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The Interleukin-6/Soluble Interleukin-6 Receptor System Induces Parathyroid Hormone–Related Protein in Human Osteoblastic Cells

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Abstract

In the present in vitro study, we tested the hypothesis that parathyroid hormone-related protein (PTHrP) might be a mediator of interleukin-6 (IL-6) and its soluble receptor (IL-6sR) in osteoblasts. We found that IL-6, within 1–20 ng/mL, added together with IL-6sR (100 ng/mL), rapidly (1 hour) increased PTHrP mRNA in human osteoblastic osteosarcoma MG-63 cells and human osteoblastic (hOB) cells from trabecular bone. PD098059, a mitogen-activated protein kinase (MAPK) kinase inhibitor, at 10 μM, and two inhibitors of protein prenylation and thus Ras activation, simvastatin (1 μM) and a farnesyltransferase (FTase) inhibitor (100 nM), but not the phosphatidylinositol 3-kinase inhibitor wortmannin, blocked the IL-6/IL-6sR-induced PTHrP expression in these cells. In addition, PD098059 as well as simvastatin and the FTase inhibitor abolished alkaline phosphatase activity and/or osteocalcin mRNA induction by the IL-6/IL-6sR in these cells. Our results support the role of the Ras/MAPK pathway as a major mechanism in the modulation of both PTHrP expression and differentiation in human osteoblasts.

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Acknowledgments

This work was supported in part by grants from the Spanish Ministry of Health (FIS 00/0125 and C03/08) and by a Fundación Española de Productos Químicos y Farmacéuticos (Bilbao, Spain) award. We thank Dr. M. E. Martínez (La Paz Hospital, Madrid) for providing us with the hOB cell cultures. We are also grateful to J. L. Martín-Ventura and N. Tejera (Laboratory of Vascular and Renal Research, Fundación Jiménez Diaz) for supplying simvastatin and anti-ERK1/ERK2 and anti-STAT-1 antibodies, respectively. C.G. and A. R. de G. are fellows of the Conchita Rábago Foundation.

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  1. Bone and Mineral Metabolism Laboratory, Research Unit, Fundación Jiménez Díaz, 28040, Madrid, Spain

    C. Guillén, A. R. de Gortázar & P. Esbrit

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  1. C. Guillén
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Guillén, C., de Gortázar, A.R. & Esbrit, P. The Interleukin-6/Soluble Interleukin-6 Receptor System Induces Parathyroid Hormone–Related Protein in Human Osteoblastic Cells. Calcif Tissue Int 75, 153–159 (2004). https://doi.org/10.1007/s00223-004-0113-1

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