Parathyroid hormone suppresses osteoblast apoptosis by augmenting DNA repair.
Parathyroid hormone suppresses osteoblast apoptosis by augmenting DNA repair.
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DOI：
10.1016/j.bone.2009.05.006
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发表时间：
2009-09
期刊：
影响因子：
4.1
通讯作者：
Midura, Ronald J.
中科院分区：
文献类型：
--
作者：
Schnoke, Matthew;Midura, Sharon B.;Midura, Ronald J.
每日注射甲状旁腺激素（PTH）是临床批准的治疗骨质疏松症。它抑制成骨细胞的凋亡，但其确切的抗凋亡机制尚不完全清楚。在本研究中，PTH处理培养成骨细胞阻断了血清戒断和营养剥夺的促凋亡作用；过氧化氢诱导氧化应激和紫外线照射。我们推测甲状旁腺激素可能通过增强DNA修复来抑制成骨细胞凋亡。有证据表明，经PTH处理的融合后非增殖性成骨细胞表现出蛋白激酶a介导的两种调节DNA修复过程的蛋白（增殖细胞核抗原和叉头盒转录因子3a）的激活，以及促凋亡生长阻滞和DNA损伤蛋白153的抑制。DNA损伤与成骨细胞凋亡之间联系的另一个证据来自一个意想不到的发现，即大多数固定psh处理的成骨细胞在末端脱氧核苷酸dUTP镍端标记（TUNEL）上呈弱阳性，即使通过胰蛋白酶复制策略确定类似的培养物是可存活的。TUNEL鉴定了DNA切除修复，而不仅仅是凋亡的DNA片段，对这些TUNEL结果最可能的解释是PTH对DNA修复过程的激活将允许核苷酸结合，从而增强了切除修复。这一解释被pth处理的细胞中溴脱氧尿苷的增强掺入证实，尽管大多数细胞群被确定为不复制。PTH对DNA修复的增强是一个未报道的发现，并为其抗凋亡机制提供了额外的解释。
Daily injection of parathyroid hormone (PTH) is a clinically approved treatment for osteoporosis. It suppresses apoptosis of bone forming osteoblasts although its exact anti-apoptotic mechanism(s) is incompletely understood. In this study, PTH treatment of cultured osteoblasts blocked the pro-apoptotic effects of serum withdrawal and nutrient deprivation; hydrogen peroxide induced oxidative stress, and UV irradiation. We hypothesized that PTH might suppress osteoblast apoptosis by enhancing DNA repair. Evidence is provided showing that post-confluent, non-proliferating osteoblasts treated with PTH exhibited a protein kinase A-mediated activation of two proteins that regulate DNA repair processes (proliferating cell nuclear antigen and forkhead box transcription factor 3a) as well as a suppression of the pro-apoptotic growth arrest and DNA damage protein 153. Additional proof of a connection between DNA damage and osteoblast apoptosis came from an unexpected finding whereby a majority of fixed PTH-treated osteoblasts scored weakly positive for Terminal Deoxynucleotidyl dUTP Nick-End Labeling (TUNEL), even though similar cultures were determined to be viable via a trypsin replating strategy. TUNEL identifies DNA excision repair, not just apoptotic DNA fragmentation, and the most likely explanation of these TUNEL results is that PTH's activation of DNA repair processes would permit nucleotide incorporation as a result of enhanced excision repair. This explanation was confirmed by an enhanced incorporation of bromodeoxyuridine in PTH-treated cells even though a majority of the cell population was determined to be non-replicating. An augmentation of DNA repair by PTH is an unreported finding, and provides an additional explanation for its anti-apoptotic mechanism(s).
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影响因子：
4.4
作者：
Charles, I;Khalyfa, A;Agarwal, N
通讯作者：
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影响因子：
4.8
作者：
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影响因子：
8
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作者：
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DOI：
10.1073/pnas.63.2.428
发表时间：
1969-01-01
影响因子：
11.1
作者：
CLEAVER, JE
通讯作者：
CLEAVER, JE