大骨节病发病机制研究现状与未来展望
Current Status and Future Prospect of Research on Pathogenesis of Kashin-Beck Disease
DOI: 10.12677/acm.2025.15113110, PDF,    科研立项经费支持
作者: 岳 浩, 朱新科, 孙正明*：西安医学院研究生院，陕西 西安；陕西省骨关节疾病基础与临床转化重点实验室，陕西 西安；陕西省人民医院骨科，陕西 西安
关键词: 大骨节病；发病机制；环境因素；遗传因素；展望；Kashin-Beck Disease； Pathogenesis； Environmental Factors； Genetic Factors； Prospects
摘要: 大骨节病(Kashin-Beck Disease, KBD)是一种地方性、慢性、退行性的骨关节病。它的主要病理特征是关节软骨和骺板软骨出现多发性坏死、修复效果差，还会出现继发性退行性改变。这种病主要分布在我国从东北到西南的低硒地区，儿童和青少年是高发人群。病情严重的患者会出现生长发育障碍，甚至终身残疾。虽然科研人员已经研究了几十年，但KBD的发病机制还没完全弄明白。现在大家普遍认为，它是环境因素、营养因素和遗传易感性共同作用的结果。本文会系统梳理KBD发病机制的研究现状，还会对未来的研究方向提出展望。
Abstract: Kashin-Beck disease (KBD) is a regional endemic, chronic degenerative bone and joint disorder. Its primary pathological features include multiple necrotic lesions in articular cartilage and epiphyseal cartilage with poor reparative capacity, accompanied by secondary degenerative changes. This condition predominantly affects low-selenium regions across China from northeastern to southwestern areas, with children and adolescents being the most vulnerable population. Severe cases may lead to growth retardation or even permanent disability. Despite decades of research, the exact pathogenesis of KBD remains incompletely understood. Current consensus suggests it results from the combined effects of environmental factors, nutritional imbalances, and genetic susceptibility. This article systematically reviews the current research status on KBD pathogenesis while proposing future research directions.
文章引用：岳浩, 朱新科, 孙正明. 大骨节病发病机制研究现状与未来展望[J]. 临床医学进展, 2025, 15(11): 389-398. https://doi.org/10.12677/acm.2025.15113110

参考文献

[1] Guo, X., Ma, W.-J., Zhang, F., Ren, F.-L., Qu, C.-J. and Lammi, M.J. (2014) Recent Advances in the Research of an Endemic Osteochondropathy in China: Kashin-Beck Disease. Osteoarthritis and Cartilage, 22, 1774-1783. [Google Scholar] [CrossRef] [PubMed]
[2] Sudre, P. and Mathieu, F. (2001) Kashin-Beck Disease: From Etiology to Prevention or from Prevention to Etiology? International Orthopaedics, 25, 175-179. [Google Scholar] [CrossRef] [PubMed]
[3] 领兄, 任海娟, 李添添, 曹艳红. 大骨节病易感基因及环境应答基因研究新进展[J]. 中华地方病学杂志, 2018, 37(3): 254-258.
[4] Alexander, J. and Olsen, A. (2023) Selenium—A Scoping Review for Nordic Nutrition Recommendations 2023. Food & Nutrition Research, 67, Article 10320. [Google Scholar] [CrossRef] [PubMed]
[5] Yao, Y.F., Pei, F.X., Li, X.B., Yang, J., Shen, B., Zhou, Z.K., et al. (2012) Preventive Effects of Supplemental Selenium and Selenium Plus Iodine on Bone and Cartilage Development in Rats Fed with Diet from Kashin-Beck Disease Endemic Area. Biological Trace Element Research, 146, 199-206. [Google Scholar] [CrossRef] [PubMed]
[6] 王婧, 李海蓉, 杨林生, 等. 西藏昌都地区环境硒分布特征及其与大骨节病的关系[J]. 地理研究, 2017, 36(2): 383-390.
[7] 李小颖, 王旭东, 安小芳, 等. 在大骨节病区示范点采取预防措施防治大骨节病效果研究[J]. 中国地方病防治, 2024, 39(1): 1-4.
[8] 栾依霖. 缺硒通过gga-miR-138-5p靶向SelM激活的线粒体通路诱导软骨细胞凋亡[D]: [硕士学位论文]. 哈尔滨: 东北农业大学, 2019.
