The interleukin-6/soluble interleukin-6 receptor system induces parathyroid hormone-related protein in human osteoblastic cells

Calcif Tissue Int. 2004 Aug;75(2):153-9. doi: 10.1007/s00223-004-0113-1. Epub 2004 Apr 29.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alkaline Phosphatase / metabolism
  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Alkyl and Aryl Transferases / metabolism
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Enzyme Inhibitors / pharmacology
  • Farnesyltranstransferase
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Osteocalcin / genetics
  • Osteogenesis / drug effects
  • Osteogenesis / physiology*
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Parathyroid Hormone-Related Protein / genetics*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Interleukin
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins / pharmacology
  • Simvastatin / pharmacology
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Interleukin-6
  • Parathyroid Hormone-Related Protein
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins
  • interleukin 6-interleukin 6 receptor fusion protein, recombinant
  • Osteocalcin
  • Simvastatin
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • Alkaline Phosphatase
  • ras Proteins