大型跨膜蛋白Piezo1在骨科相关疾病中的参与及意义

doi:10.3969/j.issn.2095-4344.2838

中国组织工程研究 ›› 2020, Vol. 24 ›› Issue (30): 4882-4888.doi: 10.3969/j.issn.2095-4344.2838

• 骨与关节综述 bone and joint review • 上一篇下一篇

大型跨膜蛋白Piezo1在骨科相关疾病中的参与及意义

何琪1，张罡瑜1，王海彬2，陈鹏2

1广州中医药大学第一临床医学院，广东省广州市 510405；2广州中医药大学第一附属医院骨科，广东省广州市 510405

收稿日期:2020-02-17 修回日期:2020-02-24 接受日期:2020-04-03 出版日期:2020-10-28 发布日期:2020-09-22
通讯作者: 陈鹏，博士，副主任医师，广州中医药大学第一附属医院，广东省广州市 510405
作者简介:何琪，男，1997年生，广东省揭阳市人，汉族，广州中医药大学第一临床医学院在读硕士，主要从事骨与关节退行性变、代谢性骨病方向的研究。
基金资助:
2017年国家自然科学基金面上项目(81774339)；2017年国家自然科学基金青年科学基金项目(81603641)；2017广东省省级科技计划项目(2017A020213030)

Involvement and significance of large transmembrane protein Piezo1 in orthopedic related diseases

He Qi1, Zhang Gangyu1, Wang Haibin2, Chen Peng2

1First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China; 2Department of Orthopedics, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China

Received:2020-02-17 Revised:2020-02-24 Accepted:2020-04-03 Online:2020-10-28 Published:2020-09-22
Contact: Chen Peng, MD, Associate chief physician, Department of Orthopedics, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
About author:He Qi, Master candidate, First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Supported by:
the National Natural Science Foundation of China in 2017, No. 81774339; the Youth Science Foundation Project of the National Natural Science Foundation of China in 2017, No. 81603641; the Science and Technology Plan Project of Guangdong Province in 2017, No. 2017A020213030

摘要/Abstract

摘要：

文题释义：

Piezo1：是一种由2 100-4 700个氨基酸构成的Fam38A基因编码的大型跨膜蛋白，与哺乳动物中的细胞生物力学机械信号密切相关，Piezo1蛋白在人体中广泛分布在全身各个组织中，以肺脏、肾脏、膀胱、血管及皮肤组织中表达较高，并且在椎间盘组织、关节韧带组织、关节软骨、间充质干细胞中也均有不同程度的表达。

机械敏感性离子通道：又称机械门控性通道或张力激活性通道，是一类能够感受细胞膜机械力变化，并能够将细胞膜感受到的机械信号转化为电信号或化学信号的离子通道，毛细胞、压力受体、肌梭、血管内皮和感觉神经组织等都有此类通道的分布。

背景：近年来研究发现间充质干细胞、成骨细胞、破骨细胞、软骨细胞、髓核细胞和骨肉瘤细胞等均可通过Piezo1蛋白接受细胞外环境的力学机械刺激，从而激活细胞信号转导途径，影响细胞的增殖、分化、迁移及凋亡，进而决定着骨骼的生理构造、关节退变及骨折的愈合等生理病理过程。

目的：文章主要针对近年来与骨质疏松症及退行性骨关节病相关的Piezo1展开综述，并通过回顾Piezo1在其他骨科疾病中的最新发现，归纳总结其最新研究进展，为骨科相关疾病的新型治疗策略提供思路。

方法：计算机检索 CNKI及PubMed 等数据库建库至 2020年1月与Piezo1在骨科疾病研究进展的相关文献，中文关键词为“机械敏感性离子通道蛋白，骨质疏松症，退行性骨关节病，骨科疾病”，英文关键词为“Piezo1，Osteoporosis，Degenerative Osteoarthropathy，Orthopedic Diseases”，进行全网检索，最终纳入60篇文献进行综述进行探讨。