[9] Cui, Y., Liao, Y., Chen, Y., Zhao, X., Zhang, Y., Wang, H., et al. (2024) Low Expression of Selenoprotein S Induces Oxidative Damage in Cartilages. Journal of Trace Elements in Medicine and Biology, 85, Article 127492. [Google Scholar] [CrossRef] [PubMed]
[10] Liu, L., Luo, P., Wen, P. and Xu, P. (2024) Effects of Selenium and Iodine on Kashin-Beck Disease: An Updated Review. Frontiers in Nutrition, 11, Article ID: 1402559. [Google Scholar] [CrossRef] [PubMed]
[11] Cheng, H., Yen, C., Huang, L., Hu, Y., Huang, T., Hsieh, B., et al. (2024) Selenium Lessens Osteoarthritis by Protecting Articular Chondrocytes from Oxidative Damage through NRF2 and NF-κB Pathways. International Journal of Molecular Sciences, 25, Article 2511. [Google Scholar] [CrossRef] [PubMed]
[12] Jiang, T., Yan, J., Tan, H., Pu, Z., Wang, O., Liu, T., et al. (2024) Prevalence of T-2 Toxin in the Food and Beverages of Residents Living in a Kashin-Beck-Disease Area of Qamdo, Tibet. Nutrients, 16, Article 1449. [Google Scholar] [CrossRef] [PubMed]
[13] 曹峻岭, 熊咏民, 张矢远, 莫东旭. 真菌毒素DON、T-2和NIV对培养软骨细胞作用的实验研究[J]. 中国地方病防治杂志, 1995(2): 69-71+126-129.
[14] Hao, S., Yao, C., Meng, P., Jia, Y., Li, L., Zhang, C., et al. (2024) HT-2 Mycotoxin and Selenium Deficiency: Effects on Femur Development and Integrity in Young Mice. Toxicon, 245, Article 107767. [Google Scholar] [CrossRef] [PubMed]
[15] 全国大骨节病监测组. 2006年全国大骨节病病情监测总结报告[J]. 中国地方病学杂志, 2007, 26(6): 646-648.
[16] Ying, G., Jia, Y. and Luan, R. (2007) Research Advance on Relation between Humic Acid and Chondrocyte Injuries. Journal of Hygiene Research, 36, 238-241.
[17] 蒋咏, 高顶学, 毛学文, 等. 基于PARAFAC分析的西藏昌都大骨节病地区水体腐殖质性质研究[J]. 北京大学学报(自然科学版), 2019, 55(4): 717-726.
[18] 陈存生. 不同层深井水对大骨节病的预防效果[J]. 中国地方病防治杂志, 1987(5): 307-309.
[19] 朱少华, Fietzek, P.P. 腐殖酸对NMRI鼠关节软骨粘弹性的影响[J]. 中国地方病学杂志, 2004(3): 31-32.
[20] 朱少华, Fietzek, P.P. 腐殖酸对鼠关节软骨胶原分子直径的影响[J]. 华中科技大学学报(医学版), 2004(4): 441-444.
[21] 应桂英, 贾勇, 栾荣生. 腐植酸与软骨损伤关系的研究进展[J]. 卫生研究, 2007(2): 238-241.
[22] Zhou, A., Wang, J., Jia, A., Zhang, Q., Duoji, Z., Yu, Z., et al. (2025) Identification of Energy Metabolism and M6a-Related Gene Clusters in Kashin-Beck Disease Based on Bioinformatics Analysis. BMC Musculoskeletal Disorders, 26, Article No. 697. [Google Scholar] [CrossRef] [PubMed]
[23] 张伟. 大骨节病的群体遗传学调查[J]. 遗传与疾病, 1987(3): 183-184.
[24] 张迪, 熊咏民. 遗传与表观遗传及其相互作用在大骨节病中的研究进展[J]. 国外医学(医学地理分册), 2018, 39(4): 357-360.
