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Inflammatory cytokines and metabolic pathways in osteomyelitis: Mendelian randomization insights and experimental
Xingyu Chen1, Ruiqing Mo1, Sijie Yang2
1Department of Bone and Joint Surgery, Guangxi Diabetic Foot Salvage Engineering Research Center for Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Background:
Osteomyelitis is a challenging orthopedic condition characterized by bone inflammation, often resulting from infection. The roles of inflammatory cytokines (ICs) and metabolites in its pathogenesis are not fully understood.
Objectives:
This study aimed to explore the potential causal relationships among ICs, metabolites, and osteomyelitis using Mendelian randomization (MR) analysis and in vitro experiments.
Material And Methods:
A 2-sample MR analysis (FinnGen: 1,881 cases and 391,037 controls) was performed to screen 91 cytokines and more than 1,400 metabolites. In vitro experiments using MC3T3-E1 cells treated with staphylococcal protein A (SPA) were conducted to evaluate the effects of p-cresol sulfate (PCS), a circulating metabolite identified through MR analysis, on cell proliferation, osteogenic differentiation, and inflammation.
Results:
Mendelian randomization analysis identified significant associations between several ICs and osteomyelitis risk. Elevated levels of CUB domain-containing protein 1 (CDCP1; odds ratio (OR) = 1.19, 95% confidence interval (95% CI): 1.03-1.38) and thymic stromal lymphopoietin (TSLP; OR = 1.26, 95% CI: 1.05-1.51) were associated with increased risk, whereas higher levels of adenosine deaminase (ADA; OR = 0.85, 95% CI: 0.74-0.98) and interleukin-5 (IL-5; OR = 0.79, 95% CI: 0.65-0.96) were associated with reduced risk. Metabolites such as PCS (OR = 0.74, 95% CI: 0.59-0.93) were identified as protective, whereas others, such as beta-cryptoxanthin (β-CX; OR = 1.33, 95% CI: 1.07-1.66), were associated with increased risk. Mediation analysis further suggested that several metabolites significantly mediated the indirect effects of cytokines on osteomyelitis risk. In vitro experiments demonstrated that PCS enhanced osteogenic potential, reduced intracellular reactive oxygen species (ROS) production, and lowered IC levels.
Conclusions:
These findings provide insight into the associations among ICs, metabolites, and osteomyelitis, suggesting potential therapeutic targets for reducing disease severity. They also highlight the complex interplay among these factors in osteomyelitis pathogenesis. Further studies are needed to clarify the mechanisms through which ICs and metabolites influence osteomyelitis, particularly through regulation of inflammatory responses and oxidative stress.
