Mitf regulates osteoclastogenesis by modulating NFATc1 activity.
Transcription factors Mitf and NFATc1 share many downstream targets that are critical for osteoclastogenesis. Since RANKL signals induce/activate both NFATc1 and Mitf isoform-E (Mitf-E), a tissue-restricted Mitf isoform in osteoclasts, it is plausible that the two factors work together to promote osteoclastogenesis. Although Mitf was shown to function upstream of NFATc1 previously, this study showed that expression of Mitf had little effects on NFATc1 and NFATc1 was critical for the induction of Mitf-E. In Mitf(mi/mi) mice, the semi-dominant mutation in Mitf gene leads to arrest of osteoclastogenesis in the early stages. However, when stimulated by RANKL, the Mitf(mi/mi) preosteoclasts responded with a significant induction of NFATc1, despite that the cells cannot differentiate into functional osteoclasts. In the absence of RANKL stimulation, very high levels of NFATc1 are required to drive osteoclast development. Our data indicate that Mitf functions downstream of NFATc1 in the RANKL pathway, and it plays an important role in amplifying NFATc1-dependent osteoclastogenic signals, which contributes to the significant synergy between the two factors during osteoclastogenesis. We propose that Mitf-E functions as a tissue-specific modulator for events downstream of NFATc1 activation during osteoclastogenesis.
['Lu|Ssu-Yi|SY|', 'Li|Mengtao|M|', 'Lin|Yi-Ling|YL|']
D000818:Animals D015153:Blotting, Western D002454:Cell Differentiation D049109:Cell Proliferation D002478:Cells, Cultured D005786:Gene Expression Regulation D051379:Mice D008810:Mice, Inbred C57BL D051739:Microphthalmia-Associated Transcription Factor D050778:NFATC Transcription Factors D010010:Osteoclasts D053245:RANK Ligand D012333:RNA, Messenger D034741:RNA, Small Interfering D060888:Real-Time Polymerase Chain Reaction D020133:Reverse Transcriptase Polymerase Chain Reaction
Mitf NFATc1 Transcription factors RANKL Osteoclasts Fusion