6-Methylprednisolone down-regulates IRAK-M in human and murine osteoclasts and boosts bone-resorbing activity: a putative mechanism for corticoid-induced osteoporosis.
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.
Soares-Schanoski
Alessandra
A
Research Unit, La Paz Hospital, Madrid 28046, Spain.
Gómez-Piña
Vanesa
V
del Fresno
Carlos
C
Rodríguez-Rojas
Alexandro
A
García
Felipe
F
Glaría
Alberto
A
Sánchez
Miriam
M
Vallejo-Cremades
María Teresa
MT
Baos
Rosa
R
Fuentes-Prior
Pablo
P
Arnalich
Francisco
F
López-Collazo
Eduardo
E
D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013644:Tartrates / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013644:Tartrates; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C029768:tartaric acid; D008775:Methylprednisolone