Histone Deacetylases in Cartilage Homeostasis and Osteoarthritis

1.

Li Y, Wen H, Xi Y, Tanaka K, Wang H, Peng D, et al. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell. 2014;159(3):558–71. doi:10.1016/j.cell.2014.09.049.PubMedPubMedCentralCrossRef

2.

Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene. 2005;363:15–23. doi:10.1016/j.gene.2005.09.010.PubMedCrossRef

3.

Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325(5942):834–40. doi:10.1126/science.1175371.PubMedCrossRef

4.

Jeon EJ, Lee KY, Choi NS, Lee MH, Kim HN, Jin YH, et al. Bone morphogenetic protein-2 stimulates Runx2 acetylation. J Biol Chem. 2006;281(24):16502–11. doi:10.1074/jbc.M512494200.PubMedCrossRef

5.

Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS, et al. Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem. 2000;275(27):20436–43. doi:10.1074/jbc.M000202200.PubMedCrossRef

6.

Luo J, Su F, Chen D, Shiloh A, Gu W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature. 2000;408(6810):377–81. doi:10.1038/35042612.PubMedCrossRef

7.

Yuan ZL, Guan YJ, Chatterjee D, Chin YE. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 2005;307(5707):269–73. doi:10.1126/science.1105166.PubMedCrossRef

8.

Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10(1):32–42. doi:10.1038/nrg2485.PubMedPubMedCentralCrossRef

9.

Bradley EW, Carpio LR, van Wijnen AJ, McGee-Lawrence ME, Westendorf JJ. Histone deacetylases in bone development and skeletal disorders. Physiol Rev. 2015;95(4):1359–81. doi:10.1152/physrev.00004.2015.PubMedCrossRef

10.

Chini CC, Escande C, Nin V, Chini EN. HDAC3 is negatively regulated by the nuclear protein DBC1. J Biol Chem. 2010;285(52):40830–7. doi:10.1074/jbc.M110.153270.PubMedPubMedCentralCrossRef

11.

Yang WM, Tsai SC, Wen YD, Fejer G, Seto E. Functional domains of histone deacetylase-3. J Biol Chem. 2002;277(11):9447–54. doi:10.1074/jbc.M105993200.PubMedCrossRef

12.

Yang XJ, Seto E. Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression. Curr Opin Genet Dev. 2003;13(2):143–53. doi:10.1016/S0959-437X(03)00015-7.PubMedCrossRef

13.

Delcuve GP, Khan DH, Davie JR. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin Epigenet. 2012;4(1):5. doi:10.1186/1868-7083-4-5.CrossRef

14.

Bantscheff M, Hopf C, Savitski MM, Dittmann A, Grandi P, Michon AM, et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat Biotechnol. 2011;29(3):255–65. doi:10.1038/nbt.1759.PubMedCrossRef

15.

Brunmeir R, Lagger S, Seiser C. Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. Int J Dev Biol. 2009;53(2–3):275–89. doi:10.1387/ijdb.082649rb.PubMedCrossRef

16.

Taplick J, Kurtev V, Kroboth K, Posch M, Lechner T, Seiser C. Homo-oligomerisation and nuclear localisation of mouse histone deacetylase 1. J Mol Biol. 2001;308(1):27–38. doi:10.1006/jmbi.2001.4569.PubMedCrossRef

17.

Hayakawa T, Nakayama J. Physiological roles of class I HDAC complex and histone demethylase. J Biomed Biotechnol. 2011;2011:129383. doi:10.1155/2011/129383.PubMedCrossRef

18.

Perissi V, Jepsen K, Glass CK, Rosenfeld MG. Deconstructing repression: evolving models of co-repressor action. Nat Rev Genet. 2010;11(2):109–23. doi:10.1038/nrg2736.PubMedCrossRef

19.

