Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells.
Recent studies have identified osteoprotegerin ligand (OPG-L) as the essential factor required for osteoclastogenesis, and that the effects are prevented by its soluble receptor, osteoprotegerin (OPG). However, there are limited data at present on the regulation of OPG-L expression in human osteoblastic cells by other cytokines. Because interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 all increase osteoclastogenesis, we assessed whether OPG-L mRNA steady-state levels were regulated by these cytokines in human osteoblastic cells. By northern analysis, IL-1beta (5 nmol/L) and TNF-alpha (9 nmol/L) increased OPG-L mRNA steady-state levels by up to two- to three-fold in normal marrow stromal cells (MS), an immortalized marrow stromal cell line (hMS), and the osteosarcoma cell line, MG-63, whereas IL-6 (2 nmol/L, with or without its soluble receptor) had no effect on OPG-L mRNA levels in any of these cells. IL-1beta and TNF-alpha increased OPG-L mRNA steady-state levels in the normal MS cells and the hMS cell line in a time- and dose-dependent fashion by up to 4.1-fold and up to 2.6-fold, respectively. Our data are thus consistent with the hypothesis that the proinflammatory and bone-resorbing cytokines, IL-1beta and TNF-alpha, but not IL-6, may stimulate osteoclastogenesis by inducing the expression of OPG-L.
Hofbauer
L C
LC
Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Lacey
D L
DL
Dunstan
C R
CR
Spelsberg
T C
TC
Riggs
B L
BL
Khosla
S
S
D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
D002352:Carrier Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha