title: Mechanical stimulation orchestrates the osteogenic differentiation of human bone marrow stromal cells by regulating HDAC1.
abstract: Mechanical stimulation and histone deacetylases (HDACs) have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding what regulates HDAC expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. In this study, we investigated whether mechanical loading regulates HDAC expression directly and examined the role of HDACs in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found that the NOTCH pathway and skeletal development gene sets were downregulated in the BMSCs of patients with osteoporosis. Then we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. NOTCH signaling was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, whereas HDAC1 protein expression was downregulated. The perturbation of HDAC1 expression also had a significant effect on matrix mineralization and JAG1-mediated Notch signaling, suggesting that HDAC1 acts as an endogenous attenuator of Notch signaling in the mechanotransduction of BMSCs. Chromatin immunoprecipitation (ChIP) assay results suggest that HDAC1 modulates the CMS-induced histone H3 acetylation level at the JAG1 promoter. More importantly, we found an inhibitory role of Hdac1 in regulating bone formation in response to hindlimb unloading in mice, and pretreatment with an HDAC1 inhibitor partly rescued the osteoporosis caused by mechanical unloading. Our results demonstrate, for the first time, that mechanical stimulation orchestrates genes expression involved in the osteogenic differentiation of BMSCs via the direct regulation of HDAC1, and the therapeutic inhibition of HDAC1 may be an efficient strategy for enhancing bone formation under mechanical stimulation.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China.
authors.forename: C D
authors.initials: CD
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China.|Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories 999077, Hong Kong.
authors.forename: N
authors.initials: N
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China.|Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories 999077, Hong Kong.
authors.forename: W X
authors.initials: WX
authors.lastname: Tong
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Y F
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Shan
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China.
authors.forename: X L
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Q F
authors.initials: QF
authors.lastname: Li
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001696:Biomechanical Phenomena; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D019417:Hindlimb Suspension; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005466:Fluorocarbons
chemical_list: D001552:Benzazepines; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D000072100:Jagged-1 Protein; D034741:RNA, Small Interfering; D051880:Receptors, Notch; C000606273:JAG1 protein, human; C110550:HDAC1 protein, human; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons