Abstract
Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets 'osteoclastic' molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1-Bcl6-osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Phosphatase / metabolism
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Animals
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Bone Remodeling / physiology*
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Bone Resorption / genetics
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Bone Resorption / pathology
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Bone and Bones / cytology
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Bone and Bones / pathology
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Cathepsin K / genetics
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Cell Count
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation / genetics
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Gene Expression / drug effects
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Gene Expression / genetics
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Gene Expression Regulation / physiology*
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Growth Plate / pathology
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Isoenzymes / metabolism
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Macrophages / drug effects
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Macrophages / metabolism
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Membrane Proteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism
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Nerve Tissue Proteins / genetics
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Osteoblasts / pathology
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Osteoclasts / cytology*
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Osteoclasts / metabolism
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Osteoclasts / pathology
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Osteopetrosis / genetics
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Osteopetrosis / pathology
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Positive Regulatory Domain I-Binding Factor 1
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-bcl-6
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RANK Ligand / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Tartrate-Resistant Acid Phosphatase
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Bcl6 protein, mouse
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DC-STAMP protein, mouse
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DNA-Binding Proteins
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Isoenzymes
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Membrane Proteins
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NFATC Transcription Factors
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Nerve Tissue Proteins
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Nfatc1 protein, mouse
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Prdm1 protein, mouse
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Proto-Oncogene Proteins c-bcl-6
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RANK Ligand
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Tnfsf11 protein, mouse
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Transcription Factors
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Positive Regulatory Domain I-Binding Factor 1
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Cathepsin K
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Ctsk protein, mouse