Wen YD, Perissi V, Staszewski LM, Yang WM, Krones A, Glass CK, et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc Natl Acad Sci U S A. 2000;97(13):7202–7. doi:10.1073/pnas.97.13.7202.PubMedPubMedCentralCrossRef

20.

Marks PA. Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions. Biochim Biophys Acta. 2010;1799(10–12):717–25. doi:10.1016/j.bbagrm.2010.05.008.PubMedPubMedCentralCrossRef

21.

Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell. 2008;30(1):61–72. doi:10.1016/j.molcel.2008.02.030.PubMedPubMedCentralCrossRef

22.

Lu J, McKinsey TA, Nicol RL, Olson EN. Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci U S A. 2000;97(8):4070–5. doi:10.1073/pnas.080064097.PubMedPubMedCentralCrossRef

23.

McKinsey TA, Zhang CL, Lu J, Olson EN. Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature. 2000;408(6808):106–11. doi:10.1038/35040593.PubMedPubMedCentralCrossRef

24.

Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, et al. Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Mol Cell Biol. 2004;24(19):8374–85. doi:10.1128/MCB.24.19.8374-8385.2004.PubMedPubMedCentralCrossRef

25.

Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, et al. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell. 2002;9(1):45–57. doi:10.1016/S1097-2765(01)00429-4.PubMedCrossRef

26.

Verdin E, Dequiedt F, Kasler HG. Class II histone deacetylases: versatile regulators. Trends Genet. 2003;19(5):286–93. doi:10.1016/S0168-9525(03)00073-8.PubMedCrossRef

27.

Chang S, Young BD, Li S, Qi X, Richardson JA, Olson EN. Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell. 2006;126(2):321–34. doi:10.1016/j.cell.2006.05.040.PubMedCrossRef

28.

Bheda P, Wolberger C. Biochemistry: sirtuin on a high-fat diet. Nature. 2013;496(7443):41–2. doi:10.1038/496041a.PubMedCrossRef

29.

Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, et al. SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature. 2013;496(7443):110–3. doi:10.1038/nature12038.PubMedPubMedCentralCrossRef

30.

Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006;126(5):941–54. doi:10.1016/j.cell.2006.06.057.PubMedCrossRef

31.

Choi JE, Mostoslavsky R. Sirtuins, metabolism, and DNA repair. Curr Opin Genet Dev. 2014;26C:24–32. doi:10.1016/j.gde.2014.05.005.CrossRef

32.

Orozco-Solis R, Sassone-Corsi P. Circadian clock: linking epigenetics to aging. Curr Opin Genet Dev. 2014;26C:66–72. doi:10.1016/j.gde.2014.06.003.CrossRef

33.

Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332–6. doi:10.1038/nature01657.PubMedCrossRef

34.

Pillai R, Coverdale LE, Dubey G, Martin CC. Histone deacetylase 1 (HDAC-1) required for the normal formation of craniofacial cartilage and pectoral fins of the zebrafish. Dev Dyn. 2004;231(3):647–54. doi:10.1002/dvdy.20168.PubMedCrossRef

35.

Ignatius MS, Unal Eroglu A, Malireddy S, Gallagher G, Nambiar RM, Henion PD. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development. PLoS One. 2013;8(5), e63218. doi:10.1371/journal.pone.0063218.PubMedPubMedCentralCrossRef

36.

Razidlo DF, Whitney TJ, Casper ME, McGee-Lawrence ME, Stensgard BA, Li X, et al. Histone deacetylase 3 depletion in osteo/chondroprogenitor cells decreases bone density and increases marrow fat. PLoS One. 2010;5(7), e11492. doi:10.1371/journal.pone.0011492.PubMedPubMedCentralCrossRef

37.

Bradley EW, Carpio LR, Westendorf JJ. Histone deacetylase 3 suppression increases PH domain and leucine-rich repeat phosphatase (Phlpp)1 expression in chondrocytes to suppress Akt signaling and matrix secretion. J Biol Chem. 2013;288(14):9572–82. doi:10.1074/jbc.M112.423723.PubMedPubMedCentralCrossRef

38.

