New Therapeutic Strategies for Osteoarthritis by Targeting Sialic Acid Receptors

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.

Ameliorative Effects of Loganin on Arthritis in Chondrocytes and Destabilization of the Medial Meniscus-Induced Animal Model

“…Mechanical stress induces the production of interleukin-1 beta (IL-1β) in chondrocytes, which increases the expression of inflammatory factors, such as matrix metalloproteinases (MMPs), cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE 2 ) [ 4 , 5 ]. In addition, nuclear factor-kappa B (NF-κB) plays a critical role in the regulation of MMP-3, MMP-13, and COX-2, which control the production of cartilage extracellular matrix (ECM) and collagen type II alpha 1 chain (Col2a1) [ 6 , 7 ]. Many pharmacological drugs used for the treatment of arthritis have focused on reducing the inflammatory response and include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and duloxetine [ 8 , 9 , 10 ].…”

Evidence that Maackia amurensis seed lectin (MASL) exerts pleiotropic actions on oral squamous cells with potential to inhibit SARS-CoV-2 infection and COVID-19 disease progression

“…Unlike antibodies, lectins can be taken orally to treat diseases [ [65] , [66] , [67] ] including cancer [ 65 ] and viral infections [ 16 ]. MASL targets sialic acid modified receptors to inhibit cancer progression and inflammation [ 18 , 19 , 21 ]. Results from this study indicate that MASL inhibits ACE2 expression, SARS-CoV-2 spike binding, and major components of the IL6 amplifier including STAT3, IL6, and NFκB as illustrated in Fig.…”

“…Indeed, COVID-19 infection causes arthralgia and myalgia in 15% and 44% of patients, respectively [ 68 , 69 ]. It should therefore be noted that MASL has been found to attenuate inflammatory NFκB signaling and inflammation in chondrocyte cell culture, and can be administered orally to alleviate arthritis progression in mice [ 21 ]. In addition, MASL has also been reported to suppress interleukin induced psoriatic inflammation in reconstituted epidermis [ 70 ].…”

“…Lectins recognize specific glycosylation motifs, and can be used as antiviral agents [ 16 ]. In particular Maackia amurensis seed lectin (MASL) has a strong affinity for sialic acid modified proteins, and targets specific receptors to inhibit viral infection [ 16 , 17 ], cancer progression [ 18 , 19 ], and inflammation [ 20 , 21 ]. Indeed, the effect of MASL on oral squamous cell carcinoma is being investigated in Phase I human clinical trial [ 22 ].…”

Circ_0038467 is Overexpressed in Osteoarthritis and it Promotes the Maturation of miR-203 to Increase the Apoptosis of Chondrocytes Induced by LPS

“…Some pathways, such as Notch pathway, NF-κB pathway and PCP/JNK-mTORC1-PTHrP cascade, have been proven to be critical players in OA (7,8). In effect, some molecular factors are promising targets for targeted OA patients (9,10). However, safe and effective targets for OA remain to be developed.…”