The work during the initial CORT funding period established the following principles: i) periosteal MSCs respond to injury with proliferation and expansion;ii) The expanded population of MSCs secretes growth factors and responds to signals that drive bone repair;iii) COX-2/PGE2 is a key early reparative signal;iv) aging results in reduced COX-2 expression during bone repair;and 5) PTH{1-34} (PTH) compensates for the reduced healing observed in aging and COX-2[-/-] mice. The ongoing goal of Project 2 is to provide a clear and comprehensive paradigm of the cell populations and signaling mechanisms regulated by PTH during bone repair responsible for its anabolic effects.
Aims 1 and 2 use in vivo models of bone repair, while Aim 3 uses a complementary in vivo approach. Experiments in Aim 1 define periosteum as a key target for bone repair with age dependent responsiveness. The experiments will show that PTH acts specifically on periosteal MSC and stimulates three signaling pathways that are potent mediators of bone formation: Wnt/p- catenin, BMP/Smad, and lhh/Gli-2/Ptc.
Aim 2 provides genetic evidence that Wnt/Beta-catenin signaling is an essential component of the mechanism whereby PTH stimulates bone repair.
Aim 3 uses a highly innovative approach to isolate and culture periosteal stem cells. Using genetically altered mice the signals that are sequentially activated downstream of PTH are examined in isolated periosteal stem cells. Collectively, the experiments in the 3 Aims will establish that 1) PTH enhances Wnt/p-catenin and BMP/Smad signaling (stem cell proliferation/expansion, osteoblast differentiation) from periosteal/endosteal MSCs);ii) Wnt/p-catenin stimulates BMP-2 expression and BMP/Smad signaling (osteoblast differentiation/bone formation and chondrogenesis);c) BMP/Smad and Wnt/Beta-catenin signaling stimulate Ihh/Ptc signaling (bone formation). The CORT Program is based upon the unifying concept that i) expansion and differentiation of the MSC population as a critical event in musculoskeletal repair;and ii) PTH is key anabolic agent that promotes tissue specific MSC expansion and repair events. The integration of Project 2 with the other CORT Projects through an Administrative Core that enhances collaborations and access to an innovative and comprehensive Molecular and Anatomic Imaging Core will leverage the remarkable progress of the initial funding period and lead to important novel insights and therapies for orthopaedic trauma patients.

Public Health Relevance

The goal of Project 2 is to provide a clear and comprehensive paradigm of the cell populations and signaling mechanisms regulated by PTH during bone repair responsible for its anabolic effects. This provides the compelling rationale for the translation of PTH therapies to patients with bone injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR054041-07
Application #
8531858
Study Section
Special Emphasis Panel (ZAR1-KM)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
7
Fiscal Year
2013
Total Cost
$307,926
Indirect Cost
$109,313
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Wang, Cuicui; Shen, Jie; Yukata, Kiminori et al. (2015) Transient gamma-secretase inhibition accelerates and enhances fracture repair likely via Notch signaling modulation. Bone 73:77-89
Zhang, Minjie; Feigenson, Marina; Sheu, Tzong-jen et al. (2015) Loss of the PGE2 receptor EP1 enhances bone acquisition, which protects against age and ovariectomy-induced impairments in bone strength. Bone 72:92-100
David, Michael A; Jones, Khyrie H; Inzana, Jason A et al. (2014) Tendon repair is compromised in a high fat diet-induced mouse model of obesity and type 2 diabetes. PLoS One 9:e91234
Dhillon, Robinder S; Zhang, Longze; Schwarz, Edward M et al. (2014) The murine femoral bone graft model and a semiautomated histomorphometric analysis tool. Methods Mol Biol 1130:45-59
Shi, Jixiang; Liang, Qianqian; Zuscik, Michael et al. (2014) Distribution and alteration of lymphatic vessels in knee joints of normal and osteoarthritic mice. Arthritis Rheumatol 66:657-66
Varrone, John J; de Mesy Bentley, Karen L; Bello-Irizarry, Sheila N et al. (2014) Passive immunization with anti-glucosaminidase monoclonal antibodies protects mice from implant-associated osteomyelitis by mediating opsonophagocytosis of Staphylococcus aureus megaclusters. J Orthop Res 32:1389-96
Jonason, Jennifer H; O'Keefe, Regis J (2014) Isolation and culture of neonatal mouse calvarial osteoblasts. Methods Mol Biol 1130:295-305
Nishitani, Kohei; Schwarz, Edward M (2014) Regenerative medicine: Cartilage transplants hold promise for challenging bone defects. Nat Rev Rheumatol 10:129-30
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
Yin, Guoyong; Sheu, Tzong-Jen; Menon, Prashanthi et al. (2014) Impaired angiogenesis during fracture healing in GPCR kinase 2 interacting protein-1 (GIT1) knock out mice. PLoS One 9:e89127

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