Transcription factor C/EBPβ isoform ratio regulates osteoclastogenesis through MafB

Abstract

Disequilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts is central to many bone diseases. Here, we show that dysregulated expression of translationally controlled isoforms of CCAAT/enhancerbinding protein b (C/EBPb) differentially affect bone mass. Alternative translation initiation that is controlled by the mammalian target of rapamycin (mTOR) pathway generates long transactivating (LAP*, LAP) and a short repressive (LIP) isoforms from a single C/EBPb transcript. Rapamycin, an inhibitor of mTOR signalling increases the ratio of LAP over LIP and inhibits osteoclastogenesis in wild type (WT) but not in C/EBPb null (c/ebpb À/À ) or in LIP knock-in (L/L) osteoclast precursors. C/EBPb mutant mouse strains exhibit increased bone resorption and attenuated expression of MafB, a negative regulator of osteoclastogenesis. Ectopic expression of LAP and LIP in monocytes differentially affect the MafB promoter activity, MafB gene expression and dramatically affect osteoclastogenesis. These data show that mTOR regulates osteoclast formation by modulating the C/EBPb isoform ratio, which in turn affects osteoclastogenesis by regulating MafB expression.

CCAAT enhancer-binding proteins have long boney fingers

“…Smink et al showed earlier how C/EBPβ differentially affects bone mass [11]. The group found that rapamycin inhibited osteoclast generation from monocyte precursors in wild-type mice.…”

“…How can we tie these components together? The answers follow years of effort from the Leutz laboratory [9][10][11][12][13]. The story begins with their elucidation of how translational control of C/EBPβ isoforms is regulated.…”

“…Their data revealed that the C/EBPβ LIP isoform downregulates MafB gene expression, while the LAP isoform enhanced MafB expression. Moreover, ectopic expression in monocytes of either LAP or LIP C/EBPβ isoforms dramatically affected osteoclastogenesis and "knock in" mice that expressed only the LAP or the LIP isoforms instead of the wild-type C/EBPβ gene had tiny or massively enlarged osteoclasts in their bones, respectively [11,12]. We can imagine a schema in which monocyte precursors are transformed to osteoclasts largely through the C/EBPβ LIP isoform via attenuation of MafB.…”

Everolimus restrains the IL-17A-dependent osteoclast-like transdifferentiation of dendritic cells in multiple myeloma

“…Finally, IL)17A promotes the fusion of DCs, resulting in the multinucleated bone resorbing giant cells in Langherans histiocytosis while enhances the sensitivity of OC precursors to RANK)L (11,12) IL)17A stimulates with high affinity the IL)17RA that drives the OC)like transdifferentiation of iDCs through the CEBPB (CCAAT/enhancer)binding protein beta) factor, thus leading the transcription of NFATc1 (nuclear factor of activated T)cells, cytoplasmic))1, MITF (microphthalmia) associated transcription factor) and cFos while modulates MAFB (musculoaponeurotic fibrosarcoma oncogene homolog B) as the negative regulator of OC maturation (14,15). In addition, IL)17A regulates the OC polarization and bone remodelling priming the CEBPB expression for the balance of Lip/Lap isoforms while restrains experimental and human osteoclastogenesis by MAFB up)regulation (14).…”

“…In addition, IL)17A regulates the OC polarization and bone remodelling priming the CEBPB expression for the balance of Lip/Lap isoforms while restrains experimental and human osteoclastogenesis by MAFB up)regulation (14). CEBPB controls the proliferation and differentiation of OCs as well as of other cell types through the alternative translation)initiation at distinct in frame start sites of Lap and Lip isoforms ( ").…”