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.
|Zhang, Longze; Wang, Tao; Chang, Martin et al. (2017) Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model. J Bone Miner Res 32:1870-1883|
|Zhang, Yongchun; O'Keefe, Regis J; Jonason, Jennifer H (2017) BMP-TAK1 (MAP3K7) Induces Adipocyte Differentiation Through PPAR? Signaling. J Cell Biochem 118:204-210|
|Schwarz, Edward M (2017) Confirmation of Sexual Dimorphisms in Metal Hypersensitivity and Joint Pain Following Total Joint Arthroplasty: Commentary on an article by Marco S. Caicedo, PhD, et al.: ""Females with Unexplained Joint Pain Following Total Joint Arthroplasty Exhibit a H J Bone Joint Surg Am 99:e41|
|Wang, Wensheng; Wang, Hua; Zhou, Xichao et al. (2017) Lymphatic Endothelial Cells Produce M-CSF, Causing Massive Bone Loss in Mice. J Bone Miner Res 32:939-950|
|Sun, Wen; Zhang, Hengwei; Wang, Hua et al. (2017) Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis. J Bone Miner Res 32:1469-1480|
|Le Bleu, Heather K; Kamal, Fadia A; Kelly, Meghan et al. (2017) Extraction of high-quality RNA from human articular cartilage. Anal Biochem 518:134-138|
|Nishitani, Kohei; Mietus, Zachary; Beck, Christopher A et al. (2017) High dose teriparatide (rPTH1-34) therapy increases callus volume and enhances radiographic healing at 8-weeks in a massive canine femoral allograft model. PLoS One 12:e0185446|
|Feigenson, Marina; Eliseev, Roman A; Jonason, Jennifer H et al. (2017) PGE2 Receptor Subtype 1 (EP1) Regulates Mesenchymal Stromal Cell Osteogenic Differentiation by Modulating Cellular Energy Metabolism. J Cell Biochem 118:4383-4393|
|Lawal, Rialnat A; Zhou, Xichao; Batey, Kaylind et al. (2017) The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool. J Bone Miner Res 32:1320-1331|
|de Mesy Bentley, Karen L; Trombetta, Ryan; Nishitani, Kohei et al. (2017) Evidence of Staphylococcus Aureus Deformation, Proliferation, and Migration in Canaliculi of Live Cortical Bone in Murine Models of Osteomyelitis. J Bone Miner Res 32:985-990|
Showing the most recent 10 out of 131 publications