title: Histone deacetylation mediates the rejuvenation of osteoblastogenesis by the combination of 25(OH)D3 and parathyroid hormone in MSCs from elders.
abstract: Vitamin D metabolites are important effectors of bone and mineral homeostasis. Human bone marrow stromal cells (hMSCs) are targets of 1α,25-dihydroxyvitamin D [1α,25(OH)2D] action to promote their differentiation to osteoblasts. Osteoblastogenesis is also stimulated by 25-hydroxyvitamin D [25(OH)D], an effect that requires conversion to 1α,25(OH)2D3 by 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1). These findings support an autocrine/paracrine role of vitamin D metabolism in osteoblastogenesis of hMSCs. In this study, we assessed whether and by what mechanisms osteoblastogenesis could be rejuvenated with hMSCs from elders. First, knockdown studies with VDR-siRNA showed that both the pro-differentiation and anti-proliferative effects of 1α,25(OH)2D3 required VDR. Second, 100nM 25(OH)D3 (p<0.01 vs. control, ANOVA) and 100nM PTH1-34 (p<0.05) significantly stimulated alkaline phosphatase (ALP) activity (a measure of osteoblastogenesis), with a synergistic effect when combined (p<0.001). Scriptaid, an inhibitor of histone deacetylase, blocked the effect of 25(OH)D3 and PTH on osteoblastogenesis. Scriptaid alone downregulated VDR in hMSCs. These data demonstrate that histone deacetylation is required for the synergistic effect of 25(OH)D3 and PTH on osteoblastogenesis in hMSCs. Both VDR siRNA and Scriptaid dowregulated VDR mRNA and inhibited osteoblastogenesis. Thus, epigenetic regulation of the VDR may be central to rejuvenating osteoblastogenesis in hMSCs from elders. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
authors.affiliation: Department of Orthopedic Surgery, Orthopedic Research, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. szhou@rics.bwh.harvard.edu
authors.forename: Shuanhu
authors.initials: S
authors.lastname: Zhou
authors.forename: Shuo
authors.initials: S
authors.lastname: Geng
authors.forename: Julie
authors.initials: J
authors.lastname: Glowacki
mesh_terms: D000368:Aged; D002112:Calcifediol / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000187:drug effects; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010281:Parathyroid Hormone / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000235:genetics; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; C470125:PTH protein, human; D010281:Parathyroid Hormone; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D006655:Histone Deacetylases; D002112:Calcifediol