Advanced glycation end product accumulation and AGEs–RAGE axis biomarkers in plasma and synovial fluid are associated with osteoarthritis severity

Šoštarič, Anja (author), Oblak, Iza (author), Šuput, Dušan (author), Milisav, Irina (author), Mavčič, Blaž (author)

Osteoarthritis (OA) is a common whole-joint degenerative disease characterized by cartilage degradation, subchondral bone remodeling, synovial inflammation, and incompletely understood molecular mechanisms. Advanced glycation end products (AGEs) may contribute to OA pathophysiology by altering extracellular matrix properties and activating inflammatory signaling through the receptor for advanced glycation end products (RAGE). This study investigated the association between AGE accumulation and OA severity and evaluated AGE-related biomarkers in plasma and synovial fluid. In this cross-sectional observational study with prospective recruitment and retrospective clinical and radiographic assessment, skin AGE accumulation was measured by skin autofluorescence (SAF) in 404 outpatients aged 55-75 years. Lower-limb OA burden was assessed using clinical and available radiographic data for hip and knee OA, while hand osteoarthritis (HOA) was evaluated clinically. In a surgical subgroup of 42 participants, plasma AGEs, assessed as Nε-(carboxymethyl)lysine (CML), and soluble RAGE (sRAGE) concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Paired plasma and synovial fluid analyses were performed in 21 OA patients with available synovial fluid samples. Higher SAF was independently associated with greater lower-limb OA severity after adjustment for age, sex, body mass index (BMI), and smoking status [odds ratio (OR) 4.06, 95% confidence interval (CI) 2.54-6.46; p < 0.001]. SAF was also strongly associated with HOA (OR 15.0, 95% CI 7.29-30.91; p < 0.001). In the biochemical subgroup, SAF inversely correlated with synovial sRAGE (ρ = -0.571; p = 0.007), and plasma AGEs inversely correlated with plasma sRAGE (ρ = -0.481; p = 0.027). Both AGEs and sRAGE concentrations were lower in synovial fluid than in plasma. These findings support an association between systemic AGE accumulation and OA burden and suggest that altered AGEs-RAGE axis activity may contribute to OA pathophysiology. Further longitudinal studies are needed to clarify whether SAF may serve as a non-invasive biomarker of OA burden.

• Language: English
• Keywords: osteoarthritis, advanced glycation end products, synovial fluid
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; ZF - Faculty of Health Sciences
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 2306–2316
• Numbering: Vol. 26, no. 11
• PID: 20.500.12556/RUL-189979
• UDC: 616.7
• ISSN on article: 2831-090X
• DOI: 10.17305/bb.2026.14274
• COBISS.SI-ID: 288756739
• Publication date in RUL: 20.10.2026

Record is a part of a journal

• Title: Biomolecules & biomedicine
• Shortened title: Biomol. biomed.
• Publisher: Association of Basic Medical Sciences of FBIH
• ISSN: 2831-090X
• COBISS.SI-ID: 148721411

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: osteoartritis, končni produkti napredne glikacije, sinovijska tekočina

Projects

• Funder: University Medical Centre Ljubljana
• Project number: 20210125
• Name: Developmental-Research Tertiary Projects 2021

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0019
• Name: Aplikativna in bazična fiziologija in patofiziologija v medicini