000 each year). This project addresses the biological mechanisms by which different cell types (bone cells, immune cells, and vascular cells) contribute to bone healing after a fracture or stress fracture.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050211-14
Application #
9870874
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Nicks, Kristy
Project Start
2003-07-25
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
14
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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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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