神经轴突导向因子在骨关节炎中的研究进展

doi:10.3877/cma.j.issn.1674-134X.2025.03.009

骨关节炎（OA）是一种以关节软骨退变、骨赘增生、软骨下骨重塑以及滑膜炎症等为特征的退行性疾病。OA最常见的症状是疼痛，正常的关节软骨是没有神经分布的，随着OA的进展，在缺乏神经支配的区域出现神经支配，然而其原因尚未探明。神经轴突导向因子在神经长入过程中起到重要作用，神经支配对于损伤修复、软骨下骨重塑以及减轻滑膜炎症等具有一定作用，但其也使疼痛更为敏感或者一定程度上加剧了疼痛症状。神经元轴突连接到组织中是由细胞外环境中的特定线索引导的，主要有4种轴突导向因子：轴突生长诱向因子-1（netrin-1）、狭缝蛋白引导配体（SLIT）、促红细胞生成素肝细胞激酶受体膜结合配体（ephrin）和脑信号蛋白3A（Sema3A）。本文围绕轴突导向因子在OA进展中的作用开展综述，阐述OA进展过程中诱导神经长入的机制及作用。

关键词: 轴突导向, 关节炎, 轴突生长诱向因子-1, 配体, 肝配蛋白, 脑信号蛋白-3A

Osteoarthritis is a degenerative disease marked by articular cartilage degradation, osteophyte hyperplasia, subchondral bone remodeling, and synovial inflammation, primarily manifesting as pain. Notably, normal articular cartilage is devoid of nerve innervation; however, as osteoarthritis advances, innervation emerges in previously uninnervated regions. Axon guidance cues serve as pivotal regulators of nociceptive nerve growth, playing a dual role. On one hand, nerve innervation facilitates injury repair, subchondral bone remodeling, and mitigatessynovial inflammation. Conversely, it heightens pain sensitivity or exacerbates pain symptoms. This intricate interplay is orchestrated by four primary axon guidance cues: netrin-1, slit guidance ligand(SLIT), Eph receptor-interacting proteins (ephrin), and semaphorin3A (Sema3A). This review delved into the intricate role of these cues in the progression of osteoarthritis and elucidates the mechanisms underlying nerve innervation in areas previously lacking innervation.

Key words: Axon guidance, Osteoarthritis, Netrin-1, Ligands, Ephrins, Semaphorin-3A