结果与结论：①Piezo1在骨质疏松症发展过程中可通过直接检测成骨细胞谱系细胞中的机械负荷来释放出生物信号，调节破骨细胞活性；②在退行性骨关节病进展过程中，软骨细胞膜上的Piezo1能够有效识别不同强度和类型的外界机械应力刺激，最终诱导软骨细胞凋亡；③在骨代谢性疾病、关节退变性关节炎等骨科疾病中，Piezo1均参与了疾病的病理进展过程，Piezo1的出现为机械性刺激在骨科中的应用提供了更具体的分子基础，打开了新的思路和视角，也为以后双联给药和精准医疗提供了参考依据。

ORCID: 0000-0001-9461-6671(何琪)

中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程

关键词: 骨, 软骨, 骨质疏松症, 成骨, 破骨, 退行性骨病, 退行性椎间盘疾病, 蛋白, 综述

Abstract:

BACKGROUND: Recent studies found that mesenchymal stem cells, osteoblasts and osteoclasts, cartilage cells, nucleus pulposus cells, and osteosarcoma cells can receive mechanical stimulation from extracellular environment through Piezo1 protein so as to activate cell signal transduction pathways, affecting cell proliferation, differentiation, migration and apoptosis, which determines physiological and pathological processes of physiological structure of bone, joint degeneration, and fracture healing.

OBJECTIVE: To review Piezo1 related to osteoporosis and degenerative osteoarthropathy, summarize the latest advances by reviewing the latest discovery of Piezo1 in other orthopedic diseases, and provide ideas for novel treatment strategies for orthopedic related diseases.

METHODS: A computer search was conducted on the literatures related to the research progress of Piezo1 in orthopedic diseases in CNKI and PubMed from inception to January 2020. The Chinese keywords were “mechanically sensitive ion channel proteins, osteoporosis, degenerative osteoarthropathy, orthopedic diseases”, and the English keywords were “Piezo1, osteoporosis, degenerative osteoarthropathy, orthopedic diseases”. A full web search was conducted, and finally 60 literatures were included for review and discussion.

RESULTS AND CONCLUSION: (1) Piezo1 can release biological signals and regulate osteoclast activity during the development of osteoporosis by directly detecting the mechanical load in osteoblastic lineage cells. (2) In the progression of degenerative osteoarthropathy, Piezo1 on the cartilage cell membrane was able to effectively recognize stimuli of different strengths and types of external mechanical stress and eventually induce chondrocyte apoptosis. (3) In bone metabolic diseases, degenerative arthritis of joints and other orthopedic diseases, Piezo1 is involved in the pathological process of the disease. The emergence of Piezo1 provides a more specific molecular basis for the application of mechanical stimulation in orthopedics, opens a new thinking and perspective, and also lays a “hint” for the future dual drug administration and precision medicine.

Key words: bone, cartilage, osteoporosis, osteogenesis, osteoclast, degenerative osteopathy, degenerative disc disease, protein, review

中图分类号:

何琪, 张罡瑜, 王海彬, 陈鹏. 大型跨膜蛋白Piezo1在骨科相关疾病中的参与及意义[J]. 中国组织工程研究, 2020, 24(30): 4882-4888.

He Qi, Zhang Gangyu, Wang Haibin, Chen Peng. Involvement and significance of large transmembrane protein Piezo1 in orthopedic related diseases[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(30): 4882-4888.

