title: Inhibition of histone deacetylases potentiates BMP9-induced osteogenic signaling in mouse mesenchymal stem cells.
abstract: OBJECTIVE
  We have demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent BMPs in regulating osteoblast differentiation of mesenchymal stem cells (MSCs) although the molecular mechanism underlying BMP9-induced osteogenesis remains to be fully elucidated. It is known that epigenetic regulations play an important role in regulating the stem cell potency and lineage commitment. Here, we investigate if the inhibition of histone deacetylases (Hdacs) affects BMP9-induced osteogenic differentiation of MSCs.
  
  
  METHODS
  Using the Hdac inhibitor trichostatin A (TSA), we assess that TSA enhances BMP9-mediated osteogenic markers and matrix mineralization in MSCs, and bone formation in mouse embryonic limb explants.
  
  
  RESULTS
  We find that the endogenous expression of most of the 11 Hdacs is readily detectable in MSCs. BMP9 is shown to induce most Hdacs in MSCs. We demonstrate that TSA potentiates BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs, as well as late osteogenic markers osteopontin (OPN) and osteocalcin (OCN) and matrix mineralization. Fetal limb explant culture studies reveal that TSA potentiates BMP9-induced endochondral bone formation, possibly by expanding hypertrophic chondrocyte zone of growth plate.
  
  
  CONCLUSIONS
  Our findings strongly suggest histone deacetylases may play an important role in fine-tuning BMP9-mediated osteogenic signaling through a negative feedback network in MSCs. Thus, Hdac inhibitors may be used as novel therapeutics for bone fracture healing.
authors.affiliation: Department of Orthopaedic Surgery of the First Affiliated Hospital, and the Institute for Orthopaedic Research and Education of Chongqing Medical University, Chongqing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Hu
authors.forename: Changdong
authors.initials: C
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Liang
authors.forename: Liangjun
authors.initials: L
authors.lastname: Yin
authors.forename: Xiaoji
authors.initials: X
authors.lastname: Luo
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Shui
authors.forename: Guoxin
authors.initials: G
authors.lastname: Nan
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Ningning
authors.initials: N
authors.lastname: Wu
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: He
authors.forename: Sheng
authors.initials: S
authors.lastname: Wen
authors.forename: Fang
authors.initials: F
authors.lastname: Deng
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Liao
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D055427:Growth Differentiation Factor 2 / Q000378:metabolism*; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D055427:Growth Differentiation Factor 2; D056572:Histone Deacetylase Inhibitors