What question did this study set out to answer?

This study aims to identify plasma proteins that may cause knee osteoarthritis and assess their biological relevance.

April 26, 2026Frontiers in Medicine0 citationsOpen Access

Identification of novel protein biomarkers for knee osteoarthritis by integrating human plasma proteome: evidence from Mendelian randomization and preliminary in vitro investigation

WHWang HuangShanghai Traditional Chinese Medicine Hospital WHWeiWei HuShanghai Traditional Chinese Medicine Hospital JCJiaYu ChenCounty Hospital

Key Points

This study aims to identify plasma proteins that may cause knee osteoarthritis and assess their biological relevance.
Conducted two-sample Mendelian randomization using genetic data from four large-scale studies.
Assessed genetic associations with knee osteoarthritis through a genome-wide association study.
Performed preliminary in vitro experiments with macrophages and synovial fibroblasts.
Galectin-3 was identified as a biomarker for knee osteoarthritis with an odds ratio of 1.07 (95% CI: 1.03–1.11, p = 0.00048).
Moderate-to-strong co-localization support was found with a shared causal variant (PPH4 = 77.3%).
In vitro experiments showed that galectin-3 stimulation increased inflammatory cytokine expression in macrophages.

Abstract

Objective This study sought to identify candidate plasma proteins with potential causal associations with knee osteoarthritis (KOA) through Mendelian randomization, and to provide preliminary biological evidence through in vitro experiments. Methods Two-sample Mendelian randomization (MR) was conducted utilizing genetic instruments on 4,489 plasma proteins as exposures. Protein quantitative trait locus (pQTL) data were sourced from three large-scale studies. Genetic associations with KOA were obtained from a genome-wide association study (GWAS) of the European ancestry (accession ID: ebi-a-GCST007090; n = 403,124). The primary MR method was inverse variance weighting (IVW), supplemented by MR-Egger, weighted median, and weighted mode. Pleiotropy and reverse causality were assessed in sensitivity analyses, along with co-localization and protein–protein interaction (PPI) analyses. Preliminary in vitro exploration was conducted using macrophages (MØs) and synovial fibroblasts (SF) to assess biological plausibility. Results Galectin-3 (encoded by LGALS3 prot-b-6) was identified as a biomarker of KOA (odds ratio OR = 1.07, 95% confidence interval CI:1.03–1.11, p = 0.00048), with moderate-to-strong co-localization support for a shared causal variant (posterior probability of H4 PPH4 = 77.3%, lead single nucleotide polymorphism SNP: rs9323280). Exploratory in vitro experiments revealed that galectin-3 stimulation upregulated the expression of inflammatory cytokines (tumor necrosis factor alpha, interleukin-1β, and interleukin-18) and related inflammatory mediators (proteinase 3 encoded by PRTN3 and myeloperoxidase encoded by MPO) in MØs, suggesting a potential pro-inflammatory association. Conclusion This study identifies galectin-3 as a preferred plasma protein biomarker of KOA. The in vitro experiments provide preliminary biological plausibility for galectin-3-mediated inflammatory responses, suggesting potential involvement of myeloperoxidase and proteinase 3. These findings offer novel etiological insights and position galectin-3 as a therapeutic target, which warrants further exploration.

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