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Originally published online as doi:10.1189/jlb.1106673 on June 18, 2007

Published online before print June 18, 2007
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(Journal of Leukocyte Biology. 2007;82:700-709.)
© 2007 by Society for Leukocyte Biology

6-Methylprednisolone down-regulates IRAK-M in human and murine osteoclasts and boosts bone-resorbing activity: a putative mechanism for corticoid-induced osteoporosis

Alessandra Soares-Schanoski*,1, Vanesa Gómez-Piña*,1, Carlos del Fresno*,1, Alexandro Rodríguez-Rojas*, Felipe García{dagger}, Alberto Glaría{ddagger}, Miriam Sánchez*, María Teresa Vallejo-Cremades*, Rosa Baos*, Pablo Fuentes-Prior§, Francisco Arnalich|| and Eduardo López-Collazo*,2

* Research Unit, ‘La Paz’ Hospital, and
|| Department of Medicine, ‘La Paz’ Hospital Medical School, Universidad Autónoma de Madrid, Madrid, Spain;
{dagger} Discovery Unit, EMPIREO S.L., Madrid, Spain;
{ddagger} Instituto Madrileño de Oncología, Madrid, Spain; and
§ Cardiovascular Research Center, ICCC-CSIC, Sant Antoni Ma. Claret 167, Barcelona, Spain

2 Correspondence: Research Unit, ‘La Paz’ Hospital, Madrid 28046, Spain. E-mail: elopezc.hulp{at}salud.madrid.org

Osteoclasts are large, multinucleated cells, which originate from the fusion of macrophages. They play a central role in bone development and remodeling via the resorption of bone and are thus important mediators of bone loss, which leads to osteoporosis. IL-1R-associated kinase (IRAK)-M is a pseudokinase, which acts as a negative modulator of innate immune responses mediated by TLRs and IL-1R. Recently, it has been reported that IRAK-M also participates in the control of macrophage differentiation into osteoclasts. In addition, it was shown that IRAK-M knockout mice develop a strong osteoporosis phenotype, suggesting that down-regulation of this molecule activates osteoclast-mediated bone resorption. We studied the effect of the osteoporosis-inducing glucocorticoid, 6-methylprednisolone (6-MP), on IRAK-M expression in osteoclasts. Our results showed that osteoclasts, derived from THP-1 and RAW cells as well as human blood monocytes, differentiated into osteoclasts, express high levels of IRAK-M at mRNA and protein levels. In addition, 6-MP down-regulates IRAK-M expression, which correlates with an increased activation of bone resorption. These findings suggest a mechanism of corticosteroid-induced osteoporosis and open new avenues for treating this endemic disease of Western societies.

Key Words: glucocorticoids • TLR • IL-1R




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