This Project 1 proposal is part of a revised renewal application for the CORT Program entitled "Translating molecular signal pathways to orthopaedic trauma care". During the previous funding period, we published results contributing to the general hypothesis that inappropriate articular chondrocyte (AC) hypertrophy is a mechanism of OA pathogenesis. Given that PTH 1-34 (teriparatide) is an inhibitor of hypertrophy and inducer of matrix synthesis in chondrocytes, several of our recent breakthrough discoveries have solidified rationale for its use as a novel therapy for OA. Most important is our remarkable finding that teriparatide has dramatic chondro- regenerative effects in a mouse model of injury-induced knee OA. This is plausible mechanistically based on our published result that teriparatide induces the cyclinDI-dependent degradation of Runx2 in chondrocytes. Since Forteo (teriparatide) is already FDA-approved, and since patients enrolled in the NIH-sponsored OAI that were prescribed Forteo for osteoporosis had improved WOMAC knee function scores compared to matched controls, the rationale for clinical study is compelling. Based on this series of findings, we propose a continuation of this project that involves testing the following central hypotheses: The chondro-protective and -regenerative effect of teriparatide in murine posttraumatic OA involves stimulation of matrix production coupled with the inhibition of inappropriate articular chondrocytes maturation that is mechanistically linked to a reduction/inhibition of RUNX2. To address this hypothesis, we propose the following 3 Specific Aims: 1) To establish that the chondro-regenerative effects of teriparatide in posttraumatic knee OA are mediated by articular chondrocytes, 2) To characterize the molecular basis for the stimulation of matrix production and the inhibition of maturation induced by teriparatide in articular chondrocytes, and 3) To investigate the role of Jag1/Notch signaling in the effects of teriparatide on arthritic cartilage. If successful, completion of these aims will establish teriparatide as a candidate therapy for OA, a disease that currently is only treated palliatively.
The studies proposed in Project 1 aim to establish teriparatide as a therapy for osteoarthritis, a disease for which the current strategies for treatment are only palliative. Molecular mechanisms that underiie the cartilage regenerating effect of teriparatide will be comprehensively characterized with the aim of setting the stage for a future clinical study aimed at evaluating its chondro-regenerative potential in humans.
|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|
Showing the most recent 10 out of 74 publications