骨质疏松中衰老相关分泌表型调控机制的研究进展

doi:10.12114/j.issn.1007-9572.2023.0721

中国全科医学 ›› 2024, Vol. 27 ›› Issue (29): 3685-3695.DOI: 10.12114/j.issn.1007-9572.2023.0721

所属专题：骨健康最新文章合辑；骨质疏松最新文章合辑

骨质疏松中衰老相关分泌表型调控机制的研究进展

杨超富¹, 谭国庆²^,^*(), 徐展望²

1．250039　山东省济南市，山东中医药大学
2．250013　山东省济南市，山东中医药大学附属医院脊柱脊髓科

收稿日期:2023-09-25 修回日期:2024-01-20 出版日期:2024-10-15 发布日期:2024-07-16
通讯作者: 谭国庆
作者贡献：
杨超富负责收集文献并撰写论文；谭国庆、徐展望负责对论文提供建设性意见并提供基金支持。杨超富和谭国庆对稿件整体负责。
基金资助:
国家自然科学基金面上项目(82174410); 山东省自然科学基金资助项目(ZR2020KH011); 山东省自然科学基金面上项目(ZR2020MH362); 全国名老中医专家传承工作室建设项目(国中医药人教函[202275号])

Research Progress on the Regulation Mechanism of Senescence-associated Secretory Phenotype in Osteoporosis

YANG Chaofu¹, TAN Guoqing²^,^*(), XU Zhanwang²

1. Shandong University of Traditional Chinese Medicine, Jinan 250039, China
2. Spinal Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250013, China

Received:2023-09-25 Revised:2024-01-20 Published:2024-10-15 Online:2024-07-16
Contact: TAN Guoqing

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摘要/Abstract

摘要： 衰老相关分泌表型（SASP）是细胞衰老的重要特征，在调控疾病微环境中具有重要作用。目前，对于SASP干预骨代谢、诱导骨流失的作用机制了解有限，因此，本文探讨了在骨质疏松模型中SASP的调控机制，并归纳总结了其调控特点：SASP在衰老骨细胞中充分表达，以自分泌/旁分泌的方式将衰老效应传递到间充质干细胞，从而干预其成骨分化；SASP激活免疫细胞，并促进其衰老，从而诱导炎性组织微环境的形成，加重骨流失；线粒体稳态失调、病理性血糖升高、肥胖诱导的脂肪蓄积均会促进SASP的表达，从而扰乱微环境稳态，将衰老效应传递到骨组织。所以，有必要深入了解SASP在骨质疏松中的作用，为后续开发抗SASP疗法治疗骨质疏松提供借鉴。

Abstract:

Senescence-associated secretory phenotype (SASP) is an important feature of cellular senescence and plays an important role in regulating the disease microenvironment. At present, the role of SASP in intervening bone metabolism and inducing bone loss is very limited. Therefore, this paper discusses the regulatory mechanism of SASP in osteoporosis models and summarizes its regulatory characteristics: SASP is fully expressed in senescent bone cells and transmits aging effects to mesenchymal stem cells in an autocrine/paracrine manner, thereby interfering with osteogenic differentiation. SASP activates immune cells and promotes their aging, thus inducing the formation of inflammatory tissue microenvironment and aggravating bone loss. Mitochondrial homeostasis, pathologic hyperglycemia, and obesity-induced fat accumulation all promote SASP expression, thus disrupting microenvironmental homeostasis and transmitting aging effects to bone tissue. To sum up, understanding the role of SASP in osteoporosis lays a solid foundation for us to develop anti-SASP therapy for osteoporosis in the future.

Key words: Osteoporosis, Senescence-associated secretory phenotype, Cell senescence, Metabolic disorders, Immunomodulation

杨超富,谭国庆,徐展望. 骨质疏松中衰老相关分泌表型调控机制的研究进展[J]. 中国全科医学, 2024, 27(29): 3685-3695. DOI: 10.12114/j.issn.1007-9572.2023.0721.
YANG Chaofu,TAN Guoqing,XU Zhanwang. Research Progress on the Regulation Mechanism of Senescence-associated Secretory Phenotype in Osteoporosis[J]. Chinese General Practice, 2024, 27(29): 3685-3695. DOI: 10.12114/j.issn.1007-9572.2023.0721.