图/表（结果） 2

1.3 数据分析通过对检索词的组合后检索得到相关文献650篇，排除与文章研究目的不密切及重复性研究，最终纳入60篇文献。文献检索流程见图1。

2.2 Piezo1离子通道的门控特点作为细胞表达一系列的力传感器，在细胞机械转导时，Piezo1的门控特点在细胞质膜内外部所受力的过程中不可或缺，见图2。当Piezo1机械敏感离子通道在生理条件下感受机械应力刺激后产生内向电流, 这种门控功能介导的机械-电转导非常迅速，在胞膜去极化的同时伴随胞内正电荷增加，从而在2 ms内即可将机械刺激转化为一系列下游细胞信号^[14]。Piezo1通道通过直接的膜张力进行门控, 所以任何改变膜张力的生理作用力理论上都可激活通道,如戳刺、拉伸、流体剪切力等^[15]。Piezo1通道对阳离子具有非选择渗透性，对Na⁺，K⁺，Ca²⁺，Mg²⁺全部渗透，但更偏向Ca^2+[16]。通过双层膜结构重建技术^[17]，当膜表面的张力足够大，便可引起Piezo1通道的激活，引起钙内流；当使用细胞松弛素D干预细胞破坏细胞骨架后，可观察到细胞上Piezo1通道激活的频率增加，从而验证了Piezo1是一种成孔通道亚基，它对机械性刺激敏感，但也会受到细胞骨架因素的影响^[22-24]，这证明了Piezo1通道的门控性。人造液滴脂质双分子层实验表明，Piezo1响应机械力的过程不需要任何其他细胞组分, 说明Piezo1的机械敏感性是固有的，不需要其他蛋白质或第二信使信号激活^[25]。另外有研究发现，除了机械刺激之外Piezo1通道也受电压调控, 甚至可以切换到纯电压门控模式^[26]。某些引起人类疾病的突变^[27](如干瘪细胞增多症及淋巴发育不良)会极大改变Piezo1通道对静息膜电位的电压敏感性，并强烈促进电压门控。

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引言

材料方法

讨论

骨质疏松症是一种全身性代谢骨病，可以通过不同的策略来治疗由于衰老或激素相关性骨质疏松引起的骨量减少，包括合成代谢疗法以增加骨骼形成和分解代谢疗法以减少骨骼吸收等^[58]。宇航员及长期卧床所致的失用性骨质疏松引起的骨量减少通常在1个月内损失的骨量要比绝经后妇女在1年内损失的骨量要多，为每月1%-2%，而骨骼强度的降低甚至更大^[59]。但是，由于微重力或缺乏机械力导致的大量骨质流失通过一般治疗方法却不能得到有效抑制，而Piezo1作为机械敏感性离子蛋白可通过直接检测成骨细胞谱系细胞中的机械负荷来释放出生物信号，调节破骨细胞活性，将为长期卧床休息或长期处于空间微重力环境中的骨质疏松症的治疗策略提供参考。

退行性骨关节病的发生和发展主要是由于在异常的负荷条件下引起的软骨细胞的凋亡所致。在软骨细胞膜上的Piezo1离子通道蛋白能够有效识别不同强度和类型的外界机械应力刺激, 通过调控Ca²⁺内流完成机械-电信号转导, 随后通过内质网应激和线粒体凋亡途径最终诱导软骨细胞凋亡^[60]。因此，Piezo1蛋白可以被认为是抑制软骨细胞凋亡的潜在治疗靶点。

Piezo1的出现则为机械性刺激在骨科中的应用提供了更具体的分子基础，打开了新的思路和视角。在骨代谢性疾病、关节退变性关节炎等骨科疾病中，Piezo1均参与了疾病的病理进展过程，为以后双联给药和精准医疗埋下了“伏笔”。但目前骨科中研究数量相对局限，如衰老或激素相关性骨质疏松中Piezo1是否参与Wnt/β-catenin等经典信号通路对破骨细胞的调节、发生骨关节炎的软骨细胞是如何感应凋亡信号、Piezo1介导下适当机械应力是否对软骨细胞起促进作用以及Piezo1具体是如何对下游基因表达和信号转导起调控作用仍不完全清楚，这也为继续深入研究Piezo1在骨科疾病中的应用提供了方向。相信随着研究的深入，Piezo1作为离子通道治疗骨科疾病将会成为新的里程碑。

中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程

大型跨膜蛋白Piezo1在骨科相关疾病中的参与及意义

Involvement and significance of large transmembrane protein Piezo1 in orthopedic related diseases

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