Author contributions: SA planned and executed the glycomic analysis, KT and LA planned and executed the glycoproteomic analysis, SH performed ELISA analysis, SR performed SPR analysis, YM and JH designed the recombinant expression and experiments executed by YM. OR, LB, RK, TS and TE were responsible for control and patient sample collection. TS and GJ contributed with design and provision of rhPRG4 for the analysis, MS and AK participated in planning and supervision of galectin-3 experiments. SF, KT and NK performed the writing with input from all contributors. NK coordinated and directed the research. All authors signed off on the final version.ABSTRACT Synovial fluid lubricin (proteoglycan 4) is a mucin-type O-linked glycosylated (60% of the mass) biological lubricant involved in osteoarthritis (OA) development. Lubricin has been reported to be cross-linked by synovial galectin-3 on the lubricating articular surface. Here, we confirm that binding to galectin-3 depended on core-2 O-linked glycans, where surface plasmon resonance of a recombinant lubricin (rhPRG4) devoid of core-2 structures lacked binding capacity to recombinant galectin-3. Both galectin-3 levels and interactions with synovial lubricin were found to be decreased in late-stage OA patients coinciding with an increase of truncated and less sialylated core 1 O-glycans. These data suggest a defect cross-linking of surface active molecules in OA and provides novel insights into OA molecular pathology.
Osteoarthrithis (OA) is an endemic disease due to the increase of the world′s elderly population. Previously thought to be a consequence of an imbalance between cartilage degradation and biosynthesis, it is now recognized as a disease also involving inflammation, hence influencing the level of inflammatory cytokines, growth factors and chemokines. Lubricin is a mucin type molecule where its OA induced glycosylation truncation propels a deteriorating lubrication of the articular cartilage. The objective of this study was to explore the OA driven truncation of O-linked glycosylation of synovial lubricin and its cross talk with systemic and local inflammation. We compared the systemic level of cytokines/chemokine in OA patients′ and controls plasma with their local level in synovial fluid (SF) using a 44 plex screen. The level of 27 cytokines and chemokines was consistently measured in both plasma and SF. The data showed that the levels of cytokines and chemokines in OA plasma display limited correlation to their counterpart in SF. The level of synovial IL-8 and MIP-1α and VEGFA in OA patients, but not their plasma level, where the only cytokines that displayed a significant correlation to the observed lubricin O-linked glycosylation truncation. These cytokines were also shown to be upregulated exposing fibroblast like synoviocytes from healthy and OA patients to recombinant lubricin with truncated glycans mainly consisting of Tn-antigens, while lubricin with sialylated and non-sialylated T anigens did not have any effect. The data suggest that truncated glycans of lubricin as found in OA, promotes the synovial cytokine production and exerebate the local synovial inflammation.
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