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.
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.


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.
Dovio
Andrea
A
Medicina Interna I, Dipartimento di Scienze Cliniche e Biologiche, University of Turin, Orbassano, Italy. andrea.dovio@unito.it
Perazzolo
Laura
L
Saba
Laura
L
Termine
Angela
A
Capobianco
Marco
M
Bertolotto
Antonio
A
Angeli
Alberto
A
D000328:Adult; D015415:Biomarkers; D001862:Bone Resorption / Q000097:blood / Q000139:chemically induced* / Q000276:immunology; D002118:Calcium / Q000097:blood / Q000652:urine; D050822:Cytokine Receptor gp130 / Q000097:blood*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D010010:Osteoclasts / Q000187:drug effects; D010758:Phosphorus / Q000097:blood; D011239:Prednisolone / Q000008:administration & dosage / Q000009:adverse effects*; D019947:Receptors, Interleukin-6 / Q000097:blood*; D012995:Solubility; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
D015415:Biomarkers; D005938:Glucocorticoids; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130; D014807:Vitamin D; D010758:Phosphorus; D011239:Prednisolone; C104450:25-hydroxyvitamin D; D002118:Calcium