Regulation of the gp80 and gp130 subunits of the IL-6 receptor by sex steroids in the murine bone marrow

• Published in: The Journal of clinical investigation 1997-10, Vol.100 (8), p.1980-1990
• Main Authors: Lin, S C, Yamate, T, Taguchi, Y, Borba, V Z, Girasole, G, O'Brien, C A, Bellido, T, Abe, E, Manolagas, S C
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow - drug effects; Bone Marrow Cells - drug effects; Cells, Cultured; Connective Tissue Cells - drug effects; Dihydrotestosterone - pharmacology; Estradiol - pharmacology; Female; Gene Expression Regulation; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Mice; Osteoblasts - drug effects; Ovariectomy; Receptors, Interleukin-6 - biosynthesis; Receptors, Interleukin-6 - genetics; Space life sciences; Stromal Cells - drug effects
• ISSN: 0021-9738
• DOI: 10.1172/jci119729

Both estrogen and androgen exert their antiosteoporotic effects, at least in part, by inhibiting IL-6 production, thereby suppressing osteoclastogenesis. Several observations, however, suggest that besides increased IL-6 production, sensitivity of the osteoclastogenic process to this cytokine is altered after ovariectomy. Based on this and evidence that the ligand-binding subunit of the IL-6 receptor (gp80) is a limiting factor for the actions of IL-6 on bone, we hypothesized that sex steroids regulate expression of the IL-6 receptor as well. We report that 17beta-estradiol or dihydrotestosterone in vitro decreased the abundance of the gp80 mRNA as well as the mRNA of the signal-transducing subunit of the IL-6 receptor (gp130) in cells of the bone marrow stromal/osteoblastic lineage, and also decreased gp130 protein levels. These effects did not require new protein synthesis. In contrast to sex steroids, parathyroid hormone stimulated gp130 expression; this effect was opposed by sex steroids. Consistent with these findings, ovariectomy in mice caused an increase in expression of gp80, gp130, and IL-6 mRNAs in ex vivo bone marrow cell cultures as determined by quantitative reverse transcription (RT)-PCR, and confirmed on an individual cell basis using in situ RT-PCR. The demonstration of increased expression of the IL-6 receptor after loss of sex steroids provides an explanation for why IL-6 is important for skeletal homeostasis in the sex steroid-deficient, but not replete, state.