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Background <p>Osteoarthritis (OA) frequently co-exists with type 2 diabetes mellitus (T2DM) owing to shared risk factors, including age and obesity, and disease severity is often greater in individuals with both conditions (OADM). However, molecular alterations associated with this co-morbidity remain incompletely understood. Here, we applied a proteomics-based approach to investigate glycated/ glycosylated synovial fluid (SF) proteins and to identify molecular patterns potentially linked to joint degeneration in OADM.</p> Methods <p>We performed the first global proteomic analysis of phenylboronic acid (PBA)-enriched cis-diol–containing glycation/ glycosylation-associated proteins from knee SF samples of OA and OADM patients. Enriched proteins were fractionated by SDS-PAGE and analyzed by LC-MS/MS, followed by quantitative SWATH-MS and bioinformatic pathway analyses. Selected proteins showing increased abundance in OADM were evaluated in SF and paired serum samples from a larger cohort using ELISA, and their discriminatory performance was explored using receiver operating characteristic (ROC) curve analysis.</p> Results <p>Three proteins, high-temperature requirement protein A1 (HTRA1), cathepsin G (CTSG), and alpha-1-acid glycoprotein 1 (AGP1), were consistently more abundant in OADM compared with OA. Functional annotation associated HTRA1 and CTSG with extracellular matrix remodeling and degradative processes, while AGP1 was linked to inflammatory responses. Exploratory ROC analyses in both SF and serum suggested that these proteins have potential utility in distinguishing OADM from OA within the studied cohort, with SF and serum levels showing significant concordance in OADM patients.</p> Conclusions <p>These findings suggest an association between T2DM-related metabolic dysregulation, synovial protein glycation/ glycosylation, and cartilage degeneration in OADM. HTRA1, CTSG, and AGP1 emerge as clinically measurable proteins with potential biomarker relevance for distinguishing OADM from OA, which may support improved disease stratification in future studies. Collectively, the results provide molecular insight into the co-pathogenesis of OA and T2DM and highlight glycation/ glycosylation-associated pathways as candidates for future precision-based therapeutic investigation, with the potential to mitigate OA severity in patients with T2DM and improve joint health.</p>

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PBA-enriched glycated/ glycosylated synovial fluid proteomic signatures associated with metabolic dysregulation and cartilage degeneration in osteoarthritis with type 2 diabetes

  • 期刊论文

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  • 发表日期：

    2026年3月25日

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  • Ayushi Sharma,
  • Uttam Chand Saini,
  • Sanjay Kumar Bhadada,
  • Sadhna Sharma,
  • Jyotdeep Kaur

摘要

Background

Osteoarthritis (OA) frequently co-exists with type 2 diabetes mellitus (T2DM) owing to shared risk factors, including age and obesity, and disease severity is often greater in individuals with both conditions (OADM). However, molecular alterations associated with this co-morbidity remain incompletely understood. Here, we applied a proteomics-based approach to investigate glycated/ glycosylated synovial fluid (SF) proteins and to identify molecular patterns potentially linked to joint degeneration in OADM.

Methods

We performed the first global proteomic analysis of phenylboronic acid (PBA)-enriched cis-diol–containing glycation/ glycosylation-associated proteins from knee SF samples of OA and OADM patients. Enriched proteins were fractionated by SDS-PAGE and analyzed by LC-MS/MS, followed by quantitative SWATH-MS and bioinformatic pathway analyses. Selected proteins showing increased abundance in OADM were evaluated in SF and paired serum samples from a larger cohort using ELISA, and their discriminatory performance was explored using receiver operating characteristic (ROC) curve analysis.

Results

Three proteins, high-temperature requirement protein A1 (HTRA1), cathepsin G (CTSG), and alpha-1-acid glycoprotein 1 (AGP1), were consistently more abundant in OADM compared with OA. Functional annotation associated HTRA1 and CTSG with extracellular matrix remodeling and degradative processes, while AGP1 was linked to inflammatory responses. Exploratory ROC analyses in both SF and serum suggested that these proteins have potential utility in distinguishing OADM from OA within the studied cohort, with SF and serum levels showing significant concordance in OADM patients.

Conclusions

These findings suggest an association between T2DM-related metabolic dysregulation, synovial protein glycation/ glycosylation, and cartilage degeneration in OADM. HTRA1, CTSG, and AGP1 emerge as clinically measurable proteins with potential biomarker relevance for distinguishing OADM from OA, which may support improved disease stratification in future studies. Collectively, the results provide molecular insight into the co-pathogenesis of OA and T2DM and highlight glycation/ glycosylation-associated pathways as candidates for future precision-based therapeutic investigation, with the potential to mitigate OA severity in patients with T2DM and improve joint health.