Protein N-glycosylation aberrations and glycoproteomic network alterations in osteoarthritis and osteoarthritis with type 2 diabetes

Abstract

Abstract Whether the relationship between type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) can be solely attributed to the shared risk factors, such as obesity, remains controversial. Several studies have revealed the critical role of abnormal glycosylation in the pathogenesis of OA and T2DM. Therefore, we speculate that T2DM may contribute to the pathogenesis of OA through the intrinsic mechanisms of N-glycosylation aberrations. Using N-glycoproteomics, we compared the changes in N-glycosylated protein abundance in cartilage samples from patients with OA without and with T2DM (DM-OA), and from patients with traumatic joint injury (NC) as controls. We identified 847 N-glycosylation sites corresponding to 729 peptides fragments from 374 proteins. The number of N-glycosylated proteins in the DM-OA group tended to decrease compared with that in the OA and NC groups. We identified 22 upregulated and 1 down-regulated N-glycosylated peptides in the OA group compared to the NC group, while only fibronectin 1 (FN1) at position N1007, cartilage intermediate layer protein 1 (CILP) at N346, and collagen type VI alpha 1 chain (COL6A1) at N804, were also identified in the DM-OA group. Compared to the OA group, the downregulation of secreted protein acidic and rich in cysteine (SPARC) at N116, collagen type VI alpha 1 chain (COL6A2) at N785, and asporin (ASPN) at N282, and the upregulation of complement component C8 alpha chain (C8α) at N437, were the most remarkable alterations in the DM-OA group. The differentially expressed N-glycosylated proteins between the OA and DM-OA groups were mainly located extracellularly and enriched in the KEGG pathways involving PI3K/Akt signaling, focal adhesion, and ECM-receptor interaction. Their predicted protein–protein interactions were also depicted. We were thus able to show the general characteristics of N-glycosylation aberrations in OA and DM-OA. Moreover, the upregulated glycosylated complement C8α in the DM-OA group might augment membrane attack complex activity, thereby exacerbating cartilage destruction. Although further confirmation is required, our hypothesis proposes a possible explanation for the deduction that T2DM is an independent risk factor for OA.