[1]	Duong V, Oo WM, Ding C, et al. Evaluation and treatment of knee pain: areview[J]. JAMA, 2023, 330（16）: 1568-1580.
[2]	中华医学会骨科学分会关节外科学组, 解放军总医院第四医学中心骨科医学部, 国家骨科与运动康复临床医学研究中心. 中国膝骨关节炎非手术治疗专家共识（2023年版） [J/OL]. 中华关节外科杂志（电子版）, 2024, 18（2）: 151-159.
[3]	Li X, Martinez-Ramos S, Heedge FT, et al. Expression of semaphorin-3A in the joint and role in osteoarthritis[J/OL]. Cell BiochemFunct, 2024, 42（3）: e4012. DOI:10.1002/cbf.4012.
[4]	李鹏飞, 杨永泽, 马国榕, 等. 骨关节炎疼痛机制研究进展 [J]. 国际骨科学杂志, 2024, 45（02）: 136-140.
[5]	Miao MZ, Lee JS, Yamada KM, et al. Integrin signalling in joint development, homeostasis and osteoarthritis[J]. Nat Rev Rheumatol, 2024, 20（8）: 492-509.
[6]	Hochberg MC, Carrino JA, Schnitzer TJ, et al. Long-term safety and efficacy of subcutaneous tanezumab versus nonsteroidal antiinflammatorydrugs for hip or knee osteoarthritis: arandomized trial[J]. Arthritis Rheumatol, 2021, 73（7）: 1167-1177.
[7]	Gavioli E, Mantelli F, Cesta MC, et al. The history of nerve growth factor: from molecule to drug[J/OL]. Biomolecules, 2024, 14（6）: 635. DOI:10.3390/biom14060635.
[8]	王孟玲, 安丙辰. 神经生长因子在骨关节炎关节软骨中的病理生理作用 [J/CD]. 中华关节外科杂志（电子版）, 2022, 16（1）: 49-54.
[9]	Zhao L, Lai Y, Jiao H, et al. Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints[J/OL]. Nat Commun, 2024, 15（1）: 3225. DOI:10.1038/s41467-024-47633-6.
[10]	Mei H, Li Z, Lv Q, et al. Sema3A secreted by sensory nerve induces bone formation under mechanical loads[J/OL]. Int J Oral Sci, 2024, 16（1）: 5. DOI:10.1038/s41368-023-00269-6.
[11]	Muschter D, Fleischhauer L, Taheri S, et al. Sensory neuropeptides are required for bone and cartilage homeostasis in a murine destabilization-induced osteoarthritis model[J/OL]. Bone, 2020, 133: 115181.DOI:10.1016/j.bone.2019.115181.
[12]	Hildebrandt A, Dietrich T, Weber J, et al. The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis[J/OL]. Arthritis Res Ther, 2023, 25（1）: 244. DOI:10.1186/s13075-023-03215-3.
[13]	Cui Z, Wu H, Xiao Y, et al. Endothelial PDGF-BB/PDGFR-β signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation[J/OL]. Bone Res, 2022, 10（1）: 58. DOI:10.1038/s41413-022-00229-6.
[14]	Domínguez-Romero ME, Slater PG. Unraveling axon guidance during axotomy and regeneration[J/OL]. Int J Mol Sci, 2021, 22（15）: 8344. DOI:10.3390/ijms22158344.
[15]	Yang X, Ma L, Zhang J, et al. Hypofucosylation of Unc5b regulated by Fut8 enhances macrophage emigration and prevents atherosclerosis[J/OL]. Cell Biosci, 2023, 13（1）: 13. DOI:10.1186/s13578-023-00959-y.
[16]	NoristaniHN. Intrinsic regulation of axon regeneration after spinal cord injury: Recent advances and remaining challenges[J/OL]. Exp Neurol, 2022, 357: 114198. DOI:10.1016/j.expneurol.2022.114198.
[17]	Zhu K, Wang H, Ye K, et al. Netrin-1 signaling pathway mechanisms in neurodegenerative diseases[J]. Neural Regen Res, 2025, 20（4）: 960-972.
[18]	Maruyama K, Kawasaki T, Hamaguchi M, et al. Bone-protective functions of netrin 1 protein[J]. J Biol Chem, 2016, 291（46）: 23854-23868.
[19]	Ji S, Zhao B, Gao Y, et al. Cinnamaldehyde attenuates streptozocin-induced diabetic osteoporosis in a rat model by modulating netrin-1/DCC-UNC5B signal transduction[J/OL]. Front Pharmacol, 2024, 15: 1367806. DOI:10.3389/fphar.2024.1367806.
[20]	Mediero A, Ramkhelawon B, Wilder T, et al. Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis[J]. Ann Rheum Dis, 2016, 75（9）: 1706-1713.
[21]	Zhu S, Zhu J, Zhen G, et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain[J]. J Clin Invest, 2019, 129（3）: 1076-1093.
[22]	Mediero A, Ramkhelawon B, Perez-Aso M, et al. Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation[J]. J Bone Miner Res, 2015, 30（5）: 837-854.
[23]	Sato T, Kokabu S, Enoki Y, et al. Functional roles of netrin-1 in osteoblast differentiation[J]. In Vivo, 2017, 31（3）: 321-328.
[24]	Guzmán-Palma P, Contreras EG, Mora N, et al. Slit/robosignaling regulates multiple stages of the development of the Drosophila motion detection system[J/OL]. Front Cell Dev Biol, 2021, 9: 612645. DOI:10.3389/fcell.2021.612645.
[25]	Kellermeyer R, HeydmanLM, Gillis T, et al. Proteolytic cleavage of Slit by the Tolkin protease converts an axon repulsion cue to an axon growth cue in vivo[J/OL]. Development, 2020, 147（20）: dev196055. DOI:10.1242/dev.196055.
[26]	Liu X, Zhang P, Gu Y, et al. Type H vessels: functions in bone development and diseases[J/OL]. Front Cell Dev Biol, 2023, 11: 1236545.DOI:10.3389/fcell.2023.1236545.
