
==== Front
Zhejiang Da Xue Xue Bao Yi Xue Ban
Zhejiang Da Xue Xue Bao Yi Xue Ban
ZJYB
Journal of Zhejiang University (Medical Sciences)
1008-9292
《浙江大学学报》编辑部 杭州市天目山路148号浙江大学西溪校区浙江大学出版社415室

39183069
1008-9292(2024)04-0427-07
10.3724/zdxbyxb-2023-0615
2023-0615
R641
a
Monographic Reports
沉默信息调节因子6是骨组织再生修复的潜在作用靶点
Research advances on silence information regulator 6 as a potential therapeutic target for bone regeneration and repairhttp://orcid.org/0009-0001-4427-4199
潘 闻政 PAN Wenzheng
何 勇 HE Yong
http://orcid.org/0000-0003-3368-2127
黄 悦 HUANG Yue
浙江大学医学院附属邵逸夫医院骨科，浙江 杭州 310016
Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine Hangzhou 310016 China
沈 敏
刘 丽娜
黄悦，主任医师，硕士生导师，主要从事脊柱疾病治疗及膝关节韧带损伤和髋膝人工关节置换的微创诊疗；E-mail：2000huangyue@zju.edu.cn；https：//orcid.org/0000-0003-3368-2127
HUANG Yue, E-mail: 2000huangyue@zju.edu.cn, https://orcid.org/0000-0003-3368-2127
潘闻政，硕士研究生，主要从事退行性骨关节疾病及骨折的微创诊疗；E-mail：pwz_bone@163.com；https：//orcid.org/0009-0001-4427-4199

25 8 2024
53 4 294 427433
30 12 2023
04 6 2024
2024
The Author(s)
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND 4.0 License (https://creativecommons.org/licenses/by-nc-nd/4.0/)
创伤、感染、肿瘤或全身性疾病等因素引起的节段性骨缺损和骨折不愈合具有成骨范围局限、骨骼愈合周期长等特点。骨组织再生代谢调节因子可加速骨组织修复和高效重建骨缺损区。沉默信息调节因子6（SIRT6）作为一种去乙酰化酶和核苷酸转移酶，广泛参与成骨细胞和破骨细胞等骨细胞的分化、凋亡、代谢和炎症反应的调节，是骨代谢调节的重要因子。SIRT6通过与B淋巴细胞诱导成熟蛋白1形成复合体，并下调核因子κB通路表达，促进雌激素受体α-Fas配体轴信号表达，以抑制破骨细胞生成和成熟分化，从而阻碍骨吸收，导致骨组织骨量增加。另外，SIRT6能通过激活Akt-mTOR途径调节骨髓间充质干细胞自噬水平和成骨能力，并抑制成骨细胞内糖酵解和活性氧生成，通过CREB/CCN1/COX2途径和骨形态发生蛋白信号通路促进成骨细胞分化增加骨的形成，加速骨组织骨再生修复。本文综述了SIRT6参与骨再生病理生理机制的研究进展，揭示其可能作为骨组织修复潜在治疗靶点的意义。

Segmental bone defects and nonunion of fractures caused by trauma, infection, tumor or systemic diseases with limited osteogenesis and prolonged bone healing cycles are challenging issues in orthopedic clinical practice. Therefore, identifying regulatory factors for bone tissue regeneration and metabolism is crucial for accelerating bone repair and reconstructing defective areas. Silence information regulator 6 (SIRT6), functioning as a deacetylase and nucleotide transferase, is extensively involved in the regulation of differentiation, apoptosis, metabolism, and inflammation in bone cells including osteoblasts and osteoclasts, and is considered to be an important factor in regulating bone metabolism. SIRT6 forms a complex with B lymphocyte-induced maturation protein 1 (Blimp1), down-regulates the expression of the nuclear factor κB (NF-κB) pathway, and promotes the expression of the ERα-FasL axis signal to inhibit osteoclast formation and maturation differentiation, thereby hindering bone resorption and increasing bone mass. In addition, SIRT6 activates the Akt-mTOR pathway to regulate the autophagy level and osteogenesis of bone marrow mesenchymal stem cells, inhibits glycolysis and reactive oxygen production in osteoblasts, promotes osteoblast differentiation through the CREB/CCN1/COX2 pathway and the bone morphogenetic protein (BMP) signaling pathway, enhances bone formation, and accelerates bone regeneration and repair of skeletal tissue. This article provides an overview of the research progress on SIRT6 in the pathophysiology of bone regeneration, revealing its potential as a novel therapeutic target for bone tissue repair to alleviate the progression of skeletal pathological diseases.

