title: Glucocorticoid receptor and Histone deacetylase 6 mediate the differential effect of dexamethasone during osteogenesis of mesenchymal stromal cells (MSCs).
abstract: Lineage commitment and differentiation of mesenchymal stromal cells (MSCs) into osteoblasts in vitro is enhanced by a potent synthetic form of glucocorticoid (GC), dexamethasone (Dex). Paradoxically, when used chronically in patients, GCs exert negative effects on bone, a phenomenon known as glucocorticoid-induced osteoporosis in clinical practice. The mechanism on how GC differentially affects bone precursor cells to become mature osteoblasts during osteogenesis remains elusive. In this study, the dose and temporal regulation of Dex on MSC differentiation into osteoblasts were investigated. We found that continuous Dex treatment led to a net reduction of the maturation potential of differentiating osteoblasts. This phenomenon correlated with a decrease in glucocorticoid receptor (GR) expression, hastened degradation, and impaired sub cellular localization. Similarly, Histone Deacetylase 6 (HDAC6) expression was found to be regulated by Dex, co-localized with GR and this GR-HDAC6 complex occupied the promoter region of the osteoblast late marker osteocalcin (OCN). Combinatorial inhibition of HDAC6 and GR enhanced OCN expression. Together, the cross-talk between the Dex effector molecule GR and the inhibitory molecule HDAC6 provided mechanistic explanation of the bimodal effect of Dex during osteogenic differentiation of MSCs. These findings may provide new directions of research to combat glucocorticoid-induced osteoporosis.
authors.affiliation: Molecular Medicine Program, Taiwan International Graduate Program, Academia Sinica and Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Rimando
authors.affiliation: Institute of Biophotonics, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Hao-Hsiang
authors.initials: HH
authors.lastname: Wu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Liu
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan.
authors.forename: Chien-Wei
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Kuo
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan.
authors.forename: Yin-Ping
authors.initials: YP
authors.lastname: Lo
authors.affiliation: Department of Orthopaedics, Cheng-Hsin General Hospital, Taipei 11220, Taiwan.
authors.forename: Kuo-Fung
authors.initials: KF
authors.lastname: Tseng
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yi-Shiuan
authors.initials: YS
authors.lastname: Liu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.|Taipei City Hospital, Taipei 10341, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
authors.forename: Oscar Kuang-Sheng
authors.initials: OK
authors.lastname: Lee
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D000073864:Histone Deacetylase 6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D000469:Alkaline Phosphatase; D000073864:Histone Deacetylase 6