Mitf induction by RANKL is critical for osteoclastogenesis.
Microphthalmia-associated transcription factor (Mitf) regulates the development and function of several cell lineages, including osteoclasts. In this report, we identified a novel mechanism by which RANKL regulates osteoclastogenesis via induction of Mitf isoform E (Mitf-E). Both Mitf-A and Mitf-E are abundantly present in osteoclasts. Unlike Mitf-A, which is ubiquitously expressed and is present in similar amounts in macrophages and osteoclasts, Mitf-E is almost nondetectable in macrophages, but its expression is significantly up-regulated during osteoclastogenesis. In addition to their different expression profiles, the two isoforms are drastically different in their abilities to support osteoclastogenesis, despite sharing all known functional domains. Unlike Mitf-A, small amounts of Mitf-E are present in nuclear lysates unless chromatin is digested/sheared during the extraction. Based on these data, we propose a model in which Mitf-E is induced during osteoclastogenesis and is closely associated with chromatin to facilitate its interaction with target promoters; therefore, Mitf-E has a stronger osteoclastogenic activity. Mitf-A is a weaker osteoclastogenic factor, but activated Mitf-A alone is not sufficient to fully support osteoclastogenesis. Therefore, this receptor activator for nuclear factor-kappaB ligand (RANKL)-induced Mitf phenomenon seems to play an important role during osteoclastogenesis. Although the current theory indicates that Mitf and its binding partner Tfe3 are completely redundant in osteoclasts, using RNA interference, we demonstrated that Mitf has a distinct role from Tfe3. This study provides the first evidence that RANKL-induced Mitf is critical for osteoclastogenesis and Mitf is not completely redundant with Tfe3.
Lu
Ssu-Yi
SY
Section of Oral Pathology, Department of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
Li
Mengtao
M
Lin
Yi-Ling
YL
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism* / Q000502:physiology*; D011485:Protein Binding; D034622:RNA Interference; D015533:Transcriptional Activation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002843:Chromatin; D008024:Ligands; D051739:Microphthalmia-Associated Transcription Factor; C069203:TFE3 protein, human