PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2 Signaling Pathway.
PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2 Signaling Pathway.
复制标题
DOI：
10.3390/ijms161024820
复制
发表时间：
2015-10-19
影响因子：
5.6
通讯作者：
Masutani M
中科院分区：
文献类型：
--
作者：
Kishi Y;Fujihara H;Kawaguchi K;Yamada H;Nakayama R;Yamamoto N;Fujihara Y;Hamada Y;Satomura K;Masutani M
聚（ADP-核糖基）化已知参与多种细胞过程，如DNA修复、细胞死亡、端粒调节、基因组稳定性和聚（ADP-核糖）聚合酶（PARP）引起的细胞分化。虽然PARP抑制剂目前正在进行癌症治疗的临床研究，但对其副作用知之甚少。然而，PARP参与间充质干细胞（MSC）分化增强了由PARP抑制引起的MSC相关副作用。在这项研究中，检查了PARP抑制剂对MSC的影响。MSC在1 μM PJ 34处理后表现出成骨分化受抑制，而无细胞毒性，而MSC分化为软骨细胞或脂肪细胞不受影响。PJ 34抑制成骨标志物如Runx 2、Osterix、骨形态发生蛋白-2、骨钙素、骨唾液蛋白和骨桥蛋白的mRNA诱导，以及骨形态发生蛋白-2、Osterix和骨钙素的蛋白质水平。PJ 34处理还抑制了转录因子调节因子，如Smad 1，Smad 4，Smad 5和Smad 8。细胞外矿化基质的形成也减少。这些结果有力地表明，PARP抑制剂能够抑制成骨分化和聚（ADP-核糖基）化可能通过调节BMP-2信号在这一过程中发挥生理作用。因此，PARP抑制可能潜在地减弱成骨代谢，暗示谨慎使用PARP抑制剂用于癌症治疗和监测患者骨代谢水平。
Poly(ADP-ribosyl)ation is known to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, genomic stability and cell differentiation by poly(ADP-ribose) polymerase (PARP). While PARP inhibitors are presently under clinical investigation for cancer therapy, little is known about their side effects. However, PARP involvement in mesenchymal stem cell (MSC) differentiation potentiates MSC-related side effects arising from PARP inhibition. In this study, effects of PARP inhibitors on MSCs were examined. MSCs demonstrated suppressed osteogenic differentiation after 1 µM PJ34 treatment without cytotoxicity, while differentiation of MSCs into chondrocytes or adipocytes was unaffected. PJ34 suppressed mRNA induction of osteogenic markers, such as Runx2, Osterix, Bone Morphogenetic Protein-2, Osteocalcin, bone sialoprotein, and Osteopontin, and protein levels of Bone Morphogenetic Protein-2, Osterix and Osteocalcin. PJ34 treatment also inhibited transcription factor regulators such as Smad1, Smad4, Smad5 and Smad8. Extracellular mineralized matrix formation was also diminished. These results strongly suggest that PARP inhibitors are capable of suppressing osteogenic differentiation and poly(ADP-ribosyl)ation may play a physiological role in this process through regulation of BMP-2 signaling. Therefore, PARP inhibition may potentially attenuate osteogenic metabolism, implicating cautious use of PARP inhibitors for cancer treatments and monitoring of patient bone metabolism levels.