权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

TLR2 唾液酸化诱导衰老过程中破骨细胞融合和 Th 17 分化

基本信息

批准号：
10650877
负责人：
Xu Cao
金额：
$ 48.66万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650877
关键词：
Acceleration Adult Age Aging Arthralgia Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Bone Diseases Bone Resorption CD4 Positive T Lymphocytes Cell Differentiation process Cell fusion Cells Collagen Arthritis Degenerative polyarthritis Deterioration Development Disease Equilibrium Excision Family Gene Expression Profile Generations Genetic Transcription Immunoglobulins Inflammatory Inflammatory Bowel Diseases Interferon Type II Interleukin-10 JAK2 gene Ligands Macrophage Macrophage Colony-Stimulating Factor Marrow Mass Spectrum Analysis Measures Modeling Mononuclear Multiple Sclerosis Mus Neuraminidase Nuclear Osteoclasts Pathogenesis Pathway interactions Persons Population Predisposition Process Proliferating Proteins RANK protein Regulatory T-Lymphocyte Rheumatoid Arthritis Saponins Serum Sialic Acids Sialyltransferases Signal Transduction Site Skeleton Soyasaponin Systemic Lupus Erythematosus T-Lymphocyte TNF gene Terpenes Testing Therapeutic Therapeutic Effect Transgenic Organisms aged bone bone loss bone mass cytokine glycosylation inhibitor joint destruction member monocyte osteoclastogenesis receptor sialic acid binding Ig-like lectin sialic acid-binding lectin sialylation soy subchondral bone therapeutic evaluation

项目摘要

Abstract Aging of skeleton becomes more susceptible to develop autoimmune disease such as rheumatoid arthritis (RA). Increased osteoclast activity and bone resorption is partly responsible for deterioration of skeleton during aging. We have shown that aberrant activation of osteoclast formation in the subchondral bone initiates uncoupled remodeling activity to induce degeneration of joints in both RA and osteoarthritis (OA). The elevated osteoclast activity in the subchondral bone is also responsible for the joint pain. However, the signaling mechanism of increased osteoclast fusion and bone resorption is unclear in RA. Interestingly, sialic acid level in serum and sialylation of cellular receptors continuously increase during with implication of skeleton aging and autoimmune disease. We found that sialylation of TLR2 induced binding to Siglec15 to initiate osteoclast fusion for bone loss. Trap+ mononuclear cells with RANKL undergo cell-cell fusion to form Trap+ multinuclear osteoclasts. The mechanism of RANKL-induced osteoclast fusion and maturation are not fully understood. Our preliminary results showed that RANKL induced transcription of α2,3-sialyltransferase ST3Gal1 in preosteoclasts. Noteworthy, the sialylation of TLR2 by ST3Gal1 induces binding to Siglec15, a member of sialic acid-binding lectins of the immunoglobulin superfamily, to promote osteoclast fusion for bone resorption. In parallel, our preliminary results also showed that the binding of sialylated TLR2 to Siglec 15 induced biased Th17 differentiation of CD4+ T cells at onset of RA development. We now know that Th17 T cells are involved in nearly all major autoimmune diseases, including RA, multiple sclerosis (MS), inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). It is critical to understand the divergent functions of Th17 cells in homeostatic and disease states. Th17 cells also promote the maturation of B cells for autoimmune antibody generation. Most importantly, our preliminary results showed that soyasaponin Bb, a triterpenoid saponin from soy, effectively inhibited α2,3-sialyltransferases activity in both aged and RA mice. Thus, we hypothesize that sialylation TLR2-induced osteoclast fusion and biased Th17 differentiation of CD4+ T cells during aging accelerates skeleton deterioration susceptible to development of autoimmune disease such as RA. In the proposed study, we will first characterize mechanism of sialylated TLR2-induced osteoclast fusion in Specific Aim 1. We will then investigate the effect of sialylation of TLR2 on T cells at onset of RA. We will finally examine the therapeutic effect of Soyasaponin Bb sialyltransferase inhibitor on RA. Inhibition of TLR2 sialylation by soyasaponin Bb could mitigate age-induced biased differentiation of Th17 and osteoclast fusion.

摘要