[27]	Xu R, Yallowitz A, Qin A, et al. Targeting skeletal endothelium to ameliorate bone loss [J]. Nat Med, 2018, 24（6）: 823-833.
[28]	Wang YN, Tang Y, He Z, et al. Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue[J]. Nat Metab, 2021, 3（11）: 1536-1551.
[29]	Li Z, Shi B, Li N, et al. Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion[J/OL]. Nat Commun, 2024, 15（1）: 6697. DOI:10.1038/s41467-024-51155-6.
[30]	Park SJ, Lee JY, Lee SH, et al. SLIT2 inhibits osteoclastogenesis and bone resorption by suppression of Cdc42 activity[J]. BiochemBiophys Res Commun, 2019, 514（3）: 868-874.
[31]	Wang L, Zheng J, Pathak JL, et al. SLIT2 overexpression in periodontitis intensifies inflammation and alveolar bone loss, possibly via the activation of MAPK pathway[J/OL]. Front Cell Dev Biol, 2020, 8: 593. DOI:10.3389/fcell.2020.00593.
[32]	Su H, Yang Y, Lv W, et al. Bone marrow mesenchymal stem cell-derived exosomal microRNA-382 promotes osteogenesis in osteoblast via regulation of SLIT2[J/OL]. J Orthop Surg Res, 2023, 18（1）: 185. DOI:10.1186/s13018-023-03667-y.
[33]	Svensson KJ, Long JZ, JedrychowskiMP, et al. A secreted Slit2 fragment regulates adipose tissue thermogenesis and metabolic function[J]. Cell Metab, 2016, 23（3）: 454-466.
[34]	Kim BJ, Lee YS, Lee SY, et al. Osteoclast-secreted SLIT3 coordinates bone resorption and formation[J]. J Clin Invest, 2018, 128（4）: 1429-1441.
[35]	Li N, Inoue K, Sun J, et al. Osteoclasts are not a source of SLIT3[J/OL]. Bone Res, 2020, 8: 11. DOI:10.1038/s41413-020-0086-3.
[36]	Zhu Y, Su SA, Shen J, et al. Recent advances of the Ephrin and Eph family in cardiovascular development and pathologies[J/OL]. iScience, 2024, 27（8）:110556.DOI:10.1016/j.isci.2024.110556.
[37]	Zhu S, Liu Z, Yuan C, et al. Bidirectional ephrinB2-EphB4 signaling regulates the osteogenic differentiation of canine periodontal ligament stem cells[J]. Int J Mol Med, 2020, 45（3）: 897-909.
[38]	Stiffel VM, Thomas A, Rundle CH, et al. The EphA4 signaling is anti-catabolic in synoviocytes but pro-anabolic in articularchondrocytes[J]. Calcif Tissue Int, 2020, 107（6）: 576-592.
[39]	Arthur A, Gronthos S. Eph-ephrin signaling mediates cross-talk within the bone microenvironment[J/OL]. Front Cell Dev Biol, 2021, 9: 598612.DOI:10.3389/fcell.2021.598612.
[40]	Zhu S, Chen W, Masson A, et al. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis[J/OL]. Cell Discov, 2024, 10（1）: 71. DOI:10.1038/s41421-024-00689-6.
[41]	Xu H, Wang W, Liu X, et al. Targeting strategies for bone diseases: signaling pathways and clinical studies[J/OL]. Signal Transduct Target Ther, 2023, 8（1）: 202. DOI:10.1038/s41392-023-01467-8.
[42]	Stiffel VM, Rundle CH, Sheng MH, et al. A novel EphA4 signaling-based therapeutic strategy for osteoarthritis in mice[J]. J Bone Miner Res, 2022, 37（4）: 660-674.
[43]	Piffko A, Uhl C, Vajkoczy P, et al. EphrinB2-EphB4 signaling in neurooncological disease[J/OL]. Int J Mol Sci, 2022, 23（3）: 1679. DOI:10.3390/ijms23031679.
[44]	Bao Z, Wang P, Li Y, et al. EphrinB2-mediated chondrocyte autophagy induces post-traumatic arthritis via rupture of cartilage homeostasis[J/OL]. J Cell Mol Med, 2024, 28（18）: e70095. DOI:10.1111/jcmm.70095.
[45]	Wu W, Zhang J, Chen Y, et al. Genes in axonal regeneration[J]. Mol Neurobiol, 2024, 61（10）: 7431-7447.
[46]	Wu K, Huang D, Huang X. The effects of semaphorin 3A in bone and cartilage metabolism: fundamental mechanism and clinical potential[J/OL]. Front Cell Dev Biol, 2023, 11: 1321151.DOI:10.3389/fcell.2023.1321151.
[47]	Stöckl S, Reichart J, Zborilova M, et al. Semaphorin 3A-neuropilin-1 signaling modulates MMP13 expression in human osteoarthritic chondrocytes[J/OL]. Int J Mol Sci, 2022, 23（22）: 14180. DOI:10.3390/ijms232214180.
[48]	Sumi C, Hirose N, Yanoshita M, et al. Semaphorin 3A inhibits inflammation in chondrocytes under excessive mechanical stress[J/OL]. Mediators Inflamm, 2018, 2018: 5703651.DOI:10.1155/2018/5703651.
[49]	Fukuda T, Takeda S, Xu R, et al. Sema3A regulates bone-mass accrual through sensory innervations[J]. Nature, 2013, 497（7450）: 490-493.
[50]	Shen M, Zhou C, Tian Y, et al. Effects of Semaphorin3A on the growth of sensory and motor neurons[J/OL]. Exp Cell Res, 2023, 424（2）: 113506.DOI:10.1016/j.yexcr.2023.113506.
[51]	Sagar DR, Ashraf S, Xu L, et al. Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis[J]. Ann Rheum Dis, 2014, 73（8）: 1558-1565.
[52]	Gupta S, Viotti A, Eichwald T, et al. Navigating the blurred path of mixed neuroimmune signaling[J]. J Allergy Clin Immunol, 2024, 153（4）: 924-938.

