National Institute on Aging 5R01AG076783-05

Sialylation of TLR2 Induces Osteoclast Fusion and Th 17 differentiation During Aging

Research project funded by the National Institute on Aging to study how sialylation of TLR2 influences osteoclast fusion and Th17 cell differentiation during aging, with implications for autoimmune diseases like rheumatoid arthritis. The project also explores the therapeutic potential of Soyasaponin Bb to inhibit these processes.

Description

This project explores the role of sialylation in osteoclast fusion and autoimmune disease progression, with a focus on therapeutic intervention using Soyasaponin Bb. Aging of skeleton becomes more susceptible to develop autoimmune disease such as rheumatoid arthritis (RA). Increased osteoclast activity and bone resorption are partly responsible for deterioration of skeleton during aging. Aberrant activation of osteoclast formation in the subchondral bone initiates uncoupled remodeling activity to induce joint degeneration in RA and osteoarthritis (OA). Elevated osteoclast activity in the subchondral bone also contributes to joint pain. The signaling mechanisms of increased osteoclast fusion and bone resorption in RA are unclear. Sialic acid levels in serum and sialylation of cellular receptors increase during aging, implicating their role in skeletal aging and autoimmune disease. Sialylation of TLR2 induces binding to Siglec15, initiating osteoclast fusion for bone loss. RANKL induces transcription of α2,3-sialyltransferase ST3Gal1 in preosteoclasts, which sialylates TLR2, promoting osteoclast fusion. Sialylated TLR2 binding to Siglec15 also biases Th17 differentiation of CD4+ T cells at RA onset, involved in autoimmune diseases like MS, IBD, and SLE. Soyasaponin Bb inhibits α2,3-sialyltransferases activity, potentially mitigating osteoclast fusion and Th17 bias. The study aims to characterize sialylated TLR2-induced osteoclast fusion, investigate its effect on T cells, and evaluate the therapeutic potential of Soyasaponin Bb.

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