title: Hdac3 Deficiency Increases Marrow Adiposity and Induces Lipid Storage and Glucocorticoid Metabolism in Osteochondroprogenitor Cells.
abstract: Bone loss and increased marrow adiposity are hallmarks of aging skeletons. Conditional deletion of histone deacetylase 3 (Hdac3) in murine osteochondroprogenitor cells causes osteopenia and increases marrow adiposity, even in young animals, but the origins of the increased adiposity are unclear. To explore this, bone marrow stromal cells (BMSCs) from Hdac3-depleted and control mice were cultured in osteogenic medium. Hdac3-deficient cultures accumulated lipid droplets in greater abundance than control cultures and expressed high levels of genes related to lipid storage (Fsp27/Cidec, Plin1) and glucocorticoid metabolism (Hsd11b1) despite normal levels of Pparγ2. Approximately 5% of the lipid containing cells in the wild-type cultures expressed the master osteoblast transcription factor Runx2, but this population was threefold greater in the Hdac3-depleted cultures. Adenoviral expression of Hdac3 restored normal gene expression, indicating that Hdac3 controls glucocorticoid activation and lipid storage within osteoblast lineage cells. HDAC3 expression was reduced in bone cells from postmenopausal as compared to young women, and in osteoblasts from aged as compared to younger mice. Moreover, phosphorylation of S424 in Hdac3, a posttranslational mark necessary for deacetylase activity, was suppressed in osseous cells from old mice. Thus, concurrent declines in transcription and phosphorylation combine to suppress Hdac3 activity in aging bone, and reduced Hdac3 activity in osteochondroprogenitor cells contributes to increased marrow adiposity associated with aging. © 2015 American Society for Bone and Mineral Research.
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.|Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA, USA.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: McGee-Lawrence
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Lomeli R
authors.initials: LR
authors.lastname: Carpio
authors.affiliation: Department of Medicine, Division of Gastroenterology and Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Schulze
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Pierce
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.|Department of Medicine, Division of Gastroenterology and Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McNiven
authors.affiliation: Department of Medicine, Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Farr
authors.affiliation: Department of Medicine, Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.|Department of Medicine, Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Merry Jo
authors.initials: MJ
authors.lastname: Oursler
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D050154:Adiposity; D000375:Aging; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D000099186:Histone Deacetylase 3
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D002352:Carrier Proteins; D005938:Glucocorticoids; D006655:Histone Deacetylases; D047495:PPAR gamma; D000070778:Perilipin-1; D010750:Phosphoproteins; D011506:Proteins; D000099186:Histone Deacetylase 3; C000602978:PLIN1 protein, human; C000602979:Plin1 protein, mouse; C525805:fat-specific protein 27, mouse
keywords: AGING; HSD11B1; LIPID DROPLETS; OSTEOPOROSIS; RUNX2