The Histone-Deacetylase-Inhibitor Suberoylanilide Hydroxamic Acid Promotes Dental Pulp Repair Mechanisms Through Modulation of Matrix Metalloproteinase-13 Activity.
The Histone-Deacetylase-Inhibitor Suberoylanilide Hydroxamic Acid Promotes Dental Pulp Repair Mechanisms Through Modulation of Matrix Metalloproteinase-13 Activity.
复制标题
DOI：
10.1002/jcp.25128
复制
发表时间：
2016-04
影响因子：
5.6
通讯作者：
Cooper PR
中科院分区：
文献类型：
--
作者：
Duncan HF;Smith AJ;Fleming GJ;Partridge NC;Shimizu E;Moran GP;Cooper PR
直接应用组蛋白去乙酰化酶抑制剂（HDACis）的牙髓细胞（DPC）诱导染色质的变化，促进基因表达和细胞修复事件。我们先前已经证明HDACis（丙戊酸，阿司他丁A）通过刺激牙本质基因表达增加牙乳头衍生细胞系和原代DPC的矿化。在这里，我们研究了HDACi，辛二酰苯胺异羟肟酸（SAHA）调控的新基因，以确定有助于DPC分化的新途径。SAHA仅在相对高浓度（5 μM）时显著损害DPC活力;而低浓度（1 μM）SAHA不增加凋亡。HDACi暴露24小时诱导矿化每细胞剂量依赖性2周后，然而，恒定的14天SAHA暴露抑制矿化。SAHA暴露培养物的微阵列分析（24小时和14天）强调，764个转录物在24小时显示出显著的>2.0倍的变化，在14天减少到36个基因。在24 h和14 d分别有59%和36%的基因表达下调。通路分析表明，SAHA增加基质金属蛋白酶（MMP）家族成员的表达。此外，补充SAHA增加了MMP-13蛋白表达（7天，14天）和酶活性（48小时，14天）。选择性MMP-13抑制（MMP-13 i）剂量依赖性加速矿化SAHA处理和未处理的文化。补充MMP-13 i促进了几种矿化相关标志物的表达，然而，HDACi诱导的细胞迁移和伤口愈合受损。数据表明，短期低剂量SAHA暴露通过调节基因通路和组织蛋白酶促进DPC的矿化。MMP-13 i进一步增加矿化相关事件，但减少HDACi细胞迁移，表明MMP-13在牙髓修复过程中的特定作用。HDAC和MMP的药理学抑制可能为牙髓修复过程提供新的见解，具有显着的翻译益处。
Direct application of histone-deacetylase-inhibitors (HDACis) to dental pulp cells (DPCs) induces chromatin changes, promoting gene expression and cellular-reparative events. We have previously demonstrated that HDACis (valproic acid, trichostatin A) increase mineralization in dental papillae-derived cell-lines and primary DPCs by stimulation of dentinogenic gene expression. Here, we investigated novel genes regulated by the HDACi, suberoylanilide hydroxamic acid (SAHA), to identify new pathways contributing to DPC differentiation. SAHA significantly compromised DPC viability only at relatively high concentrations (5 μM); while low concentrations (1 μM) SAHA did not increase apoptosis. HDACi-exposure for 24 h induced mineralization-per-cell dose-dependently after 2 weeks; however, constant 14d SAHA-exposure inhibited mineralization. Microarray analysis (24 h and 14 days) of SAHA exposed cultures highlighted that 764 transcripts showed a significant >2.0-fold change at 24 h, which reduced to 36 genes at 14 days. 59% of genes were down-regulated at 24 h and 36% at 14 days, respectively. Pathway analysis indicated SAHA increased expression of members of the matrix metalloproteinase (MMP) family. Furthermore, SAHA-supplementation increased MMP-13 protein expression (7 d, 14 days) and enzyme activity (48 h, 14 days). Selective MMP-13-inhibition (MMP-13i) dose-dependently accelerated mineralization in both SAHA-treated and non-treated cultures. MMP-13i-supplementation promoted expression of several mineralization-associated markers, however, HDACi-induced cell migration and wound healing were impaired. Data demonstrate that short-term low-dose SAHA-exposure promotes mineralization in DPCs by modulating gene pathways and tissue proteases. MMP-13i further increased mineralization-associated events, but decreased HDACi cell migration indicating a specific role for MMP-13 in pulpal repair processes. Pharmacological inhibition of HDAC and MMP may provide novel insights into pulpal repair processes with significant translational benefit.
登录
查看更多内容
影响因子：
8
作者：
Ala-aho, R;Ahonen, M;Kähäri, VM
通讯作者：
Kähäri, VM
影响因子：
5.6
作者：
Gregoretti, IV;Lee, YM;Goodson, HV
通讯作者：
Goodson, HV
影响因子：
3.7
作者：
Duncan, Henry F.;Smith, Anthony J.;Cooper, Paul R.
通讯作者：
Cooper, Paul R.
影响因子：
4.1
作者：
Jin, Hexiu;Park, Joo-Young;Choung, Pill-Hoon
通讯作者：
Choung, Pill-Hoon
影响因子：
13.6
作者：
de Groh, Eric D.;Swanhart, Lisa M.;Hukriede, Neil A.
通讯作者：
Hukriede, Neil A.