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 alpha, IL-6Ralpha) and gp130; both exist in membrane and soluble forms. Soluble IL-6Ralpha (sIL-6Ralpha) enhances, while sgp130 inhibits IL-6 signalling. In vitro, GCs enhance many effects of IL-6 by up-regulation of IL-6Ralpha. 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-6Ralpha, 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-6Ralpha 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-6Ralpha/sgp130 ratio was apparent. No correlation was found between bone turnover markers and any measured component of the IL-6 system. CONCLUSIONS: sIL-6Ralpha and sIL-6Ralpha/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-6Ralpha 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.
High-dose glucocorticoids increase serum levels of soluble IL-6 receptor alpha and its ratio to soluble gp130: an additional mechanism for early increased bone resorption
PERAZZOLO, laura;SABA, Laura;TERMINE, Angela;ANGELI, Alberto
2006-01-01
Abstract
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 alpha, IL-6Ralpha) and gp130; both exist in membrane and soluble forms. Soluble IL-6Ralpha (sIL-6Ralpha) enhances, while sgp130 inhibits IL-6 signalling. In vitro, GCs enhance many effects of IL-6 by up-regulation of IL-6Ralpha. 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-6Ralpha, 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-6Ralpha 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-6Ralpha/sgp130 ratio was apparent. No correlation was found between bone turnover markers and any measured component of the IL-6 system. CONCLUSIONS: sIL-6Ralpha and sIL-6Ralpha/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-6Ralpha 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.
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