Carpio LR, Bradley EW, Dudakovic A, van Wijnen AJ, McGee-Lawrence ME, Westendorf JJ. Histone deacetylase 3 controls extracellular matrix remodeling and proinflammatory signals in chondrocytes. Seattle: American Society for Bone and Mineral Research; 2015.

39.

Carpio LR, Bradley EW, McGee-Lawrence ME, Westendorf JJ. Histone deacetylase 3 suppresses Erk phosphorylation and subsequent matrix metalloproteinase (MMP)-13 activity in chondrocytes during endochondral ossification. Houston: American Society for Bone and Mineral Research; 2014.

40.

Haberland M, Mokalled MH, Montgomery RL, Olson EN. Epigenetic control of skull morphogenesis by histone deacetylase 8. Genes Dev. 2009;23(14):1625–30. doi:10.1101/gad.1809209.PubMedPubMedCentralCrossRef

41.

Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, et al. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell. 2004;119(4):555–66. doi:10.1016/j.cell.2004.10.024.PubMedCrossRef

42.

Shimizu E, Nakatani T, He Z, Partridge NC. Parathyroid hormone regulates histone deacetylase (HDAC) 4 through protein kinase A-mediated phosphorylation and dephosphorylation in osteoblastic cells. J Biol Chem. 2014;289(31):21340–50. doi:10.1074/jbc.M114.550699.PubMedPubMedCentralCrossRef

43.

Shimizu E, Selvamurugan N, Westendorf JJ, Olson EN, Partridge NC. HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression. J Biol Chem. 2010;285(13):9616–26. doi:10.1074/jbc.M109.094862.PubMedPubMedCentralCrossRef

44.

Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen AJ, Lian JB, et al. Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Mol Cell Biol. 2002;22(22):7982–92. doi:10.1128/MCB.22.22.7982-7992.2002.PubMedPubMedCentralCrossRef

45.

Simon D, Laloo B, Barillot M, Barnetche T, Blanchard C, Rooryck C, et al. A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia. Hum Mol Genet. 2010;19(10):2015–27. doi:10.1093/hmg/ddq083.PubMedCrossRef

46.•

Bradley EW, Carpio LR, Olson EN, Westendorf JJ. Histone deacetylase 7 (Hdac7) suppresses chondrocyte proliferation and beta-catenin activity during endochondral ossification. J Biol Chem. 2015;290(1):118–26. doi:10.1074/jbc.M114.596247. This report showed that deletion of Hdac7 in chondrocytes enhances growth plate chondrocyte proliferation.PubMedCrossRef

47.••

Gabay O, Zaal KJ, Sanchez C, Dvir-Ginzberg M, Gagarina V, Song Y, et al. Sirt1-deficient mice exhibit an altered cartilage phenotype. Joint Bone Spine. 2013;80(6):613–20. doi:10.1016/j.jbspin.2013.01.001. This study evaluated the cartilage phenotypes in Sirt1-deficient mice and confirmed chondroprotective mechanisms of Sirt1 in vivo.PubMedPubMedCentralCrossRef

48.

Lemieux ME, Yang X, Jardine K, He X, Jacobsen KX, Staines WA, et al. The Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals. Mech Ageing Dev. 2005;126(10):1097–105. doi:10.1016/j.mad.2005.04.006.PubMedCrossRef

49.

McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, et al. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol. 2003;23(1):38–54. doi:10.1128/MCB.23.1.38-54.2003.PubMedPubMedCentralCrossRef

50.

Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124(2):315–29. doi:10.1016/j.cell.2005.11.044.PubMedCrossRef

51.

Piao J, Tsuji K, Ochi H, Iwata M, Koga D, Okawa A, et al. Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling. Sci Rep. 2013;3:3022. doi:10.1038/srep03022.PubMedCrossRef

52.