图/表 2

图1 SASP的骨免疫调控网络注：CTX=Ⅰ型胶原羧基端肽β特殊序列，RANKL=核因子-κB受体激活因子配体，OPG=骨保护素，G-CSF=粒细胞集落刺激因子，cAMP=环磷酸腺苷，AMPK= AMP依赖的蛋白激酶，p38/MAPK=p38丝裂原活化蛋白激酶通路，C/EBPα=CCAAT增强子结合蛋白α，sCD163=可溶性CD163，CXCL10=C-X-C基序趋化因子10，IL=白介素，miR=微小RNA，WNT=Wingless/Integrated蛋白，GATA4= GATA结合蛋白，BMI-1=多梳无名指基因，MCP-1=单核细胞趋化蛋白1，Hedgehog=刺猬蛋白，frizzed-3=卷曲类受体-3蛋白，CNOT-6=转录调控复合物CNOT-6，TAK1=转化生长因子激酶1，γ-H2AX=γ-组蛋白H2AX（一种DNA损失标记物），NF-κB=核因子κB，TNF-α=肿瘤坏死因子α，MMP-3=基质金属肽酶3，p-16/pRB=多重肿瘤抑制基因-16/视网膜母细胞瘤蛋白基因途径，p-53/p-21=肿瘤抑制蛋白p-53基因/激活激酶-1基因途径。

Figure 1 Bone immune regulatory network of SASP

图2 线粒体稳态失调、脂代谢紊乱、糖代谢异常的SASP调控网络注：NOTCH=跨膜受体蛋白NOTCH-1，JAK=非受体型蛋白酪氨酸激酶，GLUT1=葡萄糖易化扩散转运蛋白1，NLRC4=核酸结合寡聚结构域-4，mTOR=哺乳动物雷帕霉素靶蛋白，IRF8=干扰素调节因子8，STAT3=信号传导及转录激活蛋白3，JNK=应激活化蛋白激酶，SFRP4=分泌型卷曲相关蛋白4，PDGFR=血小板衍生生长因子受体，INHBA=抑制素β亚基A，CCL2=单核细胞趋化蛋白1，p16lnk4a=一种周期蛋白依赖的激酶抑制剂，PPARγ=过氧化物酶体增殖激活受体γ，PDGF-BB=血小板衍生因子-BB，IRAK2=白介素1受体相关激酶2，OPA=视神经萎缩1蛋白，SIRT4=沉默调节蛋白4，PINK1=磷酸酶及张力蛋白同源物诱导的蛋白激酶1，Drp1=动力蛋白相关蛋白1，GRSF1=富G的RNA序列结合因子1，HMGAs=构筑性转录因子，NAMPT=烟酰胺磷酸核糖转移酶，UBE2E3=泛素结合酶E2 E3，ERdj5=一种蛋白质二硫键异构酶，CCFs=细胞质染色质片段，MOTS-c=一种线粒体基因组12S rRNA区域编码的16个氨基酸组成的线粒体衍生肽，SHLP-2，-6=一种小的类人肽-2、-6，p16-p21=多重肿瘤抑制因子-16-多重肿瘤抑制因-21途径，p53-p38MAPK=p38丝裂原活化蛋白激酶途径，JAK/STAT= JAK/STAT途径，P53/P21=多重肿瘤抑制基因-53/多重肿瘤抑制基因-21途径，ROS-JNK=活性氧-应激活化蛋白激酶途径，NF-κb/Caspase-1=核因子κb/IL-1β转换酶途径。

Figure 2 SASP regulatory network of mitochondrial homeostasis disorders，lipid metabolism disorders and glucose metabolism abnormalities

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骨质疏松中衰老相关分泌表型调控机制的研究进展

Research Progress on the Regulation Mechanism of Senescence-associated Secretory Phenotype in Osteoporosis

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