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07-12-2024 | Osteoarthritis of the Hip | ORIGINAL ARTICLE

Causal effects of circulating inflammatory proteins on knee and hip osteoarthritis: A two sample Mendelian randomization study

Authors: Rongjie Lin, Qingcong Zheng, Rui Zhang, Quan Liu, Jianlong Lin, Shaohuang Weng, Min Chen

Published in: Clinical Rheumatology | Issue 1/2025

Abstract

Introduction

Numerous circulating proteins are linked to the presence or severity of joint inflammation. However, traditional studies could not explain whether these protein biomarkers are proximate to disease progression.

Method

We conducted a study to explore the causal effects of 91 circulating inflammation-related proteins (CIPs) on knee osteoarthritis (KOA) and hip osteoarthritis (HOA), using two-sample Mendelian randomization (MR). The primary analysis utilized the inverse variance weighted (IVW) method, augmented by complementary approaches including weighted median, weighted mode, simple median, MR-Egger, and MR-PRESSO analysis. Sensitivity analysis validated the robustness of the results and ensured the absence of heterogeneity and horizontal pleiotropy.

Results

We identified 2 CIPs with a causal effect on KOA, including CXCL9 (OR = 1.249, 95% CI = 1.046–1.492, P = 0.014) and TNF-β (OR = 1.105, 95% CI = 1.014–1.204, P = 0.023). Additionally, 3 CIPs were found to have a causal effect on HOA, including CXCL6 (OR = 1.058, 95% CI = 1.004–1.116, P = 0.035), RANKL (OR = 1.067, 95% CI = 1.002–1.137, P = 0.044), and VEGFA (OR = 1.072, 95% CI = 1.008–1.140, P = 0.027).

Conclusions

In the current study, our findings indicated that CXCL9 and TNF-β had the potential to influence the risk of KOA, while CXCL6, RANKL, and VEGFA could impact the risk of HOA. These discoveries underscored the significance of these proteins as potential targets for intervention in the prevention and treatment of KOA and HOA.

Key Points

• We presented genetic evidence supporting a causal link between circulating inflammatory proteins associated with joint inflammation using MR methods.

• 5 CIPs have demonstrated promotive effects on the occurrence of KOA and HOA.

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Go C (2023) Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Rheumatology 5(9):e508–e522. https://doi.org/10.1016/s2665-9913(23)00163-7CrossRef

Ek WE, Karlsson T, Höglund J et al (2021) Causal effects of inflammatory protein biomarkers on inflammatory diseases. Sci Adv 7(50):eabl4359. https://doi.org/10.1126/sciadv.abl4359CrossRefPubMedPubMedCentral

Zhao JH, Stacey D, Eriksson N et al (2023) Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol 24(11):1540–1551. https://doi.org/10.1038/s41590-023-01588-wCrossRefPubMedPubMedCentral

Chow YY, Chin KY (2020) The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm 2020:8293921. https://doi.org/10.1155/2020/8293921CrossRefPubMedPubMedCentral

Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm 2014:561459. https://doi.org/10.1155/2014/561459CrossRefPubMedPubMedCentral

Lee KT, Chen BC, Liu SC et al (2021) Nesfatin-1 facilitates IL-1β production in osteoarthritis synovial fibroblasts by suppressing miR-204–5p synthesis through the AP-1 and NF-κB pathways. Aging 13(18):22490–22501. https://doi.org/10.18632/aging.203559CrossRefPubMedPubMedCentral

Li L, Li Z, Li Y et al (2020) Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis. BMC Musculoskelet Disord 21(1):99. https://doi.org/10.1186/s12891-020-3120-0CrossRefPubMedPubMedCentral

Wagner S, Fritz P, Einsele H et al (1997) Evaluation of synovial cytokine patterns in rheumatoid arthritis and osteoarthritis by quantitative reverse transcription polymerase chain reaction. Rheumatol Int 16(5):191–196. https://doi.org/10.1007/bf01330295CrossRefPubMed

Helmark IC, Mikkelsen UR, Børglum J et al (2010) Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial. Arthritis Res Ther 12(4):R126. https://doi.org/10.1186/ar3064CrossRefPubMedPubMedCentral

10.

Enroth S, Johansson A, Enroth SB et al (2014) Strong effects of genetic and lifestyle factors on biomarker variation and use of personalized cutoffs. Nat Commun 5:4684. https://doi.org/10.1038/ncomms5684CrossRefPubMed

11.

Sun BB, Maranville JC, Peters JE et al (2018) Genomic atlas of the human plasma proteome. Nature 558(7708):73–79. https://doi.org/10.1038/s41586-018-0175-2CrossRefPubMedPubMedCentral

12.

