IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or 1,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures

Rowena D. Devlin, Sakamuri V. Reddy, Rocco Savino, Gennaro Ciliberto, G. David Roodman

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Abstract

A potent interleukin-6 (IL-6) antagonist (Sant 5), which binds tightly to the 6α receptor but has impaired gp130 heterodimerization, has been developed recently by site-directed mutagenesis of human IL-6. We report here that Sant 5 inhibitS IL-6-stimulated osteoclast-like multinucleated cell (MNC) formation in human marrow cultures but also inhibits the stimulatory effects of IL-1 or tumor necrosis factor alpha (TNF-α in these cultures. We further show that a neutralizing antibody to IL-6 also inhibits the stimulatory effects of IL-1 or TNF-α in these cultures. In contrast, Sant 5 had no effect on parathyroid hormone related protein (PTHrP) or 1,25- dihydroxyvitamin D3 stimulated MNC formation in human marrow cultures. Transfection of a human marrow stromal cell line, which normally induces osteoclast formation through production of IL-6, with the Sant 5 cDNA driven by a cytomegalovirus (CMV) promoter blocked the capacity of these cells to stimulate osteoclast-like cell formation. These Sant 5 transfected cells and conditioned media from these cells also inhibited the stimulatory effects of the parent cell line on MNC formation. These data suggest that IL-6 mediates the effects of IL-1 and TNF on human osteoclast formation, but in contrast to murine systems, does not mediate the effects of PTHrP. These data further demonstrate that stromal cells transfected with the Sant 5 cDNA can constitutively produce high levels of the IL-6 antagonist and inhibit osteoclast formation in vitro.

Original languageEnglish (US)
Pages (from-to)393-399
Number of pages7
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume13
Issue number3
DOIs
StatePublished - 1998
Externally publishedYes

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Parathyroid Hormone-Related Protein
Osteoclasts
Interleukin-1
Interleukin-6
Bone Marrow
Stromal Cells
Complementary DNA
Cell Line
Calcitriol
Conditioned Culture Medium
Site-Directed Mutagenesis
Neutralizing Antibodies
Cytomegalovirus
Transfection
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Surgery

Cite this

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title = "IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or 1,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures",
abstract = "A potent interleukin-6 (IL-6) antagonist (Sant 5), which binds tightly to the 6α receptor but has impaired gp130 heterodimerization, has been developed recently by site-directed mutagenesis of human IL-6. We report here that Sant 5 inhibitS IL-6-stimulated osteoclast-like multinucleated cell (MNC) formation in human marrow cultures but also inhibits the stimulatory effects of IL-1 or tumor necrosis factor alpha (TNF-α in these cultures. We further show that a neutralizing antibody to IL-6 also inhibits the stimulatory effects of IL-1 or TNF-α in these cultures. In contrast, Sant 5 had no effect on parathyroid hormone related protein (PTHrP) or 1,25- dihydroxyvitamin D3 stimulated MNC formation in human marrow cultures. Transfection of a human marrow stromal cell line, which normally induces osteoclast formation through production of IL-6, with the Sant 5 cDNA driven by a cytomegalovirus (CMV) promoter blocked the capacity of these cells to stimulate osteoclast-like cell formation. These Sant 5 transfected cells and conditioned media from these cells also inhibited the stimulatory effects of the parent cell line on MNC formation. These data suggest that IL-6 mediates the effects of IL-1 and TNF on human osteoclast formation, but in contrast to murine systems, does not mediate the effects of PTHrP. These data further demonstrate that stromal cells transfected with the Sant 5 cDNA can constitutively produce high levels of the IL-6 antagonist and inhibit osteoclast formation in vitro.",
author = "Devlin, {Rowena D.} and Reddy, {Sakamuri V.} and Rocco Savino and Gennaro Ciliberto and Roodman, {G. David}",
year = "1998",
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T1 - IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or 1,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures

AU - Devlin, Rowena D.

AU - Reddy, Sakamuri V.

AU - Savino, Rocco

AU - Ciliberto, Gennaro

AU - Roodman, G. David

PY - 1998

Y1 - 1998

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AB - A potent interleukin-6 (IL-6) antagonist (Sant 5), which binds tightly to the 6α receptor but has impaired gp130 heterodimerization, has been developed recently by site-directed mutagenesis of human IL-6. We report here that Sant 5 inhibitS IL-6-stimulated osteoclast-like multinucleated cell (MNC) formation in human marrow cultures but also inhibits the stimulatory effects of IL-1 or tumor necrosis factor alpha (TNF-α in these cultures. We further show that a neutralizing antibody to IL-6 also inhibits the stimulatory effects of IL-1 or TNF-α in these cultures. In contrast, Sant 5 had no effect on parathyroid hormone related protein (PTHrP) or 1,25- dihydroxyvitamin D3 stimulated MNC formation in human marrow cultures. Transfection of a human marrow stromal cell line, which normally induces osteoclast formation through production of IL-6, with the Sant 5 cDNA driven by a cytomegalovirus (CMV) promoter blocked the capacity of these cells to stimulate osteoclast-like cell formation. These Sant 5 transfected cells and conditioned media from these cells also inhibited the stimulatory effects of the parent cell line on MNC formation. These data suggest that IL-6 mediates the effects of IL-1 and TNF on human osteoclast formation, but in contrast to murine systems, does not mediate the effects of PTHrP. These data further demonstrate that stromal cells transfected with the Sant 5 cDNA can constitutively produce high levels of the IL-6 antagonist and inhibit osteoclast formation in vitro.

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