{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T07:32:13Z","timestamp":1767598333241,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Program of the National Natural Science Foundation of China","award":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"],"award-info":[{"award-number":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"]}]},{"name":"Integration Project of the NSFC Joint Fund for Regional Innovation and Development","award":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"],"award-info":[{"award-number":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"]}]},{"name":"Science and Technology Program of Xianning, Hubei Province","award":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"],"award-info":[{"award-number":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"]}]},{"name":"19th Graduate Student Innovation Fund of Huazhong University of Science and Technology","award":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"],"award-info":[{"award-number":["32130052","U23A6008","2023GXYF102","2021yjsCXCY119"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Although clinical studies have indicated a possible association between dyslipidemia and osteoporosis, the underlying genetic basis and mechanistic pathways remain insufficiently defined. Most prior research has concentrated on conventional lipid markers, which are prone to confounding and limit causal inference. Exploring lipidomic profiles offers a more comprehensive view of lipid metabolism and may reveal novel genetic links beyond traditional lipid traits. Additionally, alterations in immune cell function, often triggered by metabolic disturbances, may contribute to osteoporosis development; however, the potential mediating role of immune cells in the lipid\u2013bone axis has not been systematically investigated. Methods: A total of 179 lipid species across 13 lipid classes were analyzed in 7174 Finnish individuals from the GeneRISK cohort. Genome-Wide Association Study (GWAS) summary statistics for osteoporosis and 731 immune cell immunophenotypes were sourced from the GWAS Catalog. A two-step, two-sample Mendelian randomization analysis, using inverse variance weighting (IVW), was conducted to explore the potential causal effects of lipids on osteoporosis and the mediating role of immune cells in the relationship between lipids and osteoporosis. Results: Mendelian randomization analysis indicated that triacylglycerol levels of 48:0 were possibly associated with an increased risk of osteoporosis (IVW: odds ratio [OR] 1.1320, 95% CI 1.0401\u20131.2321; p = 0.004), while triacylglycerol levels of 48:3 appeared to be associated with a reduced risk of osteoporosis (IVW: OR 0.9053, 95% CI 0.8364\u20130.9800; p = 0.014). Two statistically significant mediating effects were identified: First, IgD\u2212 CD38dim %B cells appeared to partially negatively mediate the association between triacylglycerol levels of 48:3 and osteoporosis, with a negative mediating effect of \u22120.00669 (95% CI: \u22120.0214, 0.00805), which accounted for 6.73% of the total effect. That is, the protective effect of triacylglycerol levels of 48:3 against osteoporosis was attenuated by IgD\u2212 CD38dim %B cells. Second, HLA DR++ monocytes% leukocytes also partially negatively mediated this relationship, with a mediating effect of \u22120.023 (95% CI: \u22120.0434, \u22120.00266), accounting for 23.2% of the total effect. This indicates that other immune cells, HLA DR++ monocytes %leukocytes, resisted the protective effect of triacylglycerol levels of 48:3 against osteoporosis, with a weakening effect stronger than that of IgD\u2212 CD38dim %B cells. Conclusions: Our findings contribute to the growing understanding of the potential causal relationships and shared pathogenic mechanisms between dyslipidemia and osteoporosis. The results suggest that the potential genetic effects of plasma lipid metabolites on osteoporosis may be partially down-regulated by specific kinds of immune cells.<\/jats:p>","DOI":"10.3390\/diagnostics15101287","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T11:50:31Z","timestamp":1747741831000},"page":"1287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune Cells as Mediators of Lipidome Influence on Osteoporosis: Evidence from a Mediation Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1133-4703","authenticated-orcid":false,"given":"Jiheng","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"},{"name":"Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China"},{"name":"NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiatai","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanbin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China"},{"name":"NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingze","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"},{"name":"Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China"},{"name":"NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China"},{"name":"School of Medicine, Nankai University, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9003-4671","authenticated-orcid":false,"given":"Liming","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1038\/s12276-020-0472-3","article-title":"Healthy bone tissue homeostasis","volume":"52","author":"Choi","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/35046196","article-title":"Bone versus immune system","volume":"408","author":"Arron","year":"2000","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"ITC17","DOI":"10.7326\/AITC201708010","article-title":"Osteoporosis","volume":"167","author":"Ensrud","year":"2017","journal-title":"Ann. Intern Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.1161\/01.ATV.20.11.2346","article-title":"Role of lipids in osteoporosis","volume":"20","author":"Parhami","year":"2000","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s00774-020-01189-9","article-title":"Blood lipid levels in patients with osteopenia and osteoporosis:a systematic review and meta-analysis","volume":"39","author":"Zhao","year":"2021","journal-title":"J. Bone Miner. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1186\/s13018-023-04275-6","article-title":"Association between triglyceride-glucose index and bone mineral density in US adults: A cross sectional study","volume":"18","author":"Zhan","year":"2023","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101122","DOI":"10.1016\/j.gendis.2023.101122","article-title":"The role of lipid metabolism in osteoporosis: Clinical implication and cellular mechanism","volume":"11","author":"Zhang","year":"2023","journal-title":"Genes. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00198-016-3844-8","article-title":"Efficacy of statins for osteoporosis: A systematic review and meta-analysis","volume":"28","author":"An","year":"2017","journal-title":"Osteoporos. Int."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tan, A., Shu, J., Huang, H., Shao, H., and Yang, J. (2023). The correlation between the serum LDL-C\/Apo B ratio and lumbar bone mineral density in young adults. BMC Musculoskelet. Disord., 24.","DOI":"10.1186\/s12891-023-06325-w"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1038\/s41467-018-04047-5","article-title":"Oxidation-specific epitopes restrain bone formation","volume":"9","author":"Ambrogini","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1359\/jbmr.070207","article-title":"Effect of blockade of TNF-\u03b1 and interleukin-1 action on bone resorption in early postmenopausal women","volume":"22","author":"Charatcharoenwitthaya","year":"2007","journal-title":"J. Bone Miner. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1007\/s00198-009-1018-7","article-title":"Immune changes in post-menopausal osteoporosis: The Immunos study","volume":"21","author":"Breuil","year":"2010","journal-title":"Osteoporos. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/jrsm.1346","article-title":"Meta-analysis and Mendelian randomization: A review","volume":"10","author":"Bowden","year":"2019","journal-title":"Res. Synth. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6934","DOI":"10.1038\/s41467-023-42532-8","article-title":"Genome-wide association analysis of plasma lipidome identifies 495 genetic associations","volume":"14","author":"Ottensmann","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1038\/s41588-020-0684-4","article-title":"Complex genetic signatures in immune cells underlie autoimmunity and inform therapy","volume":"52","author":"Steri","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Li, P., Wang, H., Guo, L., Gou, X., Chen, G., Lin, D., Fan, D., Guo, X., and Liu, Z. (2022). Association between gut microbiota and preeclampsia-eclampsia: A two-sample Mendelian randomization study. BMC Med., 20.","DOI":"10.1186\/s12916-022-02657-x"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1146\/annurev-pathol-011110-130203","article-title":"Disorders of bone remodeling","volume":"6","author":"Feng","year":"2011","journal-title":"Annu. Rev. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.biochi.2020.08.004","article-title":"Osteoporosis: A role for lipids","volume":"178","author":"During","year":"2020","journal-title":"Biochimie"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.plipres.2015.06.002","article-title":"Understanding the local actions of lipids in bone physiology","volume":"59","author":"During","year":"2015","journal-title":"Prog. Lipid Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1111\/j.1582-4934.2009.00751.x","article-title":"Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro","volume":"14","author":"Elbaz","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4081","DOI":"10.1210\/en.2015-1303","article-title":"Oleate Abrogates Palmitate-Induced Lipotoxicity and Proinflammatory Response in Human Bone Marrow-Derived Mesenchymal Stem Cells and Osteoblastic Cells","volume":"156","author":"Gillet","year":"2015","journal-title":"Endocrinology"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Van Heerden, B., Kasonga, A., Kruger, M.C., and Coetzee, M. (2017). Palmitoleic Acid Inhibits RANKL-Induced Osteoclastogenesis and Bone Resorption by Suppressing NF-\u03baB and MAPK Signalling Pathways. Nutrients, 9.","DOI":"10.3390\/nu9050441"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1359\/jbmr.2000.15.10.1974","article-title":"Rate of bone loss is associated with mortality in older women: A Prospective Study","volume":"15","author":"Kado","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Han, H., Li, R., Fu, D., Zhou, H., Zhan, Z., Wu, Y., and Meng, B. (2024). Correlation between bone density, bone metabolism markers with lipid metabolism markers and body mass index. BMC Musculoskelet. Disord., 25.","DOI":"10.1186\/s12891-024-07284-6"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1093\/ajcn\/83.1.146","article-title":"Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women","volume":"83","author":"Hsu","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yin, W., Li, Z., and Zhang, W. (2019). Modulation of Bone and Marrow Niche by Cholesterol. Nutrients, 11.","DOI":"10.3390\/nu11061394"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"25103","DOI":"10.1074\/jbc.R109.041087","article-title":"Cellular and molecular mechanisms of bone remodeling","volume":"285","author":"Raggatt","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"74","DOI":"10.5312\/wjo.v7.i2.74","article-title":"Bone and high-density lipoprotein: The beginning of a beautiful friendship","volume":"7","author":"Papachristou","year":"2016","journal-title":"World J. Orthop."