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Research Progress on the Role of HMGB1 in Regulating the Function of Osteoarthritis Chondrocytes
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摘要: 骨关节炎(osteoarthritis，OA)是一种慢性退行性关节疾病，其主要特征是关节软骨破坏，导致患者身体疼痛和残疾，严重影响其生活质量。OA可由多种病因诱发，而关节软骨的病理改变被认为是OA发生的关键驱动因素之一。高迁移率族蛋白1(high mobility group box-1 protein，HMGB1)作为一种真核细胞内的非组蛋白，可参与调节软骨细胞炎症及凋亡过程，从而导致关节软骨受损，诱发OA。本文就HMGB1在OA软骨细胞中的作用机制进行综述，以期为临床防治OA提供新思路。Abstract: Osteoarthritis (OA) is a chronic degenerative joint disease whose main characteristic is the destruction of articular cartilage, causing pain and disability in patients and seriously affecting their quality of life. OA can be induced by a variety of causes, and pathological changes in articular cartilage are considered to be one of the key driving factors for the occurrence of OA. High mobility group box-1 protein (HMGB1), as a non-histone protein in eukaryotic cells, can participate in regulating the inflammation and apoptosis process of OA chondrocytes, thus leading to the occurrence of OA. This article reviews the research on the mechanism of HMGB1 in OA chondrocytes, with a view to providing new ideas for the clinical prevention and treatment of OA.
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Keywords:
- osteoarthritis /
- high mobility group box-1 protein /
- chondrocytes /
- signal pathway
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我打算以这样一个朴素的标题，来开启这篇文字记录。这是个平淡如水的故事，这里没有抵御病魔的奇迹，没有视死如归的释然，却充斥着想要活下去的深切期望。
第一次见到H先生是在内科病房。当时他60岁，因为“频繁呕吐隔夜宿食”就诊，超声检查发现上腹部大包块，患者精神状态很好，很乐观，说话不疾不徐，神色、语气中还隐藏着细微的孩子气，让人印象深刻。住院期间，他买了一本《协和医事》捧在手里读。窗外是老协和建筑群的飞檐走壁，他坐在窗前看书，像一个从历史中走出来的人。尽管心态平和，但H先生的病情却进展得很快。他无法进食，呕吐愈加频繁，却坚决不肯放置胃管，仿佛置入胃管就宣判了他对疾病的妥协。直到某一天，他虚弱到只能卧床，我下决心严肃地对他说，你的消化道已经完全堵住了，连水都下不去，胃管可以帮助到你。H先生终于同意了，胃管置入后，很快引出500 mL胃液，随后加强肠外营养，他的感受好多了，又开始在病房里逍遥踱步。有一次值夜班，我和另一位值班医师点了丰盛的饭菜，他在外面探头探脑，然后坐在我们旁边搭讪，说你们吃得真香啊，可惜我一口都吃不了。然后，跟我们畅谈老北京的美食，说得自己恨不得口水都淌下来。
H先生的病理结果回报是“弥漫性大B细胞淋巴瘤”，主要病灶是腹部的大包块，造成了消化道梗阻症状。弥漫性大B细胞淋巴瘤属于最常见的淋巴瘤，这种淋巴瘤对化疗反应较好，具有相当高的治愈率。标准化疗3天后，肿瘤体积缩小了，H先生的消化道也通畅了，可以恢复进食，他特别高兴。他的家人们都来探望，一大家子兄弟姐妹，他是最小的一个。他很骄傲地向家人们介绍我：“这是我的主管医师王大夫，她的医术很棒，我会痊愈的。”那时我正处于工作的低谷状态，有点职业耗竭。积极鼓励患者本应是我的职责所在，此时患者相信我能治愈他的疾病，这种全然的信任同时也给予了我莫大的欣慰和力量。
可惜好景不长，H先生的肿瘤在8程化疗后卷土重来，他仅短暂品尝了食物的美味，再次陷入消化道梗阻。我们换了二线治疗方案，这次副作用太强，H先生吃了很多苦头才完成治疗，但肿瘤丝毫未缩小。我看着他逐渐从乐观、开朗变得日益焦躁。疾病最可怕的地方是在你面前一点点地把一个乐观开朗的人拆解，不仅从生理层面，更是从心理层面。