St Sauver JL, Warner DO, Yawn BP, Jacobson DJ, McGree ME, Pankratz JJ, et al. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc. 2013;88(1):56–67. doi:10.1016/j.mayocp.2012.08.020.PubMedPubMedCentralCrossRef

53.

Murray CJ, Atkinson C, Bhalla K, Birbeck G, Burstein R, Chou D, et al. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310(6):591–608. doi:10.1001/jama.2013.13805.PubMedCrossRef

54.

Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197–223. doi:10.1016/S0140-6736(12)61689-4.PubMedCrossRef

55.

Hunter DJ, Schofield D, Callander E. The individual and socioeconomic impact of osteoarthritis. Nat Rev Rheumatol. 2014;10(7):437–41. doi:10.1038/nrrheum.2014.44.PubMed

56.

Hootman JM, Helmick CG. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum. 2006;54(1):226–9. doi:10.1002/art.21562.PubMedCrossRef

57.

Houard X, Goldring MB, Berenbaum F. Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. Curr Rheumatol Rep. 2013;15(11):375. doi:10.1007/s11926-013-0375-6.PubMedPubMedCentralCrossRef

58.

Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697–707. doi:10.1002/art.34453.PubMedPubMedCentralCrossRef

59.

Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci. 2010;1192:230–7. doi:10.1111/j.1749-6632.2009.05240.x.PubMedCrossRef

60.

Hong S, Derfoul A, Pereira-Mouries L, Hall DJ. A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes. FASEB J. 2009;23(10):3539–52. doi:10.1096/fj.09-133215.PubMedPubMedCentralCrossRef

61.

Huh YH, Ryu JH, Chun JS. Regulation of type II collagen expression by histone deacetylase in articular chondrocytes. J Biol Chem. 2007;282(23):17123–31. doi:10.1074/jbc.M700599200.PubMedCrossRef

62.

Liu CJ, Prazak L, Fajardo M, Yu S, Tyagi N, Di Cesare PE. Leukemia/lymphoma-related factor, a POZ domain-containing transcriptional repressor, interacts with histone deacetylase-1 and inhibits cartilage oligomeric matrix protein gene expression and chondrogenesis. J Biol Chem. 2004;279(45):47081–91. doi:10.1074/jbc.M405288200.PubMedCrossRef

63.

Higashiyama R, Miyaki S, Yamashita S, Yoshitaka T, Lindman G, Ito Y, et al. Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. Mod Rheumatol. 2010;20(1):11–7. doi:10.1007/s10165-009-0224-7.PubMedCrossRef

64.

Abed E, Couchourel D, Delalandre A, Duval N, Pelletier JP, Martel-Pelletier J, et al. Low sirtuin 1 levels in human osteoarthritis subchondral osteoblasts lead to abnormal sclerostin expression which decreases Wnt/beta-catenin activity. Bone. 2014;59:28–36. doi:10.1016/j.bone.2013.10.020.PubMedCrossRef

65.

Dvir-Ginzberg M, Gagarina V, Lee EJ, Hall DJ. Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase. J Biol Chem. 2008;283(52):36300–10. doi:10.1074/jbc.M803196200.PubMedPubMedCentralCrossRef

66.

Mercken EM, Mitchell SJ, Martin-Montalvo A, Minor RK, Almeida M, Gomes AP, et al. SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell. 2014;13(5):787–96. doi:10.1111/acel.12220.PubMedPubMedCentralCrossRef

67.

Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A. 2003;100(19):10794–9. doi:10.1073/pnas.1934713100.PubMedPubMedCentralCrossRef

68.••

Gabay O, Sanchez C, Dvir-Ginzberg M, Gagarina V, Zaal KJ, Song Y, et al. Sirtuin 1 enzymatic activity is required for cartilage homeostasis in vivo in a mouse model. Arthritis Rheum. 2013;65(1):159–66. doi:10.1002/art.37750. This study showed that enzymatically active Sirt1 is necessary for chondroprotection and maintainence of normal cartilage homeostasis.PubMedPubMedCentralCrossRef

69.••

Wu Y, Chen L, Wang Y, Li W, Lin Y, Yu D, et al. Overexpression of Sirtuin 6 suppresses cellular senescence and NF-kappaB mediated inflammatory responses in osteoarthritis development. Sci Rep. 2015;5:17602. doi:10.1038/srep17602. This report demonstrated that the activation of Sirt6 prevents articular cartilage degradation in mouse models of osteoarthritis.PubMedPubMedCentralCrossRef

70.•

Cao K, Wei L, Zhang Z, Guo L, Zhang C, Li Y, et al. Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a novel mechanism of human osteoarthritis cartilage degeneration. Arthritis Res Ther. 2014;16(6):491. doi:10.1186/s13075-014-0491-3. This study examined Hdac4 expression in OA and normal articular cartilage and concluded that Hdac4 expression inversely correlated with OA development.PubMedPubMedCentralCrossRef

71.•

Lu J, Sun Y, Ge Q, Teng H, Jiang Q. Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis. BMC Musculoskelet Disord. 2014;15:438. doi:10.1186/1471-2474-15-438. This paper demonstrated that Hdac4 expression levels can vary depending on the severity of OA and location within the different chondrocytic zones of the articular cartilage. Repression of Hdac4 reduced matrix degrading enzymes in OA chondrocytes.PubMedPubMedCentralCrossRef

72.•

Song J, Jin EH, Kim D, Kim KY, Chun CH, Jin EJ. MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clin. 2015;3:79–89. doi:10.1016/j.bbacli.2014.11.009. In this paper, Hdac4 expression was higher in OA chondrocytes due to suppression of the micro RNA, miR-222.PubMedCrossRef

73.

Dinarello CA, Fossati G, Mascagni P. Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol Med. 2011;17(5–6):333–52. doi:10.2119/molmed.2011.00116.PubMedPubMedCentral

74.

Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13(9):673–91. doi:10.1038/nrd4360.PubMedCrossRef

75.

Lakshmaiah KC, Jacob LA, Aparna S, Lokanatha D, Saldanha SC. Epigenetic therapy of cancer with histone deacetylase inhibitors. J Cancer Res Ther. 2014;10(3):469–78. doi:10.4103/0973-1482.137937.PubMed

76.

McGee-Lawrence ME, Westendorf JJ. Histone deacetylases in skeletal development and bone mass maintenance. Gene. 2011;474(1–2):1–11. doi:10.1016/j.gene.2010.12.003.PubMedCrossRef

77.

Slingerland M, Guchelaar HJ, Gelderblom H. Histone deacetylase inhibitors: an overview of the clinical studies in solid tumors. Anticancer Drugs. 2014;25(2):140–9. doi:10.1097/CAD.0000000000000040.PubMedCrossRef

78.

Boluk A, Guzelipek M, Savli H, Temel I, Ozisik HI, Kaygusuz A. The effect of valproate on bone mineral density in adult epileptic patients. Pharmacol Res. 2004;50(1):93–7. doi:10.1016/j.phrs.2003.11.011.PubMedCrossRef

79.

Giavini E, Menegola E. Teratogenic activity of HDAC inhibitors. Curr Pharm Des. 2014;20(34):5438–42. doi:10.2174/1381612820666140205144900.PubMedCrossRef

80.

Guo CY, Ronen GM, Atkinson SA. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia. 2001;42(9):1141–7. doi:10.1046/j.1528-1157.2001.416800.x.PubMedCrossRef

81.

Oner N, Kaya M, Karasalihoglu S, Karaca H, Celtik C, Tutunculer F. Bone mineral metabolism changes in epileptic children receiving valproic acid. J Paediatr Child Health. 2004;40(8):470–3. doi:10.1111/j.1440-1754.2004.00431.x.PubMedCrossRef

82.

Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology. 2001;57(3):445–9. doi:10.1212/WNL.57.3.445.PubMedCrossRef

83.

Senn SM, Kantor S, Poulton IJ, Morris MJ, Sims NA, O’Brien TJ, et al. Adverse effects of valproate on bone: defining a model to investigate the pathophysiology. Epilepsia. 2010;51(6):984–93. doi:10.1111/j.1528-1167.2009.02516.x.PubMedCrossRef

84.

Sheth RD, Wesolowski CA, Jacob JC, Penney S, Hobbs GR, Riggs JE, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr. 1995;127(2):256–62. doi:10.1016/S0022-3476(95)70304-7.PubMedCrossRef

85.

McGee-Lawrence ME, McCleary-Wheeler AL, Secreto FJ, Razidlo DF, Zhang M, Stensgard BA, et al. Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts. Bone. 2011;48(5):1117–26. doi:10.1016/j.bone.2011.01.007.PubMedPubMedCentralCrossRef

86.

Lajeunie E, Barcik U, Thorne JA, El Ghouzzi V, Bourgeois M, Renier D. Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg. 2001;95(5):778–82. doi:10.3171/jns.2001.95.5.0778.PubMedCrossRef

87.

Ornoy A. Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod Toxicol. 2006;22(2):214–26. doi:10.1016/j.reprotox.2006.03.014.PubMedCrossRef

88.

Sharony R, Garber A, Viskochil D, Schreck R, Platt LD, Ward R, et al. Preaxial ray reduction defects as part of valproic acid embryofetopathy. Prenat Diagn. 1993;13(10):909–18. doi:10.1002/pd.1970131005.PubMedCrossRef

89.

Vajda FJ, Eadie MJ. Maternal valproate dosage and foetal malformations. Acta Neurol Scand. 2005;112(3):137–43. doi:10.1111/j.1600-0404.2005.00458.x.PubMedCrossRef

90.

Paradis FH, Hales BF. Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. Toxicol Sci. 2013;131(1):234–41. doi:10.1093/toxsci/kfs292.PubMedCrossRef

91.

Di Renzo F, Broccia ML, Giavini E, Menegola E. Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate. Toxicol Sci. 2007;98(2):582–8. doi:10.1093/toxsci/kfm115.PubMedCrossRef

92.

Di Renzo F, Cappelletti G, Broccia ML, Giavini E, Menegola E. Boric acid inhibits embryonic histone deacetylases: a suggested mechanism to explain boric acid-related teratogenicity. Toxicol Appl Pharmacol. 2007;220(2):178–85. doi:10.1016/j.taap.2007.01.001.PubMedCrossRef

93.•

Paradis FH, Hales BF. The effects of class-specific histone deacetylase inhibitors on the development of limbs during organogenesis. Toxicol Sci. 2015;148(1):220–8. doi:10.1093/toxsci/kfv174. The effects of HDAC inhibitors on the different phases of skeletal development and limb growth were studied in mice expressing fluorescent proteins that trace three skeletal lineages.PubMedCrossRef

94.••

Culley KL, Hui W, Barter MJ, Davidson RK, Swingler TE, Destrument AP, et al. Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation. Arthritis Rheum. 2013;65(7):1822–30. doi:10.1002/art.37965. This is the first study to systemically administer HDAC inhibitors to mice in the DMM model of osteoarthritis. HDAC inhibitors prevented OA development by repressing cytokine-induced expression of Mmp1 and Mmp13 expression in articular chondrocytes.PubMedCrossRef

95.

Chen WP, Bao JP, Hu PF, Feng J, Wu LD. Alleviation of osteoarthritis by Trichostatin A, a histone deacetylase inhibitor, in experimental osteoarthritis. Mol Biol Rep. 2010;37(8):3967–72. doi:10.1007/s11033-010-0055-9.PubMedCrossRef

96.

