In a compelling new analysis published in Osteoarthritis and Cartilage, researchers identified a significant association between markers of intestinal permeability and erosive hand osteoarthritis (EHOA), providing fresh insight into the systemic factors contributing to osteoarthritis pathogenesis.
The study, based on data from the DIGICOD cohort, evaluated serum levels of four intestinal permeability biomarkers, lipopolysaccharide binding protein (LBP), FABP2, sCD14, and zonulin-related proteins (ZRP), in 410 individuals with hand osteoarthritis, including 140 with erosive disease. Two of these biomarkers, LBP and ZRP, were elevated in patients with EHOA and remained independently associated with the erosive phenotype even after adjustment for age, BMI, and sex. Further analysis revealed that ZRP correlated positively with structural severity, as measured by Verbruggen and Kellgren-Lawrence scores, while LBP showed a significant association with the number of erosive joints. Both LBP and hs-CRP also demonstrated links with pain severity, underscoring the inflammatory and symptomatic dimensions of barrier dysfunction.
LBP is an acute-phase protein that plays a pivotal role in the innate immune response to Gram-negative bacteria. It facilitates the recognition of lipopolysaccharide by transferring it to membrane-bound CD14 (mCD14) and soluble CD14 (sCD14), thereby enhancing LPS-mediated immune activation. A study by Won et al. investigated the role of low-grade inflammation in OA using mouse models of posttraumatic OA induced by destabilization of the medial meniscus (DMM). Mice were exposed to systemic inflammatory stimuli via a high-fat diet or endotoxemia. The study identified Toll-like receptor (TLR) pathway components, particularly LBP and CD14, as key mediators. While overexpression of these molecules alone did not affect cartilage, inflammation significantly worsened OA severity, an effect attenuated in LBP- and CD14-deficient mice. These findings suggest that LBP and CD14 are critical amplifiers of inflammation-driven cartilage damage in OA and represent potential therapeutic targets.
Zonulin, first described by Fasano around two decades ago, increases small intestinal epithelial permeability and plays a role in innate immunity. More recent findings have shown that zonulin refers to a group of structurally and functionally related proteins derived from the haptoglobin 2 precursor (pre-HP2). As a result, the term zonulin-related proteins (ZRP) is now considered more accurate. A study by Karim et al. explored the link between intestinal mucosal disruption and knee osteoarthritis (KOA) severity in older women. Using plasma zonulin as a marker of intestinal permeability, researchers compared healthy controls with KOA patients categorized by Oxford Knee Score. KOA patients showed significantly higher zonulin levels and zonulin levels negatively correlated with functional and clinical scores and showed diagnostic potential for identifying severe KOA. The findings suggest that increased intestinal permeability may contribute to functional decline in KOA and highlight zonulin as a potential biomarker.
These findings support the hypothesis that intestinal permeability plays a role in both structural progression and symptom burden in EHOA. The identification of ZRP and LBP as potential biomarkers of disease severity and pain opens new avenues for diagnostic and therapeutic strategies. The known ability of zonulin to modulate tight junctions in the gut epithelium may provide a pharmacologic target for restoring intestinal barrier integrity. This study strengthens the rationale for investigating gut and joint interactions in osteoarthritis and suggests that future interventions aimed at modulating gut permeability through dietary changes, probiotics, or microbiota targeted therapies could transform the management of osteoarthritis.
References
- Binvignat M, Fellahi S, Bastard JP, Rousseau A, Tuffet S, Courties A, et al. Serum intestinal permeability biomarkers are associated with erosive hand osteoarthritis and radiographic severity: results from the DIGICOD cohort. Osteoarthritis Cartilage. 2025 Jun;33(6):736-744.
- Won Y, Yang JI, Park S, Chun JS. Lipopolysaccharide Binding Protein and CD14, Cofactors of Toll-like Receptors, Are Essential for Low-Grade Inflammation-Induced Exacerbation of Cartilage Damage in Mouse Models of Posttraumatic Osteoarthritis. Arthritis Rheumatol. 2021 Aug;73(8):1451-1460.
- Wang X, Memon AA, Palmér K, Hedelius A, Sundquist J, Sundquist K. The association of zonulin-related proteins with prevalent and incident inflammatory bowel disease. BMC Gastroenterol. 2022 Jan 3;22(1):3.
- Karim A, Iqbal MS, Khan HA, Ahmad F, Qaisar R. Plasma zonulin levels forecast sarcopenia and physical performance in patients with knee osteoarthritis. Geriatr Nurs. 2025 Mar-Apr;62(Pt A):115-122.