[25] Yang, Z., Xu, Y., Luo, H., Ma, X., Wang, Q., Wang, Y., et al. (2014) Whole-Exome Sequencing for the Identification of Susceptibility Genes of Kashin-Beck Disease. PLOS ONE, 9, e92298. [Google Scholar] [CrossRef] [PubMed]
[26] Shi, X., Zhang, F., Lv, A., Wen, Y. and Guo, X. (2015) COL9A1 Gene Polymorphism Is Associated with Kashin-Beck Disease in a Northwest Chinese Han Population. PLOS ONE, 10, e0120365. [Google Scholar] [CrossRef] [PubMed]
[27] Shi, B., Guo, X., Iv, A., Zhang, Z. and Shi, X. (2022) Polymorphism of MMP-3 Gene and Imbalance Expression of MMP-3 / TIMP-1 in Articular Cartilage Are Associated with an Endemic Osteochondropathy, Kashin-Beck Disease. BMC Musculoskeletal Disorders, 23, Article No. 3. [Google Scholar] [CrossRef] [PubMed]
[28] Hong Du, X., Xia Dai, X., Xia Song, R., Zhen Zou, X., Yan Sun, W., Yan Mo, X., et al. (2012) SNP and mRNA Expression for Glutathione Peroxidase 4 in Kashin-Beck Disease. British Journal of Nutrition, 107, 164-169. [Google Scholar] [CrossRef] [PubMed]
[29] Li, P., Wu, C., Guo, X., Wen, Y., Liu, L., Liang, X., et al. (2021) Integrative Analysis of Genome-Wide Association Studies and DNA Methylation Profile Identified Genetic Control Genes of DNA Methylation for Kashin-Beck Disease. CARTILAGE, 13, 780S-788S. [Google Scholar] [CrossRef] [PubMed]
[30] Wang, C., Chen, S., Yuan, Y., Li, S., Lv, X., Wu, Y., et al. (2024) Selenium Deficiency and T-2 Toxin Trigger Ferroptosis in Cartilage from Kashin-Beck Diseases. Medical Hypotheses, 192, Article 111469. [Google Scholar] [CrossRef] 
[31] Liu, J.T., Guo, X., Ma, W.J., Zhang, Y.G., Xu, P., Yao, J.F., et al. (2010) Mitochondrial Function Is Altered in Articular Chondrocytes of an Endemic Osteoarthritis, Kashin-Beck Disease. Osteoarthritis and Cartilage, 18, 1218-1226. [Google Scholar] [CrossRef] [PubMed]
[32] He, Y., Shi, Y., Zhang, Y., Zhang, R., Cao, L., Liu, Y., et al. (2023) T-2 Toxin-Induced Chondrocyte Apoptosis Contributes to Growth Plate Damage through Smad2 and Smad3 Signaling. Toxicon, 232, Article 107193. [Google Scholar] [CrossRef] [PubMed]
[33] 王世捷, 郭雄, 陈静宏, 等. 大骨节病与骨关节病患者软骨细胞凋亡及其机制的比较研究[J]. 南方医科大学学报, 2006, 26(7): 927-930.
[34] Guo, L., Zhuo, Y., Lu, C., Guo, H., Chen, Z., Wu, G., et al. (2024) The N‐Terminal Fragment of Histone Deacetylase 4 (1‐669aa) Promotes Chondrocyte Apoptosis via the P53‐Dependent Endoplasmic Reticulum Stress Pathway. Journal of Cellular and Molecular Medicine, 28, e70135. [Google Scholar] [CrossRef] [PubMed]
[35] Zhang, J., Wei, Y., Yue, Y., Jiao, H., Wu, Y., Fu, W., et al. (2024) RIPK4 Promotes Oxidative Stress and Ferroptotic Death through the Downregulation of Acsm1. Proceedings of the National Academy of Sciences, 121, e2410628121. [Google Scholar] [CrossRef] [PubMed]
[36] Xu, T., Chen, T., Shi, X., Ding, J., Chen, S. and Lin, H. (2024) Co-Exposure of Bisphenol A and Selenium Deficiency Induces Pyroptosis via ROS/NLRP3 Pathway in Chicken Spleen. Poultry Science, 103, Article 104150. [Google Scholar] [CrossRef] [PubMed]
[37] Wang, K., Shi, X., Lin, H., Xu, T. and Xu, S. (2025) Selenium Deficiency Exacerbates ROS/ER Stress Mediated Pyroptosis and Ferroptosis Induced by Bisphenol a in Chickens Thymus. Journal of Environmental Sciences, 148, 13-26. [Google Scholar] [CrossRef] [PubMed]
[38] Chen, X., Mu, P., Zhu, L., Mao, X., Chen, S., Zhong, H., et al. (2021) T-2 Toxin Induces Oxidative Stress at Low Doses via Atf3δzip2a/2b-Mediated Ubiquitination and Degradation of NRF2. International Journal of Molecular Sciences, 22, Article 7936. [Google Scholar] [CrossRef] [PubMed]
[39] 齐昕, 陈幼楠, 马芸瑄, 邢龙飞, 崔永奇, 郭长青. 针刀对膝关节骨关节炎兔软骨细胞脂质过氧化的影响[J]. 针刺研究, 2025, 50(4): 402-410.
[40] 李振伟, 侯靖宇, 林宇泽, 等. 软骨细胞线粒体损伤对骨关节炎的影响[J]. 生物化学与生物物理进展, 2024, 51(7): 1576-1588.
[41] Iantomasi, T., Aurilia, C., Donati, S., et al. (2025) Oxidative Stress, MicroRNAs, and Long Non-Coding RNAs in Osteoarthritis Pathogenesis: Cross-Talk and Molecular Mechanisms Involved. International Journal of Molecular Sciences, 26, Article 6428.
[42] 王伟, 陈静宏, 于伯泉, 等. 自由基氧化损伤与大骨节病的相关性研究[C]//中华医学会. 第七次全国地方病学术会议论文集. 2011: 10-11.