Folkersen L, Fauman E, Sabater-Lleal M et al (2017) Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. PLoS Genet 13(4):e1006706. https://doi.org/10.1371/journal.pgen.1006706CrossRefPubMedPubMedCentral

13.

Emdin CA, Khera AV, Kathiresan S (2017) Mendelian randomization. Jama 318(19):1925–1926. https://doi.org/10.1001/jama.2017.17219CrossRefPubMed

14.

Didelez V, Sheehan N (2007) Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res 16(4):309–330. https://doi.org/10.1177/0962280206077743CrossRefPubMed

15.

Chen TH, Chen L, Hsieh MS et al (2006) Evidence for a protective role for adiponectin in osteoarthritis. Biochem Biophys Acta 1762(8):711–718. https://doi.org/10.1016/j.bbadis.2006.06.008CrossRefPubMed

16.

Lin TH, Tang CH, Wu K et al (2011) 15-Deoxy-Δ(12,14) -prostaglandin-J2 and ciglitazone inhibit TNF-α-induced matrix metalloproteinase 13 production via the antagonism of NF-κB activation in human synovial fibroblasts. J Cell Physiol 226(12):3242–3250. https://doi.org/10.1002/jcp.22685CrossRefPubMed

17.

Dai SM, Shan ZZ, Nishioka K et al (2005) Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal. Ann Rheum Dis 64(5):735–742. https://doi.org/10.1136/ard.2004.026088CrossRefPubMedPubMedCentral

18.

Kroon FPB, Veenbrink AI, de Mutsert R et al (2019) The role of leptin and adiponectin as mediators in the relationship between adiposity and hand and knee osteoarthritis. Osteoarthritis Cartilage 27(12):1761–1767. https://doi.org/10.1016/j.joca.2019.08.003CrossRefPubMed

19.

Zengini E, Hatzikotoulas K, Tachmazidou I et al (2018) Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat Genet 50(4):549–558. https://doi.org/10.1038/s41588-018-0079-yCrossRefPubMedPubMedCentral

20.

Tachmazidou I, Hatzikotoulas K, Southam L et al (2019) Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet 51(2):230–236. https://doi.org/10.1038/s41588-018-0327-1CrossRefPubMedPubMedCentral

21.

Burgess S, Bowden J, Fall T et al (2017) Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology 28(1):30–42. https://doi.org/10.1097/ede.0000000000000559CrossRefPubMed

22.

Slob EAW, Groenen PJF, Thurik AR et al (2017) A note on the use of Egger regression in Mendelian randomization studies. Int J Epidemiol 46(6):2094–2097. https://doi.org/10.1093/ije/dyx191CrossRefPubMed

23.

Bowden J, Davey Smith G, Haycock PC et al (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 40(4):304–314. https://doi.org/10.1002/gepi.21965CrossRefPubMedPubMedCentral

24.

Hartwig FP, Davey Smith G, Bowden J (2017) Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol 46(6):1985–1998. https://doi.org/10.1093/ije/dyx102CrossRefPubMedPubMedCentral

25.

Bowden J, Del Greco MF, Minelli C et al (2019) Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol 48(3):728–742. https://doi.org/10.1093/ije/dyy258CrossRefPubMed

26.

Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354(6):610–621. https://doi.org/10.1056/NEJMra052723CrossRefPubMed

27.

Hasegawa T, Yoshida M, Watanabe S et al (2023) Development of a new HISCL automated CXCL9 immunoassay. Sci Rep 13(1):5342. https://doi.org/10.1038/s41598-023-32513-8CrossRefPubMedPubMedCentral

28.

Shurin GV, Yurkovetsky ZR, Chatta GS et al (2007) Dynamic alteration of soluble serum biomarkers in healthy aging. Cytokine 39(2):123–129. https://doi.org/10.1016/j.cyto.2007.06.006CrossRefPubMed

29.

Yoshida S, Arakawa F, Higuchi F et al (2012) Gene expression analysis of rheumatoid arthritis synovial lining regions by cDNA microarray combined with laser microdissection: up-regulation of inflammation-associated STAT1, IRF1, CXCL9, CXCL10, and CCL5. Scand J Rheumatol 41(3):170–179. https://doi.org/10.3109/03009742.2011.623137CrossRefPubMedPubMedCentral

30.

Shamsi A, Roghani SA, Abdan Z et al (2023) CXCL9 and its receptor CXCR3, an important link between inflammation and cardiovascular risks in RA patients. Inflammation 46(6):2374–2385. https://doi.org/10.1007/s10753-023-01884-5CrossRefPubMed

31.

Han L, Song JH, Yoon JH et al (2012) TNF-α and TNF-β polymorphisms are associated with susceptibility to osteoarthritis in a Korean population. Korean J Pathol 46(1):30–37. https://doi.org/10.4132/KoreanJPathol.2012.46.1.30CrossRefPubMedPubMedCentral

32.

