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.
Kamolmatyakul
S
S
Department of Cytokine Biology, Forsyth Institute & Harvard School of Dental Medicine, Boston, MA 02135, USA.
Chen
W
W
Li
Y P
YP
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