Exploring the Association Between Immune Cell Phenotypes and Osteoporosis Mediated by Inflammatory Cytokines: Insights from GWAS and Single-Cell Transcriptomics

被引：0
作者：
Kuang, Shouxiang [1 ]
Ma, Xiaoqing [2 ]
Sun, Lipeng [1 ]
Wang, Chang [1 ]
Li, Yang [1 ]
Wang, Guodong [1 ]
Sun, Jianmin [1 ]
Zhou, Fengge [3 ]
Zhang, Chenggui [1 ]
机构：
[1] Shandong First Med Univ, Shandong Prov Hosp, Dept Orthopaed, Tai An, Shandong, Peoples R China
[2] Shandong First Med Univ, Affiliated Hosp 2, Minimally Invas Therapy Oncol Dept, Tai An, Shandong, Peoples R China
[3] Shandong First Med Univ, Shandong Prov Hosp, Tumor Res & Therapy Ctr, Tai An, Shandong, Peoples R China
来源：
IMMUNOTARGETS AND THERAPY | 2025年 / 14卷
基金：
中国国家自然科学基金;
关键词：
osteoporosis; immune cell phenotypes; inflammatory cytokines; Mendelian randomization; single-cell sequencing; MENDELIAN RANDOMIZATION; RISK; INSTRUMENTS; GLYCOSYLATION; HISTAMINE; BIAS;
D O I：
10.2147/ITT.S510102
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
Background: Patients with osteoporosis experience increased fracture risk and decreased quality of life, which pose significant health burdens and financial challenges. Despite established links between immune cell phenotypes and inflammatory cytokines and osteoporosis, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment. Methods: Here, we performed a two-sample Mendelian randomization (MR) study to estimate the causal effects between 731 immune cell types, 91 and 41 inflammatory factors (which may have some overlap), and 5 types of osteoporosis. In subsequent mediation MR analysis, we assessed whether these inflammatory cytokines mediate the causal relationship between immune cell phenotypes and osteoporosis. Additionally, colo- calization analysis was performed using Bayesian colocalization. Single-cell transcriptomic analysis was performed using datasets from osteoporosis patients available in the Gene Expression Omnibus (GEO) database. Subsequently, single-cell sequencing analysis was performed, including dimensionality reduction, clustering, and pathway enrichment, to investigate the underlying mechanisms. Finally, to confirm the critical role of IgD'CD24'B cells and IL-17C in osteoporosis, we established vivo dexamethasone-induced osteoporosis model. Micro-CT was used to assess the effectiveness of model establishment. Flow cytometry was performed to determine the proportion of IgD'CD24' B cells within lymphocytes in the blood. ELISA and Western blotting were used to measure IL-17C levels in serum and bone tissue. Immunohistochemistry was conducted to evaluate the expression of IL-17C in bone tissue. Results: This study found that 32 immune cell phenotypes and 38 inflammatory cytokines were significantly associated with osteoporosis. Mediation analysis indicated that IgD+ CD24+ B cells exacerbated the risk of osteoporosis by influencing the levels of interleukin-17C (IL-17C). The mediated effect was 0.07837, accounting for 15.5% of the total effect. Single-cell transcriptome analysis supported that IgD+ CD24+ B cells play a key role in musculoskeletal-related pathways in osteoporosis patients. Additionally, we have demonstrated the significant involvement of IgD'CD24' B cells and IL-17C in the osteoporosis disease model. Conclusion: Inflammatory cytokines play a crucial role in the pathogenesis of immunity-related osteoporosis. In particular, IgD+ CD24+ B cell %lymphocyte increase the risk of osteoporosis by modulating the levels of interleukin-17C. Our results provide evidence to support the link between immunity and osteoporosis and offer new therapeutic strategies for targeting inflammatory pathways in immune-mediated osteoporosis.
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收藏
页码：227 / 246
页数：20
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共 66 条
  • [21] Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG., Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors, Eur J Epidemiol, 30, 7, pp. 543-552, (2015)
  • [22] Boef AG, Dekkers OM, le Cessie S., Mendelian randomization studies: a review of the approaches used and the quality of reporting, Int J Epidemiol, 44, 2, pp. 496-511, (2015)
  • [23] Orru V, Steri M, Sidore C, Et al., Complex genetic signatures in immune cells underlie autoimmunity and inform therapy, Nat Genet, 52, 10, pp. 1036-1045, (2020)
  • [24] Ahola-Olli AV, Wurtz P, Havulinna AS, Et al., Genome-wide association study identifies 27 loci influencing concentrations of circulating cytokines and growth factors, Am J Hum Genet, 100, 1, pp. 40-50, (2017)
  • [25] Zhao JH, Stacey D, Eriksson N, Et al., Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets, Nat Immunol, 24, 9, pp. 1540-1551, (2023)
  • [26] Zeng Z, Guo R, Wang Z, Et al., Circulating monocytes act as a common trigger for the calcification paradox of osteoporosis and carotid atherosclerosis via TGFB1-SP1 and TNFSF10-NFKB1 axis, Front Endocrinol, 13, (2022)
  • [27] Fei Y, Yu H, Wu Y, Gong S., The causal relationship between immune cells and ankylosing spondylitis: a bidirectional Mendelian randomization study, Arthritis Res Ther, 26, 1, (2024)
  • [28] Ding Z, Chen J, Li B, Ji X., Inflammatory factors and risk of lung adenocarcinoma: a Mendelian randomization study mediated by blood metabolites, Front Endocrinol, 15, (2024)
  • [29] Yao Z, Guo F, Tan Y, Et al., Causal relationship between inflammatory cytokines and autoimmune thyroid disease: a bidirectional two-sample Mendelian randomization analysis, Front Immunol, 15, (2024)
  • [30] Auton A, Brooks LD, Durbin RM, Et al., A global reference for human genetic variation, Nature, 526, 7571, pp. 68-74, (2015)
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