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1002\/jcb.21938","article-title":"HDL3 reduces the association and modulates the metabolism of oxidized LDL by osteoblastic cells: A protection against cell death","volume":"105","author":"Brodeur","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"115174","DOI":"10.1016\/j.bone.2019.115174","article-title":"Are blood lipids risk factors for fracture? Integrative evidence from instrumental variable causal inference and mediation analysis using genetic data","volume":"131","author":"Chen","year":"2020","journal-title":"Bone"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s00223-023-01160-6","article-title":"Lipid Metabolism, Methylation Aberrant, and Osteoporosis: A Multi-omics Study Based on Mendelian Randomization","volume":"114","author":"Zhang","year":"2024","journal-title":"Calcif. Tissue Int."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhou, P., Liu, L., Lu, K., Xu, M.-Z., Ye, Y.-W., Li, C., and Yin, Y. (2024). Association between triglycerides and lumbar bone mineral density in Chinese patients with osteoporotic fractures: A retrospective cross-sectional study. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-78926-x"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/imr.13215","article-title":"Lipid metabolism in dendritic cell biology","volume":"317","author":"You","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nri.2017.11","article-title":"Liver macrophages in tissue homeostasis and disease","volume":"17","author":"Krenkel","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41467-017-02490-4","article-title":"Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss","volume":"9","author":"Lucas","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"D\u00f6ding, A., Zimmermann, S., Maghames, A., Reimann, M., Symmank, J., Th\u00fcrmer, M., Gr\u00e4ler, M.H., Wolf, M., Jacobs, C., and Koeberle, A. (2023). Immunometabolic capacities of nutritional fatty acids in regulation of inflammatory bone cell interaction and systemic impact of periodontal infection. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1213026"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41573-019-0032-5","article-title":"Targeting metabolism to regulate immune responses in autoimmunity and cancer","volume":"18","author":"Patel","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41577-019-0178-8","article-title":"Osteoimmunology: Evolving concepts in bone\u2013immune interactions in health and disease","volume":"19","author":"Tsukasaki","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1126\/science.1105786","article-title":"Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells","volume":"190","author":"Walker","year":"1975","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/s41586-018-0482-7","article-title":"Coupling of bone resorption and formation by RANKL reverse signalling","volume":"561","author":"Ikebuchi","year":"2018","journal-title":"Nature"},{"key":"ref_41","first-page":"213","article-title":"TNF-\u03b1 and IL-6: The Link between Immune and Bone System","volume":"21","author":"Wang","year":"2020","journal-title":"Curr. Drug Targets"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Tang, M., Tian, L., Luo, G., and Yu, X. (2018). Interferon-Gamma-Mediated Osteoimmunology. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01508"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Llorente, I., Garc\u00eda-Casta\u00f1eda, N., Valero, C., Gonz\u00e1lez-\u00c1lvaro, I., and Casta\u00f1eda, S. (2020). Osteoporosis in Rheumatoid Arthritis: Dangerous Liaisons. Front. Med., 7.","DOI":"10.3389\/fmed.2020.601618"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/j.1600-065X.2010.00929.x","article-title":"New insights into the enigma of immunoglobulin D","volume":"237","author":"Chen","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Piedra-Quintero, Z.L., Wilson, Z., Nava, P., and Guerau-De-Arellano, M. (2020). CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.597959"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.eucr.2017.09.009","article-title":"Small round tumour cells (CD38, CD 79a positive) in the adrenal gland","volume":"16","author":"Nigam","year":"2017","journal-title":"Urol. Case Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wang, X., Zhang, X., Han, Y., Duan, X., Wang, J., Yan, H., Wang, S., Xu, Y., Zhu, Z., and Wang, L. (2022). Role of the major histocompatibility complex class II protein presentation pathway in bone immunity imbalance in postmenopausal osteoporosis. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.876067"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/jbmr.2090","article-title":"MHC class II transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity","volume":"29","author":"Benasciutti","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1101\/gad.13.18.2412","article-title":"RANK is essential for osteoclast and lymph node development","volume":"13","author":"Dougall","year":"1999","journal-title":"Genes Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1002\/jbmr.3364","article-title":"Estrogen Deficiency\u2013Mediated M2 Macrophage Osteoclastogenesis Contributes to M1\/M2 Ratio Alteration in Ovariectomized Osteoporotic Mice","volume":"33","author":"Dou","year":"2018","journal-title":"J. Bone Miner. Res."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/10\/1287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:36:00Z","timestamp":1760031360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/10\/1287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["diagnostics15101287"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15101287","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2025,5,20]]}}}