Impaired healing, occurring in approximately 630,000 fractures annually in the U.S., is physically disabling, costly, and poorly understood. Bone heals through formation of new bone rather than scar tissue; thus, similarities between fetal skeletal development and adult repair can be used to understand fracture healing. In both development and healing, bone forms through two mechanisms, the direct formation of bone (intramembranous ossification) and the formation of bone through a cartilage intermediate (endochondral ossification). The primary mode of healing is determined during the earliest stages of repair (inflammatory stage), as mesenchymal cells at the site of injury differentiate into osteoblasts or chondrocytes based on conditions present at the fracture site. One major determinant of progenitor cell differentiation is mechanical stability. Stabilized fractures heal predominantly by recapitulating embryonic intramembranous ossification while non-stabilized fractures heal by reinitiating endochondral ossification. Preliminary work suggests that the early events that stimulate repair, such as inflammation and angiogenesis, differ significantly in the stabilized and non-stabilized fracture environments. We hypothesize that these differences produce distinct conditions that govern mesenchymal cell differentiation into osteoblasts or chondrocytes.
The aims of this proposal are: i) to determine the post-injury inflammatory and angiogenic responses between stabilized and non-stabilized fracture healing;2) to identify the extent to which inflammation and angiogenesis regulate skeletal repair; and 3) to establish the relation between inflammation and angiogenesis to the differentiation of progenitor cells during fracture repair. We will use cellular, molecular, and genetic approaches to achieve these aims. This proposal will examine the role of the inflammatory response and vascular repair during bone healing. Bydefining these processes, we will better understand the way fractures heal and the mechanism by which cells decide to become bone or cartilage. Our goal is to use the findings from these studies to develop new treatments to stimulate fracture healing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053645-05
Application #
7741703
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Wang, Fei
Project Start
2006-02-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$313,990
Indirect Cost
Name
University of California San Francisco
Department
Orthopedics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hu, Diane P; Ferro, Federico; Yang, Frank et al. (2017) Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development 144:221-234
Toogood, Paul; Miclau, Theodore (2017) Critical-Sized Bone Defects: Sequence and Planning. J Orthop Trauma 31 Suppl 5:S23-S26
Abou-Khalil, Rana; Colnot, Céline (2014) Renal capsule transplantations to assay skeletal angiogenesis. Methods Mol Biol 1130:99-110
Abou-Khalil, Rana; Colnot, Céline (2014) Cellular and molecular bases of skeletal regeneration: what can we learn from genetic mouse models? Bone 64:211-21
Slade Shantz, Jesse Alan; Yu, Yan-Yiu; Andres, Wells et al. (2014) Modulation of macrophage activity during fracture repair has differential effects in young adult and elderly mice. J Orthop Trauma 28 Suppl 1:S10-4
Bahney, Chelsea S; Hu, Diane P; Taylor, Aaron J et al. (2014) Stem cell-derived endochondral cartilage stimulates bone healing by tissue transformation. J Bone Miner Res 29:1269-82
Lu, Chuanyong; Saless, Neema; Wang, Xiaodong et al. (2013) The role of oxygen during fracture healing. Bone 52:220-9
Wang, Xiaodong; Yu, Yan Yiu; Lieu, Shirley et al. (2013) MMP9 regulates the cellular response to inflammation after skeletal injury. Bone 52:111-9
Yu, Yan Yiu; Lieu, Shirley; Hu, Diane et al. (2012) Site specific effects of zoledronic acid during tibial and mandibular fracture repair. PLoS One 7:e31771
Colnot, Céline; Zhang, Xinping; Knothe Tate, Melissa L (2012) Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches. J Orthop Res 30:1869-78

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