他开始执着于搜寻最前沿的抗癌知识，跟我探讨最新的前沿治疗方法。5年前，淋巴瘤领域的小分子靶向药物、单抗、双抗还不像现在这样如雨后春笋般日益涌现，我内心很清楚治疗已陷入绝境，却不知如何向他交代。患者病情完全缓解是医生最闪耀的勋章，而作为跟肿瘤战斗的医生，我总希望自己可以一直摆出胜利者的姿态。老病患带着疾病缓解的化验结果来到门诊，诊室的气氛会立刻变得生动活泼起来。我们从心底里抵触没有变化、甚至还进一步增大的肿瘤，这不仅让患者和家属崩溃，也让医生感到失控。
我也在潜意识里选择了逃避，觉得无法再帮助到H先生。他一直辗转于全国各大医院求医问药。突然有一天，他联系我询问借病理切片的流程，由于当时工作太忙，未能帮助到他。后来，很长时间再也没有他的相关消息。忙碌的间隙，我有时会想起他，可能参与了不错的临床试验，或寻求到一味偏方，病情得到了有效控制……又过了许久，一位同事无意中告诉我，H先生在我们医院去世了。听到这个消息，我很震惊，立即登录病案系统查看他的最新病历。病案的文字描述是如此客观、冷静而中立——他带着一丝绝望和孤勇去外地求助更前沿的细胞治疗，却因为身体条件所限，没能入组那个最前沿的研究。肿瘤导致H先生急性上消化道大出血，由于大量呕血，逐步出现失血性休克而去世。在这字里行间，我读出了他内心深处的痛苦与不甘，不知道当时H先生怀着怎样的心情去面对他生命中的最后一刻，这些文字没有、也无法记录。
我的内心充满了自责：当我没有给予他帮助的时候，他是否觉得后面的路更加冰冷和黑暗。这件事也成为我无力化解的心结。2年后，北京协和医院成立了缓和医疗中心，我也加入了缓和医疗会诊群。在会诊群里，各专科医生针对终末期患者提出需求，宁晓红主任团队总是耐心、及时为患者会诊。作为临床医生，我第一次全面了解了缓和医疗：这是临床医学发展的一个新分支，承认现代医疗仍然存在天花板，当高强度的治疗不再有效，反而会给患者带来伤害、影响其生活质量时，医生仍然可以通过缓和医疗为患者提供帮助，医疗不再以治愈疾病为目的，而是让患者没有痛苦、平稳地渡过生命的临终阶段。
缓和医疗团队的建立者宁晓红老师听我讲述了H先生的故事后，她关切的眼神、感同深受的表情让我意识到H先生的经历是被人在意的，他存在的意义并未随着生命的流逝而消失。宁老师让我意识到，即便医生没有治愈肿瘤的手段，仍可以帮助到患者，不必因为惧怕面对自己的无力感和患者失望的眼神而去逃避或把患者推开。我们可以如实而坦然地告诉患者，我们没有办法了，但是我们可以好好计划一下接下来的生命安排。我们可以用缓和医疗的手段，帮助患者解决终末期病情带来的不适，同样可以帮助无所适从的家属，让一家人重新带着尊严去面对死亡这件大事，做好最后的告别。
缓和医疗是对患者的治疗，也是对医生的救赎。人生中总有一些时刻会触动你的心灵，留下深刻的情感体验，如看到秋风吹落黄叶，亦或看到雨后天空泛出湛蓝……我们想竭尽全力去医治疾病，也想遇见并安慰那些有趣而深刻的灵魂。即便在备选治疗极为丰富的今天，医生依然无法治愈每一位患者，但可以一直帮助和陪伴他们！
作者贡献：齐鑫负责论文撰写；陈一新、马姣姣、齐伟、胡紫阳负责查阅文献；张晓刚、于海洋、陈欣、刘建军负责论文指导；安文博、王志鹏、王多贤、罗鹏飞负责论文修订。利益冲突：所有作者均声明不存在利益冲突 -
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图 1 HMGB1在软骨细胞中的作用机制
HMGB1(high mobility group box-1 protein)：高迁移率族蛋白1；TLR4(toll-like receptor 4)：Toll样受体4；RAGE(receptor of advanced glycation end product)：晚期糖基化终末产物受体；GSK-3β(glycogen synthase kinase-3β)：糖原合成酶激酶3β；β-Catenin：β-连环蛋白；MAPK(mitogen-activated protein kinase)：丝裂原活化蛋白激酶；NF-κB(nuclear factor-κB)：核因子-κB；PI3K(phosphatidylinositol 3-kinase)：磷脂酰肌醇3-激酶；AKT(protein kinase B)：蛋白激酶B；SDF-1(stromal cell-derived factor-1)：基质细胞衍生因子1
Figure 1. Mechanism of action of HMGB1 in chondrocytes
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[1] 褚云峰, 于红燕, 杨琪, 等. 白藜芦醇在骨关节炎中的作用及机制研究进展[J]. 中国骨质疏松杂志, 2022, 28(9): 1351-1355. DOI: 10.3969/j.issn.1006-7108.2022.09.019 Chu Y F, Yu H Y, Yang Q, et al. Research progress on the role and mechanism of resveratrol in osteoarthritis[J]. Chin J Osteoporos, 2022, 28(9): 1351-1355. DOI: 10.3969/j.issn.1006-7108.2022.09.019
[2] Lubbers R, Van Schaarenburg R A, Kwekkeboom J C, et al. Complement component C1q is produced by isolated articular chondrocytes[J]. Osteoarthritis Cartilage, 2020, 28(5): 675-684. DOI: 10.1016/j.joca.2019.09.007
[3] Liu Z L, Zhang H, Wang H L, et al. Magnolol alleviates IL-1β-induced dysfunction of chondrocytes through repression of SIRT1/AMPK/PGC-1α signaling pathway[J]. J Interferon Cytokine Res, 2020, 40(3): 145-151. DOI: 10.1089/jir.2019.0139
[4] 杨昊. Navitoclax (ABT263) 改善骨关节炎中炎症微环境和减轻软骨破坏的研究[D]. 重庆: 中国人民解放军陆军军医大学, 2020. Yang H. The study of Navitoclax (ABT263) improves inflammatory microenvironment in osteoarthritis and attenuates cartilage destruction[D]. Chongqing: Army Medical University, 2020.
[5] Colavita L, Ciprandi G, Salpietro A, et al. HMGB1: a pleiotropic activity[J]. Pediatr Allergy Immunol, 2020, 31(Suppl 26): 63-65.
[6] Chen R C, Kang R, Tang D L. The mechanism of HMGB1 secretion and release[J]. Exp Mol Med, 2022, 54(2): 91-102. DOI: 10.1038/s12276-022-00736-w
[7] Dong Y J, Ming B X, Dong L L. The role of HMGB1 in rheumatic diseases[J]. Front Immunol, 2022, 13: 815257. DOI: 10.3389/fimmu.2022.815257
[8] 王晓艳, 杜虹. 高迁移率族蛋白B1在脓毒症和创伤后炎症反应中的作用[J]. 微生物学免疫学进展, 2020, 48(3): 79-83. Wang X Y, Du H. The role of high mobility group box-1 protein in inflammation caused by sepsis and trauma[J]. Prog Microbiol Immunol, 2020, 48(3): 79-83.
[9] Xue J M, Suarez J S, Minaai M, et al. HMGB1 as a therapeutic target in disease[J]. J Cell Physiol, 2021, 236(5): 3406-3419. DOI: 10.1002/jcp.30125
[10] Motta F, Barone E, Sica A, et al. Inflammaging and osteoarthritis[J]. Clin Rev Allergy Immunol, 2023, 64(2): 222-238.
[11] Ma W L, Wang X H, Wang C H, et al. Up-regulation of P21-activated kinase 1 in osteoarthritis chondrocytes is responsible for osteoarthritic cartilage destruction[J]. Biosci Rep, 2020, 40(1): BSR20191017. DOI: 10.1042/BSR20191017
[12] 唐丹, 王先斌, 杨香莲, 等. 跑台运动训练对脊髓损伤后大鼠肺损伤及HMGB1/TLR4/NF-κB信号通路表达的影响[J]. 中国康复医学杂志, 2023, 38(2): 159-166. DOI: 10.3969/j.issn.1001-1242.2023.02.004 Tang D, Wang X B, Yang X L, et al. Effects of treadmill training on lung injury and HMGB1/TLR-4/NF-κB signaling pathway after spinal cord injury in rats[J]. Chin J Rehabil Med, 2023, 38(2): 159-166. DOI: 10.3969/j.issn.1001-1242.2023.02.004
[13] Zhang C, Yu W Z, Huang C B, et al. Chrysin protects human osteoarthritis chondrocytes by inhibiting inflammatory mediator expression via HMGB1 suppression[J]. Mol Med Rep, 2019, 19(2): 1222-1229.
[14] Wang Y J, Shen S P, Li Z, et al. MiR-140-5p affects chondrocyte proliferation, apoptosis, and inflammation by targeting HMGB1 in osteoarthritis[J]. Inflamm Res, 2020, 69(1): 63-73. DOI: 10.1007/s00011-019-01294-0
[15] Li W Z, Ni J D, Song D Y, et al. Dual regulatory roles of HMGB1 in inflammatory reaction of chondrocyte cells and mice[J]. Cell Cycle, 2019, 18(18): 2268-2280. DOI: 10.1080/15384101.2019.1642680
[16] Yang H, Wang H C, Andersson U. Targeting inflammation driven by HMGB1[J]. Front Immunol, 2020, 11: 484. DOI: 10.3389/fimmu.2020.00484
[17] Jimi E, Fei H, Nakatomi C. NF-κB signaling regulates physiological and pathological chondrogenesis[J]. Int J Mol Sci, 2019, 20(24): 6275. DOI: 10.3390/ijms20246275
[18] Zhong H H, Li X L, Zhou S N, et al. Interplay between RAGE and TLR4 regulates HMGB1-induced inflammation by promoting cell surface expression of RAGE and TLR4[J]. J Immunol, 2020, 205(3): 767-775. DOI: 10.4049/jimmunol.1900860
[19] Meng Y, Qiu S Q, Sun L, et al. Knockdown of exosome-mediated lnc-PVT1 alleviates lipopolysaccharide-induced osteoarthritis progression by mediating the HMGB1/TLR4/NF-κB pathway via miR-93-5p[J]. Mol Med Rep, 2020, 22(6): 5313-5325. DOI: 10.3892/mmr.2020.11594
[20] Hu S L, Wang K, Shi Y F, et al. Downregulating Akt/NF-κB signaling and its antioxidant activity with Loureirin A for alleviating the progression of osteoarthritis: in vitro and vivo studies[J]. Int Immunopharmacol, 2020, 78: 105953. DOI: 10.1016/j.intimp.2019.105953
[21] Hu Z H, Xiao M, Cai H X, et al. Glycyrrhizin regulates rat TMJOA progression by inhibiting the HMGB1-RAGE/TLR4-NF-κB/AKT pathway[J]. J Cell Mol Med, 2022, 26(3): 925-936. DOI: 10.1111/jcmm.17149
[22] Romerio A, Peri F. Increasing the chemical variety of small-molecule-based TLR4 modulators: an overview[J]. Front Immunol, 2020, 11: 1210. DOI: 10.3389/fimmu.2020.01210
[23] Li C Z, He Y H, Li Y L, et al. A novel method to establish the rabbit model of knee osteoarthritis: intra-articular injection of SDF-1 induces OA[J]. BMC Musculoskelet Disord, 2021, 22(1): 329. DOI: 10.1186/s12891-021-04188-7
[24] Xiang Y Y, Li Y L, Yang L J, et al. MiR-142-5p as a CXCR4-targeted microRNA attenuates SDF-1-induced chondrocyte apoptosis and cartilage degradation via inactivating MAPK signaling pathway[J]. Biochem Res Int, 2020, 2020: 4508108.
[25] Liang S, Lv Z T, Zhang J M, et al. Necrostatin-1 attenuates trauma-induced mouse osteoarthritis and IL-1β induced apoptosis via HMGB1/TLR4/SDF-1 in primary mouse chondrocytes[J]. Front Pharmacol, 2018, 9: 1378. DOI: 10.3389/fphar.2018.01378
[26] Zhang J L, Cheng F Y, Rong G X, et al. Hsa_circ_0005567 activates autophagy and suppresses IL-1β-induced chondrocyte apoptosis by regulating miR-495[J]. Front Mol Biosci, 2020, 7: 216. DOI: 10.3389/fmolb.2020.00216
[27] Gao Y J, Zhao H Y, Li Y. LncRNA MCM3AP-AS1 regulates miR-142-3p/HMGB1 to promote LPS-induced chondrocyte apoptosis[J]. BMC Musculoskelet Disord, 2019, 20(1): 605. DOI: 10.1186/s12891-019-2967-4
[28] Qiu M, Liu D, Fu Q. MiR-129-5p shuttled by human synovial mesenchymal stem cell-derived exosomes relieves IL-1β induced osteoarthritis via targeting HMGB1[J]. Life Sci, 2021, 269: 118987. DOI: 10.1016/j.lfs.2020.118987
[29] Pan H, Dai H M, Wang L Z, et al. MicroRNA-410-3p modulates chondrocyte apoptosis and inflammation by targeting high mobility group box 1 (HMGB1) in an osteoarthritis mouse model[J]. BMC Musculoskelet Disord, 2020, 21(1): 486. DOI: 10.1186/s12891-020-03489-7
[30] Lin J T, Song T, Li C, et al. GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer[J]. Biochim Biophys Acta Mol Cell Res, 2020, 1867(5): 118659. DOI: 10.1016/j.bbamcr.2020.118659
[31] Yuan X L, Li L F, Shi W M, et al. TMF protects chondrocytes from ER stress-induced apoptosis by down-regulating GSK-3β[J]. Biomed Pharmacother, 2017, 89: 1262-1268. DOI: 10.1016/j.biopha.2017.03.028
[32] Ba C, Ni X H, Yu J L, et al. Ubiquitin conjugating enzyme E2 M promotes apoptosis in osteoarthritis chondrocytes via Wnt/β-catenin signaling[J]. Biochem Biophys Res Commun, 2020, 529(4): 970-976. DOI: 10.1016/j.bbrc.2020.06.095
[33] Sun Y, Wang F F, Sun X H, et al. CX3CR1 regulates osteoarthrosis chondrocyte proliferation and apoptosis via Wnt/β-catenin signaling[J]. Biomed Pharmacother, 2017, 96: 1317-1323. DOI: 10.1016/j.biopha.2017.11.080
[34] Shu Z Y, Miao X G, Tang T, et al. The GSK-3β/β-catenin signaling pathway is involved in HMGB1-induced chondro-cyte apoptosis and cartilage matrix degradation[J]. Int J Mol Med, 2020, 45(3): 769-778.
[35] 廖建青, 马富文, 张英杰, 等. 骨痹合剂对膝关节骨性关节炎原代软骨细胞PI3K/AKT信号通路的影响[J]. 中华中医药杂志, 2022, 37(4): 2322-2326. Liao J Q, Ma F W, Zhang Y J, et al. Effects of Gubi mixture on PI3K/AKT signaling pathway of KOA primary chondrocytes[J]. China J Tradit Chin Med Pharm, 2022, 37(4): 2322-2326.
[36] Shi X Q, Jie L S, Wu P, et al. Calycosin mitigates chondrocyte inflammation and apoptosis by inhibiting the PI3K/AKT and NF-κB pathways[J]. J Ethnopharmacol, 2022, 297: 115536. DOI: 10.1016/j.jep.2022.115536
[37] Li D, Ni S, Miao K S, et al. PI3K/Akt and caspase pathways mediate oxidative stress-induced chondrocyte apoptosis[J]. Cell Stress Chaperones, 2019, 24(1): 195-202. DOI: 10.1007/s12192-018-0956-4
[38] 习洋. 生长分化因子-11 (GDF11) 通过抑制MAPK和PI3K-AKT/NF-κB通路发挥抗骨关节炎作用的体内外研究[D]. 武汉: 华中科技大学, 2020. Xi Y. GDF11 exerts anti-osteoarthritic effects through MAPK and PI3K-AKT/NF-κB pathway in vitro and vivo studies[D]. Wuhan: Huazhong University of Science and Technology, 2020.
[39] Bigeard J, Hirt H. Nuclear signaling of plant MAPKs[J]. Front Plant Sci, 2018, 9: 469. DOI: 10.3389/fpls.2018.00469
[40] 张传成, 沈美花, 陈利锋. 氧化应激调控MAPK信号通路与骨关节炎治疗研究进展[J]. 中国骨质疏松杂志, 2023, 29(4): 583-588. Zhang C C, Shen M H, Chen L F. Research progress of oxidative stress regulating MAPK signal pathway and treatment of osteoarthritis[J]. Chin J Osteoporos, 2023, 29(4): 583-588.
[41] 傅永升, 谭茗月, 王卫国, 等. 中药调控膝骨关节炎相关信号通路的研究进展[J]. 中国实验方剂学杂志, 2023, 29(22): 231-243. Fu Y S, Tan M Y, Wang W G, et al. Chinese medicine regulates knee osteoarthritis-related signaling pathways: a review[J]. Chin J Exp Tradit Med Form, 2023, 29(22): 231-243.
[42] Zhou Y, Ming J H, Li Y M, et al. Ligustilide attenuates nitric oxide-induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways[J]. J Cell Mol Med, 2019, 23(5): 3357-3368. DOI: 10.1111/jcmm.14226
[43] Huang X J, Xi Y, Mao Z K, et al. Vanillic acid attenuates cartilage degeneration by regulating the MAPK and PI3K/AKT/NF-κB pathway[J]. Eur J Pharmacol, 2019, 859: 172481. DOI: 10.1016/j.ejphar.2019.172481
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