[1]	姚放鸣, 谷邦宁, 杨旭辉, 曾子俊, 吴佳威, 何敏聪, 何晓铭, 魏秋实, 何伟, 刘文刚. 下肢肌肉分布与内翻型膝骨关节炎进展及肌少症的相关性[J/OL]. 中华关节外科杂志(电子版), 2025, 19(03): 292-301.
[2]	王浩浩, 席刚, 杨家驹, 翁铭捷, 张民. 术前膝关节冠状面力线对牛津单髁术后力线的影响分析[J/OL]. 中华关节外科杂志(电子版), 2025, 19(02): 156-161.
[3]	王春久, 田向东, 谭冶彤, 薛志鹏, 张伟, 刘昂. 单平面胫骨高位截骨联合关节镜治疗内翻型膝骨关节炎[J/OL]. 中华关节外科杂志(电子版), 2025, 19(02): 185-192.
[4]	陈博, 李向毅. 骨关节炎中软骨细胞铜死亡的研究进展[J/OL]. 中华关节外科杂志(电子版), 2025, 19(02): 207-213.
[5]	张霞, 冯娅娆, 罗寰, 杨金良, 张斌, 郑学军. 尪痹胶囊联合来氟米特对类风湿关节炎炎症指标的影响[J/OL]. 中华关节外科杂志(电子版), 2025, 19(01): 55-64.
[6]	王玺玉, 赵俊杰, 黄鹏飞, 张兆坤, 赵宇昊, 赵海燕. 基质金属蛋白酶响应性水凝胶在骨关节炎的应用[J/OL]. 中华关节外科杂志(电子版), 2025, 19(01): 76-81.
[7]	林晓东, 周宜, 章家皓, 赵传喜, 刘军, 刘文刚. 如何在中度外翻膝关节置换中实现假体功能性对线[J/OL]. 中华关节外科杂志(电子版), 2025, 19(01): 116-121.
[8]	曹新超, 马永峰, 马平, 贺丽君, 谢荣景. 非小细胞肺癌围手术期程序性死亡蛋白配体1 表达分析[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(02): 251-255.
[9]	张彧超, 皋青青, 杨洋, 冉大伟, 周运海, 浦明之. 中医中药清肺化痰逐瘀汤治疗AECOPD 患者的临床疗效分析[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(01): 36-41.
[10]	张俊山, 杜晓健, 刘小刚, 王良, 张磊, 闫荣亮, 曹立海, 张玲. 改良踝关节前外侧入路与前侧入路全踝关节置换术治疗老年踝关节骨性关节炎的对比研究[J/OL]. 中华老年骨科与康复电子杂志, 2025, 11(04): 207-213.
[11]	张优佳, 丁明月, 刘之琪, 郑帅歌, 刘仕豪, 秦秉玉. PD-1/PD-L1 通路在脓毒症导致的脏器功能障碍中的作用[J/OL]. 中华重症医学电子杂志, 2025, 11(02): 198-203.
[12]	胡志恒, 任洪波, 宋志远, 曲大成, 张运刚, 朱旭. 重型颅脑损伤患者外周血CCL20、CCL23与继发性大面积脑梗死的关系[J/OL]. 中华脑科疾病与康复杂志(电子版), 2025, 15(02): 108-114.
[13]	康清源, 张克石, 肖文韬, 谢培森, 东黎光, 袁平, 关振鹏. 在职钢铁工人群体膝关节骨关节炎流行情况及其可能的危险因素调查[J/OL]. 中华临床医师杂志(电子版), 2025, 19(04): 248-255.
[14]	周俊, 王文, 臧银善, 徐艳. 阿达木单抗治疗类风湿关节炎临床疗效预测因素的研究[J/OL]. 中华临床医师杂志(电子版), 2025, 19(01): 41-47.
[15]	邓绮玲, 庄杰兰, 董家铭, 苏镜. 基于生物信息学分析原发性痛风性关节炎与高尿酸血症的关键基因及相关通路[J/OL]. 中华临床实验室管理电子杂志, 2025, 13(02): 97-105.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Research progress of axon guidance cues in osteoarthritis

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Research progress of axon guidance cues in osteoarthritis