Abstract
Lubricin is a mucinous, synovial fluid glycoprotein that enables near frictionless joint motion via adsorption to the surface of articular cartilage and its lubricating properties in solution. Extensive O-linked glycosylation within lubricin’s mucin-rich domain is critical for its boundary lubricating function; however, it is unknown exactly how glycosylation facilitates cartilage lubrication. Here, we find that the lubricin glycome is enriched with terminal β-galactosides, known binding partners for a family of multivalent lectins called galectins. Of the galectin family members present in synovial fluid, we find that galectin-3 is a specific, high-affinity binding partner for lubricin. Considering the known ability of galectin-3 to crosslink glycoproteins, we hypothesized that galectins could augment lubrication via biomechanical stabilization of the lubricin boundary layer. We find that competitive inhibition of galectin binding results in lubricin loss from the cartilage surface, and addition of multimeric galectin-3 enhances cartilage lubrication. We also find that galectin-3 has low affinity for the surface layer of osteoarthritic cartilage and has reduced affinity for sialylated O-glycans, a glycophenotype associated with inflammatory conditions. Together, our results suggest that galectin-3 reinforces the lubricin boundary layer; which, in turn, enhances cartilage lubrication and may delay the onset and progression of arthritis.
Highlights
Lubricin is a large, mucinous glycoprotein critical for boundary lubrication of articular cartilage
In order to determine what glycans were present on healthy cartilage, adult equine articular cartilage explants were incubated with fluorophore-conjugated lectins followed by nuclear staining with Hoechst 33342 and combined confocal and multiphoton microscopy (Fig. 1A)
Maackia amurensis lectin II (MALII), which preferentially binds to α 2–3 sialylated core-1 O-glycans, and jacalin, which binds to both sialylated and nonsialylated core-1 O-glycans, labelled the surface layer of articular cartilage
Summary
Mucinous glycoprotein critical for boundary lubrication of articular cartilage. Given the importance of lubricin’s O-linked β (1–3)Gal-GalNAc oligosaccharides[20] in mediating cartilage lubrication, inflammation-induced changes in the glycosylation of lubricin could potentially have a major impact on its interaction with other synovial fluid constituents and boundary lubricating ability[10,18]. Despite the critical role that O-linked glycosylation plays in mediating boundary lubrication, little effort has been devoted to characterizing the glycosylation of administered recombinant lubricin or the glycoprotein product of lubricin gene therapy approaches. It is unknown what glycan composition of lubricin could be used clinically to derive the optimal therapeutic benefit
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