Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts.
Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts.
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DOI：
10.3892/ijmm.2016.2582
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发表时间：
2016-07
影响因子：
5.4
通讯作者：
Ishisaki A
中科院分区：
文献类型：
--
作者：
Komatsu Y;Ibi M;Chosa N;Kyakumoto S;Kamo M;Shibata T;Sugiyama Y;Ishisaki A
双膦酸盐（BP）是焦磷酸盐的类似物，已知其通过抑制破骨细胞活性来防止骨吸收。含氮类生物制品，如唑来膦酸（ZA），广泛用于治疗骨质疏松症和骨转移。然而，尽管具有益处，但据报道ZA在癌症患者中诱导BP相关的颌骨骨坏死（BRONJ）。导致BRONJ发展的分子病理学机制，包括拔牙后坏死骨暴露，仍有待阐明。在这项研究中，我们研究了ZA对转化生长因子-β（TGF-β）诱导的人牙龈成纤维细胞（hGFs）的肌成纤维细胞（MF）分化和hGFs的迁移活性的影响，这对纤维组织形成的伤口闭合很重要。发现血清中ZA的最大浓度（Cmax）约为1.47 µM，这在临床上是在静脉内给予4 mg ZA后发现的，认为该剂量的ZA适用于治疗癌症骨转移或骨疾病，如Erdheim-Chester病。在Cmax时，ZA显著抑制i）TGF-β诱导的细胞活力的促进，ii）TGF-β诱导的MF标志物如α-平滑肌肌动蛋白（α-SMA）和I型胶原蛋白的表达，iii）TGF-β诱导的hGF的迁移活性和iv）hGF表面上TGF-β I型受体的表达水平，以及TGF-β诱导的Smad 2/3磷酸化。因此，ZA可能通过抑制Smad依赖性信号转导抑制TGF-β诱导的hGF纤维组织形成。我们的研究结果部分阐明了BRONJ的分子机制，可能有助于在分子水平上确定治疗这种症状的药物靶点。
Bisphosphonates (BPs) are analogues of pyro-phosphate that are known to prevent bone resorption by inhibiting osteoclast activity. Nitrogen-containing BPs, such as zoledronic acid (ZA), are widely used in the treatment of osteoporosis and bone metastasis. However, despite having benefits, ZA has been reported to induce BP-related osteonecrosis of the jaw (BRONJ) in cancer patients. The molecular pathological mechanisms responsible for the development of BRONJ, including necrotic bone exposure after tooth extraction, remain to be elucidated. In this study, we examined the effects of ZA on the transforming growth factor-β (TGF-β)-induced myofibroblast (MF) differentiation of human gingival fibroblasts (hGFs) and the migratory activity of hGFs, which are important for wound closure by fibrous tissue formation. The ZA maximum concentration in serum (Cmax) was found to be approximately 1.47 µM, which clinically, is found after the intravenous administration of 4 mg ZA, and ZA at this dose is considered appropriate for the treatment of cancer bone metastasis or bone diseases, such as Erdheim-Chester disease. At Cmax, ZA significantly suppressed i) the TGF-β-induced promotion of cell viability, ii) the TGF-β-induced expression of MF markers such as α-smooth muscle actin (α-SMA) and type I collagen, iii) the TGF-β-induced migratory activity of hGFs and iv) the expression level of TGF-β type I receptor on the surfaces of hGFs, as well as the TGF-β-induced phosphorylation of Smad2/3. Thus, ZA suppresses TGF-β-induced fibrous tissue formation by hGFs, possibly through the inhibition of Smad-dependent signal transduction. Our findings partly elucidate the molecular mechanisms underlying BRONJ and may prove to be beneficial to the identification of drug targets for the treatment of this symptom at the molecular level.
影响因子：
2.7
作者：
Kurishima K;Ohara G;Kagohashi K;Takayashiki N;Tamura T;Shiozawa T;Miyazaki K;Kawaguchi M;Satoh H;Hizawa N
通讯作者：
Hizawa N