沉默信息调节因子6
骨代谢
骨再生
修复
综述
Silence information regulator 6
Bone metabolism
Bone regeneration
Repair
Review
浙江省基础公益研究计划LGF21H060005 浙江省卫生健康科技计划2022KY826
==== Body
pmc骨缺损甚至骨不愈合引起的功能障碍和生活受限所带来的社会经济负担难以量化［1］，骨组织再生修复是临床骨科学领域面临的重大挑战。无论是骨折、炎症感染还是肿瘤病理性因素引起，骨不愈合及骨组织的缺损修复都需要新的治疗策略［2］。在机械固定不充分、骨膜过度损伤、缺血、感染、矿物质和维生素缺乏、原发性疾病、特定药物或放化疗等病理条件下，骨愈合治疗过程的改良是保证骨组织特性和功能快速恢复和重塑的必要条件［2］。临床上除了包括生物力学动态物理维持（如石膏、外固定架、内固定钛板和螺钉等）在内的标准方法来治疗骨缺损和骨折外，目前用于促进骨再生修复的其他措施主要集中在骨代谢调节因子、骨细胞和组织移植、生物活性材料方面［1］。其中，骨细胞和组织移植的疗效可能会受局部代谢因子不足、骨质疏松或基础疾病等各种因素影响，而生物活性材料的使用还存在一定局限性［3］。骨代谢调节因子是骨组织再生修复过程中的重要因素之一，通过局部使用代谢调节因子可以促进成骨细胞分化和骨组织生成以达到骨再生修复的目的［4］。

SIRT是高度保守的NAD+依赖性去乙酰化酶活性的酶家族（SIRT1~SIRT7），其中SIRT6主要存在于细胞核中，调节生命及控制衰老，其在骨骼肌肉和运动系统中也起到关键作用［5］。人SIRT6是一种NAD+依赖的去乙酰化酶，具有355个氨基酸，包括氨基端残基1~42、酶核结构域43~276和羧基端残基277~355，该蛋白具有结构保守的NAD+结合域，称为罗斯曼折叠域，并在其催化核心内有一个较少同源的锌结合域［6］。研究表明，SIRT6具有单ADP核糖转移酶活性，以NAD+作为底物将ADP核糖片段添加到自身结构上；PARP1和KAP1作为SIRT6的核糖基化底物，前者可调节细胞中DNA修复［7］。SIRT6被招募到靶向启动子，通过去乙酰化H3K9和H3K56来抑制基因转录。H3K9去乙酰化调节端粒染色质和基因表达，而H3K56的去乙酰化抑制基因表达并通过PARP1调节DNA修复途径［7］。另外，SIRT6在中心体周围位点能使H3K18去乙酰化［8］。SIRT6除了具有很强的去乙酰化酶活性，还能通过调节蛋白分泌和质膜定位调节肿瘤坏死因子-α和Ras相关因子2的活性［9-10］。此外，SIRT6通过去乙酰化CtIP切除DNA末端，以维持基因组的稳定性［11］。因此，SIRT6在代谢、DNA修复、端粒维持和衰老等方面的功能决定其在多种代谢紊乱、年龄相关疾病和癌症中具有重要意义，可用于设计潜在的药理学靶向分子来干预代谢和年龄相关疾病的病理过程。本文将阐述SIRT6在骨代谢细胞功能调控过程中的具体机制，为靶向调节加快骨骼组织再生和损伤修复提供新的治疗策略。

