The interleukin-6/soluble interleukin-6 receptor system induces parathyroid hormone-related protein in human osteoblastic cells.
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 microM, and two inhibitors of protein prenylation and thus Ras activation, simvastatin (1 microM) 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.
Guillén
C
C
Bone and Mineral Metabolism Laboratory, Research Unit, Fundación Jiménez Díaz, 28040, Madrid, Spain.
de Gortázar
A R
AR
Esbrit
P
P
D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; C104543:interleukin 6-interleukin 6 receptor fusion protein, recombinant; D015675:Osteocalcin; D019821:Simvastatin; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D000469:Alkaline Phosphatase; D018631:ras Proteins