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High-dose glucocorticoids increase serum levels of soluble IL-6 receptor and its ratio to soluble gp130: an additional mechanism for early increased bone resorption

¹ Medicina Interna I, Dipartimento di Scienze Cliniche e Biologiche and ² CRESM-Neurobiologia Clinica, University of Turin, A.S.O. San Luigi, Regione Gonzole 10, 10043 Orbassano (TO), Italy

(Correspondence should be addressed to A Dovio; Email: andrea.dovio{at}unito.it)

Objective: Glucocorticoids (GCs) at pharmacological doses stimulate bone resorption. Mechanisms of this action are unclear. The osteoclastogenic cytokine interleukin (IL)-6 acts through an oligomeric receptor consisting of two subunits, gp80 (or IL-6 receptor , IL-6R) and gp130; both exist in membrane and soluble forms. Soluble IL-6R (sIL-6R) enhances, while sgp130 inhibits IL-6 signalling. In vitro, GCs enhance many effects of IL-6 by up-regulation of IL-6R. The aim of the present study was to assess acute changes of IL-6 system in the peripheral blood of patients given high-dose GCs.

Subjects and methods: Serum levels of IL-6, sIL-6R, sgp130 and bone turnover markers were assessed before and each day during treatment in 24 multiple sclerosis (MS) patients undergoing high-dose (prednisolone, 15 mg/kg per day), short-term (3 to 5 days) intravenous GC therapy for relapse at the Regional Multiple Sclerosis Centre.

Results: An immediate and marked fall of osteocalcin and an early increase of C-terminal telopeptide of type I collagen were already noticed at day 2 (P < 0.001 and P < 0.02, respectively); both became more apparent in the subsequent days. IL-6 was always below or near the detection limit of our ELISA. sgp130 showed a slight increase. sIL-6R significantly increased, peaking at day 4 (P < 0.01). However, inter-individual variability of response was noticed. Four patients showed a slight decrease, while no change was observed in one patient and an increase was noticed in the remaining nineteen (maximum change ranging from +10% to +67% with respect to baseline). In these patients, a significant increase of sIL-6R/sgp130 ratio was apparent. No correlation was found between bone turnover markers and any measured component of the IL-6 system.

Conclusions: sIL-6R and sIL-6R/sgp130 ratio are precociously increased in the peripheral blood of the vast majority of patients given high-dose, intravenous GCs. The increase of systemically available sIL-6R conceivably results in the enhancement of IL-6-dependent osteoclastogenesis. The role of such a mechanism in the bone loss observed in inflammatory and immune-mediated diseases (where abundancy of IL-6 in the bone microenvironment is expected) requires further investigation.