[43] Karpiński, R., Prus, A., Baj, J., Radej, S., Prządka, M., Krakowski, P., et al. (2025) Articular Cartilage: Structure, Biomechanics, and the Potential of Conventional and Advanced Diagnostics. Applied Sciences, 15, Article 6896. [Google Scholar] [CrossRef] 
[44] Ning, Y., Zhang, P., Zhang, F., Chen, S., Liu, Y., Chen, F., et al. (2022) Abnormal Expression of TSG-6 Disturbs Extracellular Matrix Homeostasis in Chondrocytes from Endemic Osteoarthritis. Frontiers in Genetics, 13, Article ID: 1064565. [Google Scholar] [CrossRef] [PubMed]
[45] Zhang, A., Cao, J., Yang, B., Chen, J., Zhang, Z., Li, S., et al. (2010) Effects of Moniliformin and Selenium on Human Articular Cartilage Metabolism and Their Potential Relationships to the Pathogenesis of Kashin-Beck Disease. Journal of Zhejiang University SCIENCE B, 11, 200-208. [Google Scholar] [CrossRef] [PubMed]
[46] Hwang, I., Youm, Y., Cho, S., Choi, S., Bae, M., Park, S., et al. (2018) Synovial Fluid Levels of TWEAK and Matrix Metalloproteinase 1 in Patients with Osteoarthritis, and Associations with Disease Severity. Journal of Orthopaedic Surgery, 26, 1-7. [Google Scholar] [CrossRef] [PubMed]
[47] Claassen, H., Steffen, R., Hassenpflug, J., Varoga, D., Wruck, C.J., Brandenburg, L.O., et al. (2010) 17β-Estradiol Reduces Expression of MMP-1,-3, and-13 in Human Primary Articular Chondrocytes from Female Patients Cultured in a Three Dimensional Alginate System. Cell and Tissue Research, 342, 283-293. [Google Scholar] [CrossRef] [PubMed]
[48] 陈静宏, 曹峻岭, 王治伦, 等. 基质金属蛋白酶与大骨节病的相关性研究[J]. 中华地方病学杂志, 2014, 33(4): 357-362.
[49] 邵婉珍, 张风娥, 王森, 郭雄, 吴翠艳. 糖代谢紊乱对大骨节病软骨细胞功能的影响[J]. 四川大学学报(医学版), 2018, 49(2): 221-225,270.
[50] Zhou, Q., Liu, J., Wan, L., Zhu, Y., Qi, Y. and Hu, Y. (2024) Xinfeng Capsule Alleviates Interleukin-1β-Induced Chon-drocyte Inflammation and Extracellular Matrix Degradation by Regulating the miR-502-5p/TRAF2/NF-κB Axis. Journal of Southern Medical University, 44, 108-118.
[51] Tu, P., Guo, Y., Zheng, S., Pan, Y., Wang, L. and Ma, Y. (2019) Research Progress on Signaling Molecules Involved in Articular Cartilage Repair. Journal of Biomedical Engineering, 36, 343-348.
[52] Zhou, X., Wang, Z., Chen, J., Wang, W., Song, D., Li, S., et al. (2014) Increased Levels of IL-6, Il-1β, and TNF-Α in Kashin-Beck Disease and Rats Induced by T-2 Toxin and Selenium Deficiency. Rheumatology International, 34, 995-1004. [Google Scholar] [CrossRef] [PubMed]
[53] Liu, J., Cheng, J., Zhou, H., Zuo, Q. and Liu, F. (2024) CRNDE Alleviates Il-1β-Induced Chondrocyte Damage by Modulating miR-31/NF-κB Pathway. Journal of Orthopaedic Surgery and Research, 19, Article No. 860. [Google Scholar] [CrossRef] [PubMed]
[54] Eitner, A., König, C., Kohler, F.C., Hofmann, G.O., Wildemann, B., Aurich, M., et al. (2024) Importance of IL-6 Trans-Signaling and High Autocrine IL-6 Production in Human Osteoarthritic Chondrocyte Metabolism. Osteoarthritis and Cartilage, 32, 561-573. [Google Scholar] [CrossRef] [PubMed]
[55] Zhou, Y., Yang, X., Liu, J., Yang, M., Ye, C. and Zhu, L. (2023) Carboxyamidotriazole Alleviates Pannus Formation and Cartilage Erosion in Rats with Adjuvant Arthritis. Heliyon, 9, e20105. [Google Scholar] [CrossRef] [PubMed]
[56] Cai, D., Hu, Z., Zhu, Y., Ma, X., Wang, C., Wang, C., et al. (2025) CXCL8 and GZMB Genes Promote Cartilaginous and Synovial Lesion Formation via NF-κB and MAPK Signaling Pathways in Kaschin-Beck Disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1871, Article 167921. [Google Scholar] [CrossRef] [PubMed]

为你推荐