Buhrmann C, Popper B, Aggarwal BB et al (2017) Resveratrol downregulates inflammatory pathway activated by lymphotoxin α (TNF-β) in articular chondrocytes: comparison with TNF-α. PLoS ONE 12(11):e0186993. https://doi.org/10.1371/journal.pone.0186993CrossRefPubMedPubMedCentral

33.

Zhao J, Duan L, Wang R et al (2020) Roflumilast prevents lymphotoxin α (TNF-β)-induced inflammation activation and degradation of type 2 collagen in chondrocytes. Inflamm Res 69(12):1191–1199. https://doi.org/10.1007/s00011-020-01404-3CrossRefPubMed

34.

Grunke M, Schulze-Koops H (2006) Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade. Ann Rheum Dis 65(4):555–556. https://doi.org/10.1136/ard.2006.053272CrossRefPubMedPubMedCentral

35.

Santos MJ, Fernandes D, Caetano-Lopes J et al (2011) Lymphotoxin-α 252 A>G polymorphism: a link between disease susceptibility and dyslipidemia in rheumatoid arthritis? J Rheumatol 38(7):1244–1249. https://doi.org/10.3899/jrheum.101170CrossRefPubMed

36.

Proost P, De Wolf-Peeters C, Conings R et al (1993) Identification of a novel granulocyte chemotactic protein (GCP-2) from human tumor cells. In vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8. J Immunol 150(3):1000–1010CrossRefPubMed

37.

Dai CL, Yang HX, Liu QP et al (2023) CXCL6: A potential therapeutic target for inflammation and cancer. Clin Exp Med 23(8):4413–4427. https://doi.org/10.1007/s10238-023-01152-8CrossRefPubMed

38.

Scaife S, Brown R, Kellie S et al (2004) Detection of differentially expressed genes in synovial fibroblasts by restriction fragment differential display. Rheumatology (Oxford) 43(11):1346–1352. https://doi.org/10.1093/rheumatology/keh347CrossRefPubMed

39.

Lu J, Hu D, Zhang Y et al (2023) Current comprehensive understanding of denosumab (the RANKL neutralizing antibody) in the treatment of bone metastasis of malignant tumors, including pharmacological mechanism and clinical trials. Front Oncol 13:1133828. https://doi.org/10.3389/fonc.2023.1133828CrossRefPubMedPubMedCentral

40.

Kwan Tat S, Amiable N, Pelletier JP et al (2009) Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis. Rheumatology (Oxford) 48(12):1482–1490. https://doi.org/10.1093/rheumatology/kep300CrossRefPubMed

41.

Hamilton JL, Nagao M, Levine BR et al (2016) Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. J Bone Miner Res 31(5):911–924. https://doi.org/10.1002/jbmr.2828CrossRefPubMed

42.

Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6):653–660. https://doi.org/10.1038/nm0603-653CrossRefPubMed

43.

Binette F, McQuaid DP, Haudenschild DR et al (1998) Expression of a stable articular cartilage phenotype without evidence of hypertrophy by adult human articular chondrocytes in vitro. J Orthop Res 16(2):207–216. https://doi.org/10.1002/jor.1100160208CrossRefPubMed

44.

Ludin A, Sela JJ, Schroeder A et al (2013) Injection of vascular endothelial growth factor into knee joints induces osteoarthritis in mice. Osteoarthritis Cartilage 21(3):491–497. https://doi.org/10.1016/j.joca.2012.12.003CrossRefPubMed

45.

Pei YA, Chen S, Pei M (2022) The essential anti-angiogenic strategies in cartilage engineering and osteoarthritic cartilage repair. Cell Mol Life Sci 79(1):71. https://doi.org/10.1007/s00018-021-04105-0CrossRefPubMedPubMedCentral

Title: Causal effects of circulating inflammatory proteins on knee and hip osteoarthritis: A two sample Mendelian randomization study
Authors: Rongjie Lin
Qingcong Zheng
Rui Zhang
Quan Liu
Jianlong Lin
Shaohuang Weng
Min Chen
Publication date: 07-12-2024
Publisher: Springer International Publishing
Keywords: Osteoarthritis of the Hip
Osteoarthritis of the Hip
Knee Osteoarthritis
Knee Osteoarthritis
Osteoarthrosis
Osteoarthrosis
Published in: Clinical Rheumatology / Issue 1/2025
Print ISSN: 0770-3198
Electronic ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-024-07232-8

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Causal effects of circulating inflammatory proteins on knee and hip osteoarthritis: A two sample Mendelian randomization study

Abstract

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