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Phosphate Stimulates Matrix Gla Protein Expression in Chondrocytes through the Extracellular Signal Regulated Kinase Signaling Pathway

INSERM (Institut National de la Santé et de la Recherche Médicale), Unité (U) Mixte de Recherche 791 (M.J., M.M., P.W., J.G.), Université de Nantes, Faculté de chirurgie dentaire, LIOAD (Laboratoire d’ingénierie Ostéo-articulaire et dentaire), Nantes F-44042, France; LBCM (Laboratoire de Biologie Cellulaire et Moléculaire) (D.M.), Université du Littoral Côte d’Opale, Boulogne-sur-mer F-62327, France; INSERM U533 (M.R.-D., C.C.-T.), Institut du Thorax, Nantes F-44035, France; INSERM U443 (O.C.), Biomatériaux et Réparation Tissulaire, Bordeaux F-33076, France; and INRA (Institut National de la Recherche Agronomique) UMR703 (Y.C.), Ecole Nationale Vétérinaire, Développement et pathologie du tissu musculaire, Nantes F-44307, France

Address all correspondence and requests for reprints to: J. Guicheux, Institut National de la Santé et de la Recherche Médicale Unité 791, Laboratory of Osteoarticular and Dental Tissue Engineering, University of Nantes, 1 Place Alexis Ricordeau, 44042 Nantes cedex 1, France. E-mail: Jerome.guicheux{at}nantes.inserm.fr.

Whereas increasing evidence suggests that inorganic phosphate (Pi) may act as a signaling molecule in mineralization-competent cells, its mechanisms of action remain largely unknown. The aims of the present work were to determine whether Pi regulates expression of matrix Gla protein (MGP), a mineralization inhibitor, in growth plate chondrocytes and to identify the involved signaling pathways. Chondrogenic ATDC5 cells and primary growth plate chondrocytes were used. Messenger RNA and protein analyses were performed by quantitative PCR and Western blotting, respectively. The activation and role of MAPKs were, respectively, determined by Western blotting and the use of specific inhibitors. Immunohistological detection of ERK1/2 was performed in rib organ cultures from newborn mice. The results indicate that Pi markedly stimulates expression of MGP in ATDC5 cells and primary growth plate chondrocytes. Investigation of the involved intracellular signaling pathways reveals that Pi activates ERK1/2 in a cell-specific manner, because the stimulation was observed in ATDC5 and primary chondrocytes, MC3T3-E1 osteoblasts, and ST2 stromal cells, but not in L929 fibroblasts or C2C12 myogenic cells. Accordingly, immunohistological detection of ERK1/2 phosphorylation in rib growth plates revealed a marked signal in chondrocytes. Finally, a specific ERK1/2 inhibitor, UO126, blocks Pi-stimulated MGP expression in ATDC5 cells, indicating that ERK1/2 mediates, mainly, the effects of Pi. These data demonstrate, for the first time, that Pi regulates MGP expression in growth plate chondrocytes, thereby suggesting a key role for Pi and ERK1/2 in the regulation of bone formation.