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New Therapeutic Strategies for Osteoarthritis by Targeting Sialic Acid Receptors
Paula Carpintero-Fernandez1, Marta Varela-Eirin1, Alessandra Lacetera2
1CellCOM Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), CH-Universitario A Coruña (XXIAC), Universidade da Coruña (UDC), Servizo Galego de Saúde (SERGAS), Xubias de Arriba, 84, 15006 A Coruña, Spain.
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.
Insights
Osteoarthritis involves changes in sialic acid linkages on cartilage. Targeting α-2,3-sialylated podoplanin with Maackia amurensis seed lectin may offer a novel therapy for joint degeneration.
Area of Science:
- Biochemistry
- Immunology
- Biomolecular Engineering
Background:
- Osteoarthritis (OA) is a prevalent degenerative joint disease.
- Articular cartilage degradation in OA is linked to altered glycosylation, specifically a shift towards α-2,3-sialylation.
- The role of α-2,3-sialylation in cartilage pathophysiology remains unclear.
Purpose of the Study:
- To investigate the role of α-2,3-sialylation in osteoarthritis.
- To evaluate the therapeutic potential of targeting α-2,3-sialylated receptors with lectins.
Main Methods:
- Analysis of osteoarthritic patient cartilage for α-2,3-sialylated proteins.
- Utilizing Maackia amurensis seed lectin (MASL) to target podoplanin (PDPN).
- Assessing the effect of MASL on NF-kB activation in chondrocytes and cartilage breakdown in ex vivo and in vivo models.
- Computational 3D molecular modeling of the lectin-receptor interaction.
Main Results:
- Osteoarthritic cartilage exhibits elevated levels of α-2,3-sialylated podoplanin (PDPN).
- MASL targeting of PDPN reduced inflammatory responses in chondrocytes and protected cartilage from breakdown.
- Computational modeling provided insights into the molecular interaction.
Conclusions:
- Specific lectins targeting α-2,3-sialylated receptors like PDPN on chondrocytes show promise for inhibiting cartilage breakdown.
- This study reveals a potential novel therapeutic strategy for osteoarthritis and related degenerative joint diseases.