1 沉默信息调节因子6参与骨代谢平衡

骨组织再生修复是一个复杂的骨代谢过程，在系统和局部因素的调控下，通过一系列细胞和分子事件导致新生骨的形成［12］。骨组织的形成始于骨髓基质干细胞的生长，后者可分化为前体成骨细胞，再逐渐发育成熟。骨代谢平衡受到成骨细胞-破骨细胞偶联机制的严格控制，其中一种细胞的活性或分化直接影响另一种细胞的活性或分化，成骨细胞通过多种细胞因子（RANKL、OPG、M-CSF、SEMA3A和MCP-1）和破骨细胞（SEMA4D和补体3a）之间的通信来调节骨量和骨生成［13］。

SIRT家族蛋白在维持正常骨组织和骨代谢平衡中起着至关重要的作用，随着年龄的增长，其对骨细胞的失调控会导致进行性骨质流失［14］。研究表明，SIRT6过表达可以抑制类风湿关节炎、缺血性骨坏死等炎症性疾病，促进创面愈合［15］。Sirt6基因缺陷小鼠可预防皮质激素诱导的骨骼肌萎缩，但肌肉中缺乏SIRT6会导致葡萄糖稳态和胰岛素敏感性受损，降低总能量消耗继而影响运动表现［16］。SIRT6在骨髓基质细胞和骨相关细胞中均有表达，Sirt6基因敲除小鼠表现出体重明显下降和侏儒症，同时骨骼中缺乏软骨和矿化骨组织，说明SIRT6是骨代谢的重要调节因子［17］。此外，人膝关节软骨细胞中SIRT6缺失会导致DNA损伤和端粒功能障碍，伴骨和关节过早衰老及退变［18］。SIRT6过表达可通过减少炎症反应和软骨细胞衰老来阻止骨关节炎的发生，延缓椎间盘退变小鼠模型中髓核细胞的衰老及凋亡［19-20］。另外，SIRT6在染色质水平上通过H3K9、H3K18和H3K56的去乙酰化作用使基因转录广泛沉默，这对于骨骼发育和骨骼稳态是必不可少的［21-22］。与SIRT1和SIRT3不同，SIRT6作为叉头蛋白O3a的下游因子，其对性别相关骨丢失的影响可能通过激活SIRT6-AMPK-PGC1α途径介导，该途径与线粒体未折叠蛋白反应中的ERα-NRF1-HTRA2/蛋白酶体途径相互作用［23］。Sirt6敲除小鼠在出生后两周出现急性多器官退行性综合征，其表型包括严重的代谢缺陷、脊柱弯曲异常、淋巴细胞损耗、皮下脂肪减少和低骨密度［24］。研究表明，相比野生型，Sirt6基因敲除小鼠表现出成骨细胞分化降低、骨形成减弱，而破骨细胞分化增强、骨吸收增加；体重明显减轻且体型小，骨密度降低约30%，骨小梁形成受抑制，皮质骨厚度减小［25］。然而野生型和Sirt6杂合子小鼠之间骨骼未见明显差异，推测可能是由于SIRT6表达部分降低对骨代谢的影响较小，或通过其他代偿方式维持骨代谢的平衡［25］。此外，成年小鼠条件性敲除Sirt6后破骨细胞数减少，骨组织体积增大，骨小梁增加，骨密度增大，可见SIRT6通过影响成年小鼠破骨细胞增殖来干预骨吸收功能［26］。SIRT6激活剂花青素可通过抑制去卵巢绝经期小鼠的破骨细胞形成和骨吸收有效防止骨质流失［27］。

2 沉默信息调节因子6作用于破骨细胞导致骨吸收减弱

破骨细胞由骨髓巨噬细胞分化而来，是骨组织中唯一具有骨吸收功能的细胞。破骨细胞的成熟是由成骨细胞分泌的RANKL和M-CSF协同作用的结果［28］。研究表明，SIRT6通过调节破骨细胞凋亡抑制骨吸收，通过调节成骨细胞和骨细胞中RANKL启动子区域的去乙酰化抑制RANKL表达［29］。SIRT6过表达的骨髓巨噬细胞显示出破骨细胞形成较少，而SIRT6缺乏导致破骨细胞分化更多［17， 19］。然而，也有报道称SIRT6缺乏可导致破骨细胞分化减少［30］。SIRT6的强制表达可以抑制炎症反应，并通过减少破骨细胞的形成来保护小鼠骨破坏［31］。另有研究发现，SIRT6可与Blimp1形成复合物，抑制破骨细胞分化抑制因子的表达，髓系特异性缺失SIRT6的小鼠破骨细胞数减少，骨量增加［26］。在破骨细胞发生过程中，Blimp1位于MafB、IRF8和Bcl-6等破骨细胞生成抑制因子的上游。RANKL刺激后Blimp1表达增加有助于下调破骨细胞生成抑制因子的表达。SIRT6在破骨细胞中的作用与Blimp1类似，均由RANKL-NFATc1轴诱导，抑制参与抗破骨细胞生成的基因。此外，SIRT6亦可通过结合MafB、IRF8和Bcl-6基因启动子来上调控破骨细胞的生成［32］。SIRT6缺乏可通过上调NF-κB信号相关基因Nemo、Icam-1n、C/Ebpα和iNos来增加破骨细胞数，从而降低骨量［33］。SIRT6过表达通过泛素化降低TRPV1表达促进破骨细胞的作用［34］。SIRT6还通过调节破骨细胞形成过程中ER的稳定性，使破骨前体细胞中ERα的赖氨酸171和赖氨酸299去乙酰化，促进破骨细胞前体凋亡，从而抑制破骨细胞数［22］。FasL（ERα的靶基因）表达增加可能以自分泌或旁分泌的方式导致破骨细胞前体凋亡。然而，在老年和雌激素缺乏的受试者中，SIRT6蛋白水平和ERα-FasL轴下调，导致成熟破骨细胞形成增强［22］。也有报道认为Sirt6缺失小鼠骨细胞中RANKL的表达增加，OPG和RANKL的表达降低［35］。总而言之，激活破骨细胞中的SIRT6可能是骨组织再生修复治疗中一种潜在的新策略。

3 沉默信息调节因子6作用于成骨细胞导致骨生成增加

成骨细胞来源于骨髓间充质干细胞的前体细胞，分化为成熟成骨细胞后促进骨形成［36］。SIRT6在成骨细胞和骨细胞中广泛表达，Sirt6敲除小鼠表现为低周转性骨质疏松症［37］。研究证实SIRT6能促进骨髓间充质干细胞成骨分化，抑制其脂肪分化。骨髓间充质干细胞中SIRT6缺失可导致成骨功能受损，然而SIRT6过表达会损害人间充质干细胞的成骨细胞分化［14］。Sirt6敲除小鼠骨髓间充质干细胞在成骨分化后期ALP表达明显降低，钙结节形成减少，成骨分化能力下降。此外，SIRT6能通过激活Akt-mTOR途径调节线粒体自噬，从而改善骨髓间充质干细胞调节骨代谢的能力，而抑制SIRT6会导致骨髓间充质干细胞中自噬水平和成骨能力下降［38］。SIRT6通过结合RUNX2和OSX的启动子，以去乙酰H3K9来调节成骨细胞的骨代谢［30］。Sirt6敲除显著降低了ALP、RUNX2和骨钙素等成骨标志物的mRNA水平，而Sirt6基因过表达则反之。另外，SIRT6与NF-κB在骨代谢过程中相互作用，Sirt6敲除能激活NF-κB转录活性，上调乙酰化NF-κB p65的表达［39］。SIRT6与NF-κB p65亚基结合，可通过修饰NF-κB靶基因的染色质来减弱NF-κB信号传导，在炎症和代谢调节中具有多种功能［19］。p65单倍体不足可挽救Sirt6缺陷小鼠的早期致死和衰老样表型［24］。在真皮成纤维细胞中抑制SIRT6可使NF-κB p65蛋白的表达增加，导致骨骼主要结构成分Ⅰ型胶原合成减少［40］。SIRT6有助于细胞内线粒体蛋白稳态的保存，在缺氧条件下抑制成骨细胞的凋亡［41］，通过抑制糖酵解和活性氧生成影响成骨细胞的成骨作用，并抑制炎症环境下成骨细胞产生CC基序趋化因子配体2和炎性细胞因子［42］。Lin等［43］报道了SIRT6通过调节成骨细胞中CREB/CCN1/COX2途径影响骨吸收。骨钙素启动子驱动的成骨细胞特异性Sirt6敲除小鼠显示骨量减少，这缘于与OPG表达减少相关的破骨细胞增加［37］。研究发现，SIRT6能通过BMP信号通路促进骨髓间充质干细胞的成骨分化，这一过程依赖于p300/CBP相关因子，并且在去卵巢小鼠的骨髓间充质干细胞和骨切片中观察到SIRT6表达受损［44］。Zhao等［45］研究表明，miR-128过表达通过靶向SIRT6可显著抑制C2C12细胞中骨钙素、ALP和Ⅰ型胶原-α1蛋白及其mRNA表达，而沉默Sirt6可明显抑制miR-128抑制剂对成骨细胞标志物表达的积极作用。因此，成骨细胞中SIRT6表达上调或许能够缓解炎症等病理情况下骨不愈，利于骨组织骨再生修复。