Chen WP, Bao JP, Tang JL, Hu PF, Wu LD. Trichostatin A inhibits expression of cathepsins in experimental osteoarthritis. Rheumatol Int. 2011;31(10):1325–31. doi:10.1007/s00296-010-1481-7.PubMedCrossRef

97.

Wang X, Song Y, Jacobi JL, Tuan RS. Inhibition of histone deacetylases antagonized FGF2 and IL-1beta effects on MMP expression in human articular chondrocytes. Growth Factors. 2009;27(1):40–9. doi:10.1080/08977190802625179.PubMedPubMedCentralCrossRef

98.

Young DA, Lakey RL, Pennington CJ, Jones D, Kevorkian L, Edwards DR, et al. Histone deacetylase inhibitors modulate metalloproteinase gene expression in chondrocytes and block cartilage resorption. Arthritis Res Ther. 2005;7(3):R503–12. doi:10.1186/ar1702.PubMedPubMedCentralCrossRef

99.•

Saito T, Nishida K, Furumatsu T, Yoshida A, Ozawa M, Ozaki T. Histone deacetylase inhibitors suppress mechanical stress-induced expression of RUNX-2 and ADAMTS-5 through the inhibition of the MAPK signaling pathway in cultured human chondrocytes. Osteoarthr Cartil. 2013;21(1):165–74. doi:10.1016/j.joca.2012.09.003. This is one of the initial studies investigating how Hdac inhibitors repress matrix degrading enzymes in human chondrocytes.PubMedCrossRef

100.•

Zhong HM, Ding QH, Chen WP, Luo RB. Vorinostat, a HDAC inhibitor, showed anti-osteoarthritic activities through inhibition of iNOS and MMP expression, p38 and ERK phosphorylation and blocking NF-kappaB nuclear translocation. Int Immunopharmacol. 2013;17(2):329–35. doi:10.1016/j.intimp.2013.06.027. This in vitro study showed that the Hdac inhibitor, vorinostat, represses matrix degrading enzymes and the overproduction of nitric oxide by inhibiting MAPK signaling and nuclear translocation and transcriptional activity of NF-kappaB in human chondrocytes.PubMedCrossRef

101.•

Makki MS, Haqqi TM. HDAC inhibitor SAHA induces MCPIP1 expression and suppresses Il-6 expression in human OA chondrocytes. Osteoarthr Cartil. 2015;23:A156. doi:10.1016/j.joca.2015.02.911. This in vitro study showed that SAHA (vorinostat) induces the expression of a negative regulator of Il-6 in human OA chondrocytes, which suppressed Il-6 and reduced matrix degradation.

102.••

Cai D, Yin S, Yang J, Jiang Q, Cao W. Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis. Arthritis Res Ther. 2015;17:269. doi:10.1186/s13075-015-0774-3. This report showed that Nrf2 regulates expression of antioxidant enzymes and is necessary for chrondroprotection by HDIs in an OA model.PubMedPubMedCentralCrossRef

103.•

Wang JH, Shih KS, Wu YW, Wang AW, Yang CR. Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1beta signaling in osteoarthritis fibroblast-like synoviocytes. Osteoarthr Cartil. 2013;21(12):1987–96. doi:10.1016/j.joca.2013.09.008. This paper showed that Hdac inhibitors indirectly modulates cytokine signaling through microRNAs that block cytokine-induced signaling in OA synoviocytes.PubMedCrossRef

104.

Lee S, Park JR, Seo MS, Roh KH, Park SB, Hwang JW, et al. Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells. Cell Prolif. 2009;42(6):711–20. doi:10.1111/j.1365-2184.2009.00633.x.PubMedCrossRef

Medicine Matters Rheumatology

Histone Deacetylases in Cartilage Homeostasis and Osteoarthritis

Abstract