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Distinct roles for mitogen-activated protein kinase phosphatase-1 (MKP-1) and ERK-MAPK in PTH1R signaling during osteoblast proliferation and differentiation
Authors:Nabanita S Datta  Rola Kolailat  Alemu Fite  Glenda Pettway  Abdul B Abou-Samra
Institution:1. Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Korea;2. School of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea;3. Department of Neurosurgery, College of Medicine, Hallym University, Chuncheon, Korea;4. Division of Endocrinology and Metabolism, Department of Internal Medicine, Konyang University, Daejeon, Korea;5. Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Korea;6. School of Pharmacy, Sungkyunkwan University, Suwon, Korea;7. Department of Agrofood Resources, National Academy of Agricultural Science, RDA, Suwon, Republic of Korea;8. Departemnt of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon, Korea;1. Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark;2. DanStem (Danish Stem Cell Center), Panum Institute, University of Copenhagen, Copenhagen, Denmark;3. Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Saudi Arabia
Abstract:Parathyroid hormone (PTH) and PTH-related protein (PTHrP) activate one single receptor (PTH1R) which mediates catabolic and anabolic actions in the bone. Activation of PTH1R modulates multiple intracellular signaling responses. We previously reported that PTH and PTHrP down-regulate pERK1/2 and cyclin D1 in differentiated osteoblasts. In this study we investigate the role of MAPK phosphatase-1 (MKP-1) in PTHrP regulation of ERK1/2 activity in relation to osteoblast proliferation, differentiation and bone formation. Here we show that PTHrP increases MKP-1 expression in differentiated osteoblastic MC3T3-E1 cells, primary cultures of differentiated bone marrow stromal cells (BMSCs) and calvarial osteoblasts. PTHrP had no effect on MKP-1 expression in proliferating osteoblastic cells. Overexpression of MKP-1 in MC-4 cells inhibited osteoblastic cell proliferation. Cell extracts from differentiated MC-4 cells treated with PTHrP inactivate/dephosphorylate pERK1/2 in vitro; immunodepletion of MKP-1 blocked the ability of the extract to dephosphorylate pERK1/2; these data indicate that MKP-1 is involved in PTHrP-induced pERK1/2 dephosphorylation in the differentiated osteoblastic cells. PTHrP regulation of MKP-1 expression is partially dependent on PKA and PKC pathways. Treatment of nude mice, bearing ectopic ossicles, with intermittent PTH for 3 weeks, up-regulated MKP-1 and osteocalcin, a bone formation marker, with an increase in bone formation. These data indicate that PTH and PTHrP increase MKP-1 expression in differentiated osteoblasts; and that MKP-1 induces growth arrest of osteoblasts, via inactivating pERK1/2 and down-regulating cyclin D1; and identify MKP-1 as a possible mediator of the anabolic actions of PTH1R in mature osteoblasts.
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