title: HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch.
abstract: The bone-resorbing osteoclast is essential for skeletal remodeling, yet its deregulation contributes to diseases such as osteoporosis and cancer bone metastasis. Here we identify histone deacetylase 7 (HDAC7) as a key negative regulator of osteoclastogenesis and bone resorption using both in vitro cellular and molecular analyses and in vivo characterization of conditional HDAC7-knockout mice. Bone marrow osteoclast differentiation assays reveal that HDAC7 overexpression suppresses, whereas HDAC7 deletion enhances, osteoclastogenesis. Mechanistically, in the absence of receptor activator of nuclear factor κ-B ligand (RANKL), HDAC7 attenuates β-catenin function and cyclin D1 expression, thereby reducing precursor proliferation; upon RANKL activation, HDAC7 suppresses NFATc1 and prevents β-catenin down-regulation, thereby blocking osteoclast differentiation. Consequently, HDAC7 deletion in the osteoclast lineage results in a 26% reduction in bone mass (P = 0.003) owing to 102% elevated bone resorption (P = 0.01). These findings are clinically significant in light of the remarkable therapeutic potentials of HDAC inhibitors for several diseases such as cancer, diabetes, and neurodegeneration.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zixue
authors.initials: Z
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Paul C
authors.initials: PC
authors.lastname: Dechow
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D015519:Bone Density; D016723:Bone Remodeling; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism; D015536:Down-Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010024:Osteoporosis; D053245:RANK Ligand / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D051176:beta Catenin; D019938:Cyclin D1; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases