Interferon-gamma down-regulates gene expression of cathepsin K in osteoclasts and inhibits osteoclast formation.
The cytokine, IFN-gamma, has been shown in vitro to inhibit bone resorption, but the mechanisms responsible for this inhibition have not been clearly defined. Cathepsin K is a major protease responsible for bone resorption. IFN-gamma may inhibit bone resorption through down-regulation of osteoclast genes, including cathepsin K. To test the hypothesis, we investigated the effect of IFN-gamma on cathepsin K expression in the MOCP-5 and wild-type mouse bone marrow co-culture systems by Northern blot as well as osteoclast formation at different stages of differentiation. The results show that IFN-gamma down-regulates mRNA levels of cathepsin K in a time- and dose-dependent manner. Consequently, cathepsin K protein production is also reduced by IFN-gamma. Moreover, our results indicate that IFN-gamma inhibits osteoclast formation only early in osteoclast differentiation. IL-6 and TNFalpha did not significantly affect cathepsin K gene expression in osteoclasts. However, IL-1alpha stimulated gene expression. In conclusion, our data suggest that the actions of IFN-gamma on osteoclastic bone resorption may be mediated by its effects on both osteoclast formation at an early stage and osteoclast gene expression in mature osteoclasts.
Department of Cytokine Biology, Forsyth Institute & Harvard School of Dental Medicine, Boston, MA 02135, USA.
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Kamolmatyakul
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Chen
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Li
D000818:Animals; D015152:Blotting, Northern; D001862:Bone Resorption / Q000378:metabolism / Q000517:prevention & control*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004794:Enzyme Repression; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D007371:Interferon-gamma; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse