骨关节炎中的滑膜巨噬细胞作用与特点

doi:10.3969/j.issn.2095-4344.2790

摘要/Abstract

摘要：

文题释义：

滑膜巨噬细胞：滑膜巨噬细胞在骨关节炎软骨损伤中发挥着至关重要的作用，活化的巨噬细胞可分泌大量可溶性促炎因子，加速了骨关节炎的病理进程。而巨噬细胞作为滑膜炎的主要参与者，在骨关节炎发展中炎症因子表达和极化机制逐渐成为研究的热点。

滑膜的结构：正常滑膜分为两层，即薄的细胞层(内腔层)和血管层(内膜下层)，是血管丰富的关节囊内膜，贴附于非关节面部分，覆盖于关节囊内的骨面上，不在软骨面上，此部分称为边缘区或“裸区”。滑膜呈粉红色，光滑发亮、湿而润滑，有时可见绒毛，内含胶原性纤维。滑膜的功能是制造和调节滑液等。

背景：骨关节炎的确切发病机制尚不清楚，研究表明滑膜组织中巨噬细胞参与滑膜炎症反应及软骨基质降解酶的产生。

目的：基于滑膜巨噬细胞在骨关节炎中的重要作用，回顾总结该领域的主要研究成果及重要的研究方法，为将来滑膜巨噬细胞的研究奠定基础。

方法：由第一作者应用计算机检索PubMed、维普数据库中1990至2019年出版的文献，英文检索词为“osteoarthritis，synovitis，synovial macrophages”；中文检索词为“骨关节炎，滑膜炎，滑膜巨噬细胞”。按入选标准进行人工筛选，排查与主题相关性差及重复、陈旧的文献，最终纳入46篇文献。

结果与结论：①滑膜组织中存在炎症反应，且滑膜炎的严重程度与骨关节炎症状和疾病的进展密切相关；在不同阶段骨关节炎患者滑膜组织中均发现有大量不同活化状态的巨噬细胞的浸润；②M1型巨噬细胞是骨关节炎炎症因子产生、软骨降解、骨赘形成的主要巨噬细胞亚群，而M2型巨噬细胞通过分泌抗炎因子，对骨关节炎具有保护作用；抑制巨噬细胞向M1型分化，促进其向M2型分化可减轻骨关节炎病理改变，延缓骨关节炎进展；③通过调节滑膜巨噬细胞的极化状态可能成为治疗骨关节炎有效手段。

ORCID: 0000-0003-1620-5978(曹建刚)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 骨关节炎, 滑膜炎, 滑膜, 巨噬细胞

Abstract:

BACKGROUND: The exact pathogenesis of osteoarthritis is unclear. Studies have shown that macrophages in synovial tissue are involved in sliding-inflammation response and the production of cartilage matrix degradation enzyme.

OBJECTIVE: Based on the important role of synovial macrophages in osteoarthritis, to review and summarize the major research achievements and important research methods in this field, laying a foundation for future research on synovial macrophages.

METHODS: The first author used computer to search relevant literatures included in PubMed and VIP from 1999 to 2019. The search terms were “osteoarthritis, synovitis, synovial macrophages” in English and Chinese, respectively. Manual screening was conducted according to the inclusion criteria, and irrelevant, repetitive and obsolete articles were excluded. Finally, 46 eligible articles were included.

RESULTS AND CONCLUSION: There is an inflammatory response in the synovial tissue, and the severity of synovitis is closely related to osteoarthritis symptoms and progression. A large number of macrophages with different activation states are infiltrated in the synovial tissues of osteoarthritis patients at different stages. M1 macrophages are the main subgroup of macrophages involved in the production, cartilage degradation and osteophyte formation of osteoarthritis inflammatory factors, while M2 macrophages have a protective effect on osteoarthritis by secreting anti-inflammatory factors. Inhibiting the differentiation of macrophages into M1 type and promoting their M2 type differentiation can alleviate the pathological changes of osteoarthritis and delay the progression of osteoarthritis. It may be an effective method to treat osteoarthritis by regulating the polarization state of synovial macrophages.

Key words: osteoarthritis, synovitis, macrophages

中图分类号:

曹建刚, 陈德生. 骨关节炎中的滑膜巨噬细胞作用与特点[J]. 中国组织工程研究, 2020, 24(29): 4731-4736.

Cao Jiangang, Chen Desheng. Synovial macrophages in osteoarthritis: roles and features[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(29): 4731-4736.

图/表（结果） 3

骨关节炎是最常见的关节病变，其可发生于几乎所有动关节，是一种累及关节软骨、软骨下骨、滑膜、韧带、关节囊及关节周围肌肉的复杂病症^[1-3]。作为一种常见的致残性疾病，随着全球人口老龄化和肥胖率以及关节损伤个体数量的增加，在世界范围内估计，目前约有2.5亿人受骨关节炎影响，这不仅给患病个体带来巨大的生活障碍，给卫生保健系统带来新的挑战，还给社会带来了沉重的经济负担^[4-5]。在老化、肥胖、性别、遗传、创伤等致病因素作用下，关节组织的损伤与修复之间的动态平衡被打破，致使软骨腐蚀缺损、骨赘形成、软骨下骨硬化、滑膜的肥厚增生，在临床上最初表现为关节的疼痛、肿胀、活动受限，最终导致整个关节的畸形和功能丧失，见图1^[3，6-7]。最新的骨关节炎治疗理念强调以患者为中心，对其加强健康教育，使其在自我管理的基础上适当的锻炼和减肥，在这些温和治疗手段无效时再采取手术治疗^[4]。预防、延缓进展和改善病情一直是各类骨关节炎研究的主要目的，然而至今尚无有效的治疗措施^[8]。

1.5 数据的提取信息记录侧重滑膜巨噬细胞在骨关节炎中作用的研究进展。文献检索流程图见图2。

2.1.1 组织学研究早在1991年ATHANASOU等^[30]就对4例接受髋关节置换骨关节炎患者的关节滑膜组织抗原表位进行了分析，发现滑内膜细胞和内膜下细胞表达多种巨噬细胞抗体(CD11b，CD14，CD16，CD68)。这些抗原表位均是静息状态下组织巨噬细胞所表达的，不能反映滑膜中巨噬细胞的活化状态。此后，相继又有多个研究对骨关节炎患者滑膜巨噬细胞进行了分析，HAYWOOD等^[32] (2003年)、BENITO等^[33](2005年)、BONDESON等^[34] (2006年)均发现与正常滑膜组织相比骨关节炎患者滑膜组织中巨噬细胞数量明显增多，类似的结果在小动物骨关节炎模型中亦得到证实，见图3^{[24，29，31]}。上述研究均表明滑膜巨噬细胞在骨关节炎患者滑膜炎中发挥重要作用，但均未对不同极化状态的巨噬细胞进行标记分析。

参考文献

[1] MARTEL-PELLETIER J, BARR AJ, CICUTTINI FM, et al. Osteoarthritis. Nat Rev Dis Primers.2016;2:16072.

[2] BRANDT KD, RADIN EL, DIEPPE PA, et al. Yet more evidence that osteoarthritis is not a cartilage disease. Ann Rheum Dis. 2006;65:4.

[3] LOESER RF, GOLDRING SR, SCANZELLO CR, et al. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697-1707.

[4] ROEMER FW, GUERMAZI A, FELSON DT, et al. Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study.Ann Rheum Dis. 2011;70(10): 1804-1809.

[5] BORTOLUZZI A, FURINI F, SCIRE CA. Osteoarthritis and its management-Epidemiology, nutritional aspects and environmental factors. Autoimmun Rev.2018;17(11):1097-1104.

[6] FU K, ROBBINS SR, MCDOUGALL JJ.Osteoarthritis: the genesis of pain. Rheumatology(Oxford). Rheumatology (Oxford). 2018; 57(suppl_4):iv43-iv50.

[7] KRASNOKUTSKY S, ATTUR M, PALMER G, et al. Current concepts in the pathogenesis of osteoarthritis. Osteoarthritis Cartilage.2008;16 Suppl 3:S1-3.

[8] HUNTER DJ, BIERMA-ZEINSTRA S. Osteoarthritis. Lancet. 2019;393(10182):1745-1759.

[9] FURMAN BD, KIMMERLING KA, ZURA RD, et al. Articular ankle fracture results in increased synovitis, synovial macrophage infiltration, and synovial fluid concentrations of inflammatory cytokines and chemokines. Arthritis Rheum. 2015;67(5): 1234-1239.

[10] AYRAL X, PICKERING EH, WOODWORTH TG, et al.Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis-results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage. 2005;13(5):361-367.

[11] HENROTIN Y, LAMBERT C, RICHETTE P. Importance of synovitis in osteoarthritis: Evidence for the use of glycosaminoglycans against synovial inflammation. Semin Arthritis Rheum. 2014;43(5):579-587.

[12] LIU-BRYAN R. Synovium and the innate inflammatory network in osteoarthritis progression. Curr Rheumatol Rep. 2013;15(5):323.

[13] SCANZELLO CR, GOLDRING SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51(2):249-257.

[14] BONDESON J, BLOM AB, WAINWRIGHT S, et al. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum.2010;62(3):647-657.

[15] DE LANGE-BROKAAR BJE, IOAN-FACSINAY A, VAN OSCH GJVM, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage. 2012;20(12):1484-1499.

[16] 戴冽,许赤多,汤美安,等.佐剂性关节炎大鼠滑膜巨噬细胞在关节破坏中的作用[J].中国病理生理杂志,2003,19(7):950-953

[17] GINHOUX F, JUNG S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14(6):392-404.

[18] YONA S, KIM KW, WOLF Y, et al.Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38(1):79-91.

[19] HASHIMOTO D, CHOW A, NOIZAT C,et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013; 38(4):792-804.

[20] LAPENNA A, DE PALMA M, LEWIS CE. Perivascular macrophages in health and disease. Nat Rev Immunol.2018; 18(11):689-702.

[21] XIE J, HUANG Z, YU X,et al. Clinical implications of macrophage dysfunction in the development of osteoarthritis of the knee. Cytokine Growth Factor Rev. 2019;46:36-44.

[22] GORDON S, PLUDDEMANN A. Tissue macrophages: heterogeneity and functions. BMC Biol. 2017;15(1):53.

[23] MOSSER DM, EDWARDS JP.Exploring the full spectrum of macrophage activation. Nat Rev Immunol.2008;8(12):958-969.

[24] KRAUS VB, MCDANIEL G, HUEBNER JL, et al. Direct in vivo evidence of activated macrophages in human osteoarthritis. Osteoarthritis Cartilage. 2016;24(9):1613-1621.

[25] PISCAER TM, MULLER C, MINDT TL, et al. Imaging of activated macrophages in experimental osteoarthritis using folate-targeted animal single-photon-emission computed tomography/computed tomography. Arthritis Rheum.2011; 63(7):1898-1907.

[26] DE VISSER HM, KORTHAGEN NM, MULLER C,et al. Imaging of Folate Receptor Expressing Macrophages in the Rat Groove Model of Osteoarthritis: Using a New DOTA-Folate Conjugate. Cartilage. 2018;9(2):183-191.

[27] DAGHESTANI HN, PIEPER CF, KRAUS VB. Soluble macrophage biomarkers indicate inflammatory phenotypes in patients with knee osteoarthritis. Arthritis Rheum.2015;67(4): 956-965.

[28] WU CL, MCNEILL J, GOON K, et al. Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice. Arthritis Rheum. 2017;69(9):1772-1783.

[29] ZHANG H, LIN C, ZENG C,et al. Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Ann Rheum Dis.2018;77(10):1524-1534.

[30] ATHANASOU NA, QUINN J.Immunocytochemical analysis of human synovial lining cells: phenotypic relation to other marrow derived cells.Ann Rheum Dis.1991;50(5):311-315.

[31] BLOOM O, HERMAN PE, SPUNGEN AM. Systemic inflammation in traumatic spinal cord injury. Exp Neurol. 2020;325:113143.

[32] HAYWOOD L, MCWILLIAMS DF, PEARSON CI, et al. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum. 2003;48(8):2173-2177.

[33] BENITO MJ, VEALE DJ, FITZGERALD O, et al. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64(9):1263-1267.

[34] BONDESON J, WAINWRIGHT SD, LAUDER S, et al. The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther. 2006;8(6):R187.

[35] MANFERDINI C, PAOLELLA F, GABUSI E, et al. From osteoarthritic synovium to synovial-derived cells characterization: synovial macrophages are key effector cells. Arthritis Res Ther. 2016;18:83.