4 结语

SIRT6是一种重要的表观遗传调控因子，通过组蛋白去乙酰化酶活性广泛参与DNA修复、端粒完整性维持、核小体和染色质重塑等过程。这些SIRT6介导的细胞过程与骨细胞分化、衰老、代谢和炎症反应的调节有关，在骨健康和骨相关疾病预防中发挥作用［46］。目前，全球学者对SIRT6在骨再生修复和骨代谢方面的调控机制研究大多局限于细胞分子及动物个体层面。本文主要总结了SIRT6的结构特点和生物学效应及其在促进和（或）抑制成骨细胞、破骨细胞及骨代谢中的具体机制和影响因素，对后续研发生物制剂在骨组织损伤修复中的高效应用至关重要，为提高骨折不愈合/骨缺损相关骨病的诊疗水平提供新的见解和潜在的特异性靶点。目前，临床尚无针对SIRT6的特异性激活剂，且SIRT是一类家族蛋白，今后需要进一步深入研究其他成员在骨代谢和骨再生修复方面的作用，并同时关注Sirt基因的多种表达对骨再生修复的潜在影响。

研究得到浙江省基础公益研究计划（LGF21H060005）和浙江省卫生健康科技计划（2022KY826）支持

This work was supported by the Zhejiang Province Fundamental Public Interest Research Program (LGF21H060005) and Zhejiang Provincial Health Science and Technology Program (2022KY826)

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所有作者均声明不存在利益冲突

Conflict of Interests

The authors declare that there is no conflict of interests

［缩略语］

沉默信息调节因子（silence information regulator，SIRT）；烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide，NAD+）；腺苷二磷酸（adenosine diphosphate，ADP）；多聚ADP核糖转移酶（poly ADP-ribose polymerase family，PARP）；组蛋白3赖氨酸（histone 3 lysine，H3K）；羧基末端结合蛋白相互作用蛋白（C-terminal binding protein interacting protein，CtIP）；核因子κB（nuclear factor κB，NF-κB）；NF-κB受体活化因子配体（receptor activator of NF-κB ligand，RANKL）；护骨因子（osteoprotegeri，OPG）；巨噬细胞集落刺激因子（macrophage colony-stimulating factor，M-CSF）；信号素（semaphorin，SEMA）；单核细胞趋化蛋白（monocyte chemoattractant protein，MCP）；雌激素受体（estrogen receptor，ER）；B淋巴细胞诱导成熟蛋白（blymphocyte-induced maturation protein，Blimp）；干扰素调节因子（interferon regulatory factor，IRF）；B细胞淋巴瘤蛋白（B cell lymphoma，Bcl）；瞬时受体电位香草酸1型受体（transient receptor potential cation channel subfamily V member 1，TRPV1）；Fas配体（Fas ligand，FasL）；碱性磷酸酶（alkaline phosphatase，ALP）；蛋白激酶B（protein kinase B，Akt）；Runt相关转录因子（Runt-related transcription factor，RUNX）；信使RNA（messenger RNA，mRNA）；骨形态发生蛋白（bone morphogenetic protein，BMP）；微RNA（microRNA，miR）
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