REGULATION OF THE GP80 AND GP130 SUBUNITS OF THE IL-6 RECEPTOR BY SEXSTEROIDS IN THE MURINE BONE-MARROW

Both estrogen and androgen exert their antiosteoporotic effects, at le ast in part, by inhibiting IL-6 production, thereby suppressing osteoc lastogenesis. Several observations, however, suggest that besides incr eased 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 limi ting factor for the actions of IL-6 on bone, are hypothesized that sex steroids regulate expression of the IL-6 receptor as well. We report that 17 beta-estradiol or dihydrotestosterone in vitro decreased the a bundance of the gp80 mRNA as well as the mRNA of the signal-transducin g subunit of the IL-6 receptor (gp130) in cells of the bone marrow str omal/osteoblastic lineage, and also decreased gp130 protein levels. Th ese 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, ovariect omy in mice caused an increase in expression of gp80, gp130, and IL-6 mRNAs in ex vivo bone marrow cell cultures as determined by quantitati ve 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 explanati on for why IL-6 is important for skeletal homeostasis in the sex stero id-deficient, but not replete, state.