[36] VAN DEN BOSCH MH, BLOM AB, SCHELBERGEN RF, et al. Alarmin S100A9 Induces Proinflammatory and Catabolic Effects Predominantly in the M1 Macrophages of Human Osteoarthritic Synovium. J Rheumatol. 2016;43(10):1874-1884.

[37] SHEN J, HILGENBRINK AR, XIA W, et al. Folate receptor-beta constitutes a marker for human proinflammatory monocytes. J Leukoc Biol.2014;96(4):563-870.

[38] VAN LENT PL, BLOM AB, VAN DER KRAAN P, et al. Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. Arthritis Rheum. 2004;50(1):103-111.

[39] BLOM AB, VAN LENT PL, HOLTHUYSEN AE,et al. Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage. 2004; 12(8):627-635.

[40] LI J, HSU HC, YANG P, et al. Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model. Arthritis Rheum. 2012;64(4):1098-1109.

[41] BLOM AB, VAN LENT PL, LIBREGTS S, et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3.Arthritis Rheum.2007;56(1):147-157.

[42] TOPOLUK N, STECKBECK K, SIATKOWSKI S, et al. Amniotic mesenchymal stem cells mitigate osteoarthritis progression in a synovial macrophage-mediated in vitro explant coculture model. J Tissue Eng Regen Med. 2018; 12(4):1097-1110.

[43] TAKANO S, UCHIDA K, INOUE G, et al. Nerve growth factor regulation and production by macrophages in osteoarthritic synovium. Clin Exp Immunol. 2017;190(2):235-243.

[44] SAMAVEDI S, DIAZ-RODRIGUEZ P, ERNDT-MARINO JD, et al. A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis. Tissue Eng Part A. 2017;23(3-4):101-114.

[45] UTOMO L, BASTIAANSEN-JENNISKENS YM, VERHAAR JA, et al. Cartilage inflammation and degeneration is enhanced by pro-inflammatory (M1) macrophages in vitro, but not inhibited directly by anti-inflammatory (M2) macrophages. Osteoarthritis Cartilage. 2016;24(12):2162-2170.

[46] DAI M, SUI B, XUE Y, et al.Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes. Biomaterials. 2018;180:91-103.

引言

作为一种全关节疾病，很多研究已证实在骨关节炎患者关节滑膜中存在炎症反应，且滑膜炎的严重程度与骨关节炎的严重程度和疾病的进展密切相关^[4，9-10]。滑膜炎是指发生在关节滑膜的炎症反应，其主要病理改变为滑膜细胞及血管的增生和炎性细胞的浸润^[11-13]。巨噬细胞是病变滑膜组织中主要的炎症细胞，其分泌的促炎因子和软骨基质降解酶是加重骨关节炎、加速关节退变的重要因素^[14-16]。因此详尽了解滑膜巨噬细胞在骨关节炎的发生和发展中的作用尤为重要。单核细胞和巨噬细胞是多细胞生物体内的主要吞噬细胞，在组织稳态和免疫中具有关键但截然不同的作用^[17]。最新研究表明：在稳定状态或某些类型的炎症过程中，单核细胞基本不影响大多数组织巨噬细胞构成；成年组织巨噬细胞来源于出生前的胚胎前体细胞；组织巨噬细胞可通过自我更新来维持自身的成年状态^[18-19]。根据表型和功能，单核细胞主要分为2个不同亚群：第一个亚群为小鼠的CX3R1^low、CCR2^high、Ly6C^high和人类的CD14^highCD16^low 的巨噬细胞群；第二个亚群为小鼠的CX3R1^high、CCR2^low、Ly6C^low和人类的CD14^lowCD16^high细胞群^[20-21]。第一个亚群细胞具有经典的单核细胞功能，例如向损伤部位快速浸润，补充组织内树突状细胞和巨噬细胞的数量^[22]；第二个亚群的主要功能是监测内皮完整性^[22]。在组织中，静息态巨噬细胞(M0)，可在干扰素γ/脂多糖等因子的作用下活化成促炎性(M1)巨噬细胞或在白细胞介素白细胞介素4/白细胞介素13等细胞因子作用下活化成抑制炎症反应、促进组织修复的(M2)型巨噬细胞^[23-24]。很多研究已证实在骨关节炎患者滑膜组织中存在不同活化状态的巨噬细胞，且这些巨噬细胞在骨关节炎的发生发展中发挥重要作用^[24-31]。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程