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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >DNA damage drives accelerated bone aging via an NF- κ B-dependent mechanism
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DNA damage drives accelerated bone aging via an NF- κ B-dependent mechanism

机译：DNA损伤通过NF-κB依赖性机制促进骨骼老化

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Advanced age is one of the most important risk factors for osteoporosis. Accumulation of oxidative DNA damage has been proposed to contribute to age-related deregulation of osteoblastic and osteoclastic cells. Excision repair cross complementary group 1-xeroderma pigmentosum group F (ERCC1-XPF) is an evolutionarily conserved structure-specific endonuclease that is required for multiple DNA repair pathways. Inherited mutations affecting expression of ERCC1-XPF cause a severe progeroid syndrome in humans, including early onset of osteopenia and osteoporosis, or anomalies in skeletal development. Herein, we used progeroid ERCC1-XPF-deficient mice, including Ercc1-null (Ercc1 -/-) and hypomorphic (Ercc1-/Δ) mice, to investigate the mechanism by which DNA damage leads to accelerated bone aging. Compared to their wild-type littermates, both Ercc1-/- and Ercc1 -/Δ mice display severe, progressive osteoporosis caused by reduced bone formation and enhanced osteoclastogenesis. ERCC1 deficiency leads to atrophy of osteoblastic progenitors in the bone marrow stromal cell (BMSC) population. There is increased cellular senescence of BMSCs and osteoblastic cells, as characterized by reduced proliferation, accumulation of DNA damage, and a senescence-associated secretory phenotype (SASP). This leads to enhanced secretion of inflammatory cytokines known to drive osteoclastogenesis, such as interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and receptor activator of NF-κB ligand (RANKL), and thereby induces an inflammatory bone microenvironment favoring osteoclastogenesis. Furthermore, we found that the transcription factor NF-κB is activated in osteoblastic and osteoclastic cells of the Ercc1 mutant mice. Importantly, we demonstrated that haploinsufficiency of the p65 NF-κB subunit partially rescued the osteoporosis phenotype of Ercc1-/Δ mice. Finally, pharmacological inhibition of the NF-κB signaling via an I-κB kinase (IKK) inhibitor reversed cellular senescence and SASP in Ercc1 -/Δ BMSCs. These results demonstrate that DNA damage drives osteoporosis through an NF-κB-dependent mechanism. Therefore, the NF-κB pathway represents a novel therapeutic target to treat aging-related bone disease.
机译：高龄是骨质疏松症最重要的危险因素之一。已经提出了氧化DNA损伤的积累有助于成骨细胞和破骨细胞的年龄相关的失调。交叉修复互补组1-干性色素皮炎组F（ERCC1-XPF）是进化上保守的结构特异性核酸内切酶，是多种DNA修复途径所必需的。影响ERCC1-XPF表达的遗传突变会导致人类严重的早衰综合症，包括骨质疏松症和骨质疏松症的早期发作，或骨骼发育异常。在本文中，我们使用了包括Ercc1-null（Ercc1-/-）和亚型（Ercc1- /Δ）小鼠在内的早衰型ERCC1-XPF缺陷小鼠，来研究DNA损伤导致骨骼加速老化的机制。与野生型同窝仔相比，Ercc1-/-和Ercc1-//Δ小鼠均表现出严重的进行性骨质疏松症，这是由于骨形成减少和破骨细胞增多引起的。 ERCC1缺乏导致骨髓基质细胞（BMSC）人口中的成骨祖细胞萎缩。 BMSC和成骨细胞的细胞衰老增加，其特征在于增殖减少，DNA损伤积累和衰老相关的分泌表型（SASP）。这导致已知可驱动破骨细胞生成的炎性细胞因子（如白介素6（IL-6），肿瘤坏死因子α（TNFα）和NF-κB配体的受体激活剂（RANKL））的分泌增加，从而诱发了炎性骨有利于破骨细胞形成的微环境。此外，我们发现转录因子NF-κB在Ercc1突变小鼠的成骨细胞和破骨细胞中被激活。重要的是，我们证明了p65NF-κB亚基的单倍剂量不足可以部分挽救Ercc1- /Δ小鼠的骨质疏松症表型。最后，通过I-κB激酶（IKK）抑制剂对NF-κB信号传导的药理学抑制作用逆转了Ercc1- /ΔBMSCs中的细胞衰老和SASP。这些结果表明DNA损伤通过NF-κB依赖性机制驱动骨质疏松症。因此，NF-κB通路代表了一种治疗衰老相关的骨病的新型治疗靶标。

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