Research Article: Identification of novel protein biomarkers for knee osteoarthritis by integrating human plasma proteome: evidence from Mendelian randomization and preliminary in vitro investigation
Abstract:
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.
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.
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-1?, 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.
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.
Introduction:
Osteoarthritis (OA), a common degenerative joint disease, affects about 344 million individuals globally with soaring prevalence and disability rates, imposing a substantial global health burden ( 1 ). It predominantly targets weight-bearing joints. Consequently, knee osteoarthritis (KOA) becomes a major contributor to disability and a primary focus of research ( 2 ). The understanding of KOA has evolved from a mechanical “wear-and-tear” model to one centered on chronic low-grade inflammation, while synovitis is…
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