New Therapeutic Strategies for Osteoarthritis by Targeting Sialic Acid Receptors.

Paula Carpintero-Fernandez,Raquel Gago-Fuentes,Alessandra Lacetera,Sonsoles Martin-Santamaria,Eduardo Fonseca,Marta Varela-Eirin,Maria D Mayan

doi:10.3390/biom10040637

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease characterized by articular cartilage degradation and joint degeneration. The articular cartilage is mainly formed by chondrocytes and a collagen-proteoglycan extracellular matrix that contains high levels of glycosylated proteins. It was reported that the shift from glycoproteins containing α-2,6-linked sialic acids to those that contain α-2,3 was associated with the onset of common types of arthritis. However, the pathophysiology of α-2,3-sialylation in cartilage has not been yet elucidated. We show that cartilage from osteoarthritic patients expresses high levels of the α-2,3-sialylated transmembrane mucin receptor, known as podoplanin (PDPN). Additionally, the Maackia amurensis seed lectin (MASL), that can be utilized to target PDPN, attenuates the inflammatory response mediated by NF-kB activation in primary chondrocytes and protects human cartilage breakdown ex vivo and in an animal model of arthritis. These findings reveal that specific lectins targeting α-2,3-sialylated receptors on chondrocytes might effectively inhibit cartilage breakdown. We also present a computational 3D molecular model for this interaction. These findings provide mechanistic information on how a specific lectin could be used as a novel therapy to treat degenerative joint diseases such as osteoarthritis.

Highlights

Articular cartilage functions as a cushion to cover and protect the joints between bones
These findings suggest that Maackia amurensis seed lectin (MASL) inhibits the activation of signal transduction pathways mediated by NF-κβ that lead to progressive cartilage destruction during the pathogenesis of arthritis by increasing reactive oxygen species (ROS), inflammatory cytokines, and metalloproteinases [43]
We have previously showed that the treatment of cartilage explants and primary chondrocytes with the ATP synthase inhibitor oligomycin, which mimics the arthritic condition and increases the binding of MASL, the reactive oxygen species (ROS) production by more than 10-fold, and the expression of enzymes responsible for extracellular matrix (ECM) degradation including matrix metalloproteinase 3 (MMP3) and matrix metalloproteinase 13 (MMP13) [43]

Summary

Introduction

Articular cartilage functions as a cushion to cover and protect the joints between bones. The cartilage is formed by an extracellular matrix (ECM) of collagen II consisting of fibrils that are integrated within an abundant anionic network of proteoglycan aggregates. These proteoglycans and collagen fibres, along with glycoproteins and water, form a macromolecular network to produce a protective matrix that facilitates articular movement. Chondrocytes contain a dense coat of carbohydrates on their surfaces. These carbohydrate moieties mediate a wide variety of cell-to-cell and cell–matrix interactions that are critical for cartilage and bone development and function. Carbohydrate chains vary according to cell and tissue type and undergo modifications during a range of processes involving cellular differentiation, phenotypic changes, and oncogenesis [3,4,5,6]

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