This competing renewal application builds on findings from the initial funding period that establish COX-2 as a critical signal for fracture repair. The role of COX-2 extends to fracture healing in aging. Decreased COX-2 expression is observed in the fracture callus of aged mice and preliminary data show that the reduced fracture repair observed in these animals can be rescued by delivery of an agonist targeting the PGE2 receptor, EP4. Based on our finding that COX-2 is induced specifically in mesenchymal chondroprogenitors and immature chondrocytes during early endochondral bone healing, the proposal addresses the role of mesenchyme specific and chondrocyte specific COX-2/EP4 receptor expressions during fracture healing using conditional gene deletion technology. In addition, we will also define the signaling mechanisms downstream of COX-2 by which Indian Hedgehog (Ihh) is induced by COX-2/PGE2 via activation of ATF4 phosphorylation. Our overall hypotheses are 1) induction of COX-2 in early fractures by mesenchymal stem cells and immature chondrocytes plays a critical role in bone repair;2) COX-2/EP4 signaling targets cartilage and activates the Ihh pathway, which is essential for chondrocyte proliferation, early vascular invasion, and the transition from cartilage to bone formation.
In Aim1, we will characterizes fracture healing in COX-2f/f;Prx-1Cre and EP4f/-;Prx1Cre mice, in which COX-2 or EP4 receptor are deleted in mesenchymal cells or chondrocytes respectively.
In Aim2, we will examine the signaling mechanisms by which Ihh is induced via activation of ATF4 phosphorylation downstream COX-2/PGE2.
In Aim3, important translational studies will definitively establish that EP4 agonists can compensate for the reduced fracture repair observed in aging. Related in vivo approaches with HH gain and loss of function will further establish a role for hedgehog signaling downstream of COX2/PGE2/EP4 during fracture healing. This studies will advance our current limited knowledge regarding mesenchymal cell initiated endochondral bone repair, with the potential to provide novel therapeutic approaches to treat elderly patients with impaired fracture healing.

Public Health Relevance

Fracture healing, which is necessary for maintenance of skeletal integrity, typically efficiently occurs, but is compromised in certain conditions, including aging. This proposal investigates the role of a key gene, cyclooxygenase-2, and its expression and function during key processes of fracture healing. Insights gained from this work will enhance the understanding and treatment of fractures in patients with compromised healing, and has particular potential to improve bone repair in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048681-09
Application #
8286051
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Wang, Fei
Project Start
2002-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$330,383
Indirect Cost
$116,543
Name
University of Rochester
Department
Orthopedics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Hadjiargyrou, Michael; O'Keefe, Regis J (2014) The convergence of fracture repair and stem cells: interplay of genes, aging, environmental factors and disease. J Bone Miner Res 29:2307-22
Yukata, Kiminori; Xie, Chao; Li, Tian-Fang et al. (2014) Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment. Bone 62:79-89
Huang, Chunlan; Xue, Ming; Chen, Hongli et al. (2014) The spatiotemporal role of COX-2 in osteogenic and chondrogenic differentiation of periosteum-derived mesenchymal progenitors in fracture repair. PLoS One 9:e100079
Li, T-F; Yukata, K; Yin, G et al. (2014) BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway. Osteoarthritis Cartilage 22:481-9
Shah, Krupa; Majeed, Zahraa; Jonason, Jennifer et al. (2013) The role of muscle in bone repair: the cells, signals, and tissue responses to injury. Curr Osteoporos Rep 11:130-5
Wang, Qun; Huang, Chunlan; Xue, Ming et al. (2011) Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing. Bone 48:524-32
Zhang, Minjie; Ho, Hsin-chiu; Sheu, Tzong-jen et al. (2011) EP1(-/-) mice have enhanced osteoblast differentiation and accelerated fracture repair. J Bone Miner Res 26:792-802
Li, Dan; Gromov, Kirill; Proulx, Steven T et al. (2010) Effects of antiresorptive agents on osteomyelitis: novel insights into the pathogenesis of osteonecrosis of the jaw. Ann N Y Acad Sci 1192:84-94
Dao, Debbie Y; Yang, Xue; Flick, Lisa M et al. (2010) Axin2 regulates chondrocyte maturation and axial skeletal development. J Orthop Res 28:89-95
Clark, Christine A; Li, Tian-Fang; Kim, Kyung-Ok et al. (2009) Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturation. J Orthop Res 27:785-92

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