The physiological process of bone remodeling is tightly regulated by local and endocrine factors, and any disturbance will lead to various skeletal diseases including craniofacial deformities and orthopedic disorders. Parathyroid hormone (PTH) has been shown clinically to induce bone formation. However the exact biological mechanisms of bone formation and regeneration by PTH remain elusive. Our broad, long-term goal is to identify molecular mechanisms of PTH/PTHrP (PTH related protein) action and bone turnover. Preliminary data suggest that cell cycle control may be a mechanism through which PTHrP impacts the life span and bone forming activity of osteoblasts. Down-regulation of cyclin D1 and elevated expression of JunB suggested involvement of AP-1 transcription factors to the cell cycle machinery of osteoblasts and led us to hypothesize that the action of PTHrP on cyclin D1 is developmental stage specific and associated with specific signal transduction mediators. Using in vitro and in vivo models, 2 specific aims will test this hypothesis.
In specific aim 1 cyclin D1 promoter constructs and Luciferase assays will determine if PTHrP effects on cyclin D1 are dependent on osteoblast proliferation and differentiation stage. We will determine if JunB plays a role in modulating cyclin D1 expression utilizing RNA interference (RNAi) technology, over expression of dominant negative AP-1 protein (TAM 67) and CDK1.
Specific Aim 2 will utilize a novel ectopic ossicle model system to verify cyclin D1 as 1 of the downstream mediators of PTHrP signaling in vivo. Finally, using immunohistochemistry, effects of PTHrP on cyclin D1 will be elucidated at various stages of osteoblast differentiation in vivo. The outcome of this investigation will advance our knowledge of PTH/PTHrP action in bone and contribute to understanding the anabolic actions of PTH. Identifying these mechanisms related to PTH action will have applicability as potential targets for new therapeutic agents for the treatment of diseases which adversely affect bone, including osteoporosis and periodontal diseases. ? ?
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| Datta, Nabanita S; Kolailat, Rola; Fite, Alemu et al. (2010) Distinct roles for mitogen-activated protein kinase phosphatase-1 (MKP-1) and ERK-MAPK in PTH1R signaling during osteoblast proliferation and differentiation. Cell Signal 22:457-66 |
| Datta, Nabanita S; Abou-Samra, Abdul B (2009) PTH and PTHrP signaling in osteoblasts. Cell Signal 21:1245-54 |
| Datta, Nabanita S; Pettway, Glenda J; Chen, Chen et al. (2007) Cyclin D1 as a target for the proliferative effects of PTH and PTHrP in early osteoblastic cells. J Bone Miner Res 22:951-64 |
| Noth, Ulrich; Tuli, Richard; Seghatoleslami, Reza et al. (2003) Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts. Exp Cell Res 291:201-11 |
