Bisphosphonates Induce Senescence in Normal Human Oral Keratinocytes
Bisphosphonates Induce Senescence in Normal Human Oral Keratinocytes
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DOI：
10.1177/0022034511402995
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发表时间：
2011-06-01
影响因子：
7.6
通讯作者：
Park, N. -H.
中科院分区：
文献类型：
--
作者：
Kim, R. H.;Lee, R. S.;Park, N. -H.
双磷酸盐相关性颌骨骨坏死（BRONJ）通常发生在接受双磷酸盐（BP）治疗的个体中，临床表现为骨坏死暴露。虽然在BRONJ中经常观察到软组织的伤口愈合缺陷，但BP对口腔软组织或细胞的影响仍不清楚。为了研究BPs对口腔粘膜组织细胞的影响，我们研究了帕米膦酸盐（PAM），最常用于癌症患者的BPs之一，对正常人口腔角质形成细胞（NHOK）和成纤维细胞（NHOF）表型的影响。当暴露于10 μ M的PAM时，NHOK而不是NHOF经历衰老：NHOK过表达衰老相关的β-半乳糖苷酶（SA-β-Gal）、p16 INK 4A、IL-6和IL-8。当暴露于较高水平（50 μ M）的PAM，NHOK保持衰老表型，但NHOF进行凋亡。PAM诱导的NHOK衰老部分是通过甲羟戊酸途径的香叶基香叶基化介导的。我们的体外3D口腔粘膜组织构建研究进一步证明PAM诱导口腔粘膜衰老和受损的再上皮化。对这些数据的分析表明，口腔粘膜细胞的过早衰老和随后的有缺陷的软组织伤口愈合可能是接受PAM或其他BP的个体中BRONJ发展的部分原因。
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) commonly occurs in individuals receiving bisphosphonates (BPs) with clinical manifestations of the exposed necrotic bone. Although defective wound healing of soft tissue is frequently, if not always, observed in BRONJ, the effects of BPs on oral soft tissue or cells remain unknown. To investigate the effects of BPs on cells of oral mucosal tissue, we studied the effect of pamidronate (PAM), one of the BPs most commonly administered to cancer patients, on the phenotypes of normal human oral keratinocytes (NHOK) and fibroblasts (NHOF). When exposed to PAM at 10 mu M, NHOK, not NHOF, underwent senescence: NHOK overexpressed senescence-associated beta-galactosidase (SA-beta-Gal), p16INK4A, IL-6, and IL-8. When exposed to a higher level (50 mu M) of PAM, NHOK maintained senescent phenotypes, but NHOF underwent apoptosis. PAM-induced senescence in NHOK is mediated, in part, via geranylgeranylation of the mevalonate pathway. Our in vitro 3D oral mucosal tissue construction studies further demonstrated that PAM induced senescence and impaired re-epithelialization of oral mucosa. Analysis of these data indicates that premature senescence of oral mucosal cells and subsequent defective soft-tissue wound healing might be partly responsible for the development of BRONJ in individuals receiving PAM or other BPs.