Defective co-activator recruitment in osteoclasts from microphthalmia-oak ridge mutant mice

Sudarshana M. Sharma, Said Sif, Michael C. Ostrowski, Uma Sankar

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The three basic DNA-binding domain mutations of the microphthalmia- associated transcription factor (Mitf), Mitfmi/mi, Mitf or/or, and Mitfwh/wh affect osteoclast differentiation with variable penetrance while completely impairing melanocyte development. Mitfor/or mice exhibit osteopetrosis that improves with age and their osteoclasts form functional multinuclear osteoclasts, raising the question as to why the Mitfor/or mutation results in osteopetrosis. Here we show that Mitfor/or osteoclasts express normal levels of acid phosphatase 5 (Acp5) mRNA and significantly lower levels of Cathepsin K (Ctsk) mRNA during receptor activator of nuclear factor kappa B (NFκB) ligand (RANKL)-mediated differentiation. Studies using chromatin immunoprecipitation (ChIP) analysis indicate that low levels of Mitfor/or protein are recruited to the Ctsk promoter. However, enrichment of Mitf-transcriptional co-activators PU.1 and Brahma-related gene 1 (Brg1) are severely impaired at the Ctsk promoter of Mitfor/or osteoclast precursors, indicating that defective recruitment of co-activators by the mutant Mitfor/or results in impaired Ctsk expression in osteoclasts. Cathepsin K may thus represent a unique class of Mitf-regulated osteoclast-specific genes that are important for osteoclast function.

Original languageEnglish (US)
Pages (from-to)230-237
Number of pages8
JournalJournal of cellular physiology
Volume220
Issue number1
DOIs
StatePublished - Jul 1 2009

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ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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