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

The three basic DNA‐binding domain mutations of the microphthalmia ‐associated transcription factor (Mitf), Mitf mi/mi , Mitf or/or , and Mitf wh/wh affect osteoclast differentiation with variable penetrance while completely impairing melanocyte development. Mitf or/or mice exhibit osteopetrosis that improves with age and their osteoclasts form functional multinuclear osteoclasts, raising the question as to why the Mitf or/or mutation results in osteopetrosis. Here we show that Mitf or/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 Mitf or/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 Mitf or/or osteoclast precursors, indicating that defective recruitment of co‐activators by the mutant Mitf or/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. J. Cell. Physiol. 220: 230–237, 2009. © 2009 Wiley‐Liss, Inc.