OA is the leading cause of disability worldwide. It mainly occurs in weight-bearing joints, such as HOA and KOA, and it often manifests as joint pain and dysfunction. The incidence of OA increases with age[1]. According to a systematic analysis of the Global Burden of Disease Study, the number of KOA and HOA cases is approximately 303.1 million[2]. At present, the pathogenesis of OA has not been fully understood, and understanding its etiology is very important for the treatment and prevention of the disease.
Gal-3 is a multifunctional protein that exists inside and outside human cells, playing a role in regulating inflammation[3]. Gal-3 has a protective effect in chondrocytes[4]. The expression level of Gal-3 is increased in OA chondrocytes, which may play a role in osteoarthritis[5]. High levels of extracellular Gal-3 have deleterious effects on both cartilage and subchondral bone tissue[6]. Extracellular Gal-3 inhibitors, such as modified citrus pectin (MCP), have been shown to reduce inflammation in preclinical models[7]. However, Zhang et al. proved through experiments that MCP can promote the repair of chondrocyte damage in rabbits[8]. In the treatment of patients with KOA, Andrews et al. found no significant difference in the efficacy between MCP and a placebo, and no significant difference in Gal-3 levels between the two groups[9].
Numerous animal and in vitro human chondrocyte studies have highlighted Gal-3 as a risk factor for OA[5, 6, 8, 10], but there is little supporting evidence from human studies. The inconsistent results of Gal-3 inhibitors may be influenced by many factors, such as different study design types (cohort or cross-sectional), confusion of confounding factors and diagnostic indicators, small sample size of existing observational studies, and confusion caused by various biases and reverse causal reasoning.
Obesity is a major risk factor for OA, especially KOA[11]. Previous studies have found that the circulating Gal-3 levels are positively correlated with the occurrence of obesity[12, 13]. Due to the influence of reverse causation, the cause and effect are unclear, and the effect of the Gal-3 levels in the blood on OA may be obesity-mediated.
In order to further understand the risk correlation linking Gal-3 levels, obesity, and OA, we applied the MR study method to further explore their relationship.In contrast to previous animal and in vitro experiments, Mendelian randomization studies use genetic variations as instrumental variables (IVs), which can reduce the confounding factors and avoid the interference of reverse causality. The research population constituted the European population. The research results can directly reflect the causal relationship linking Gal-3 levels, obesity, and OA[14]. The purpose of this study was to use whole-genome data as a tool. Firstly, a two-sample MR study was conducted to analyze the potential impact of Gal-3 level on OA in the cycle of obtaining gene prediction and provide evidence for the increase in OA risk, depending on Gal-3 levels. Secondly, the causal relationship between Gal-3 levels and obesity in circulation was studied using bidirectional two-sample MR. Thirdly, mediated MR was used to analyze whether the effect of circulating Gal-3 levels on KOA predicted by genes was mediated by obesity.