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A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [Denatonium]

ABSTRACT: A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [Denatonium]

PROVIDER: PRJNA1046553 | ENA |

REPOSITORIES: ENA

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A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [Denatonium]

Project description:Bone remodeling, crucial for skeletal integrity, involves osteoclasts and osteoblasts. Osteoclastogenesis, regulated by NFATc1, is activated by c-Fos and NF-κB signaling in response to RANKL. Excessive RANKL signaling contributes to bone loss pathology. Here we reveal denatonium as an inhibitor of RANKL-induced osteoclast differentiation through the p65 pathway. RNA-seq identified downregulated osteoclast-related genes. Affinity chromatography pinpointed 35 denatonium-interacting proteins, with PRDX1 showing specificity. PRDX1 deficiency led to osteoporosis with increased osteoclast activity and enhanced RANKL-induced osteoclast formation. Denatonium blocked PRDX1 lysosomal degradation, stabilizing PRDX1. Through transcription factor binding site analysis, p65 emerged as a major target suppressed by the denatonium-PRDX1 interaction. Chromatin immunoprecipitation confirmed that the denatonium-PRDX1 complex inhibited p65 enrichment at promoter regions critical for osteoclast differentiation. In an osteoporosis animal model, denatonium treatment restored bone health. This study uncovers denatonium's novel role in bone formation regulation by selectively targeting PRDX1, suggesting its potential in osteoporosis treatment.

2024-06-30 | GSE248992 | GEO

A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [PRDX KO]

2024-06-30 | GSE248993 | GEO

PRDX1-TLR4-p65 axis inhibits RANKL-mediated osteoclast differentiation

Project description:Peroxiredoxin 1 (PRDX1), traditionally known as an intracellular antioxidant enzyme, has emerged as a regulator of inflammatory responses via Toll-like receptor 4 (TLR4) signaling. Despite this, the mechanistic details of the PRDX1-TLR4 axis and its impact on osteoclast differentiation remain elusive. Here, we show that PRDX1 suppresses RANKL-induced osteoclast differentiation. Utilizing pharmacological inhibitors, we reveal that PRDX1 inhibits osteoclastogenesis through both TLR4/TRIF and TLR4/MyD88 pathways. Transcriptome analysis revealed PRDX1-mediated alterations in gene expression, particularly upregulating serum amyloid A3 (SAA3) and aconitate decarboxylase 1 (ACOD1), known inhibitors of osteoclast differentiation. Mechanistically, PRDX1-TLR4 signaling activates p65, promoting SAA3 and ACOD1 expression while inhibiting NFATc1, a master regulator of osteoclastogenesis. Remarkably, PRDX1 redirects p65 binding from NFATc1 to SAA3/ACOD1 promoters, thereby suppressing osteoclast formation. Structural analysis showed that monomeric variants of PRDX1 with enhanced TLR4 binding exhibit potent inhibition of osteoclast differentiation. Our findings elucidate the inhibitory role of PRDX1-TLR4 axis in osteoclastogenesis, providing insights into therapeutic strategies for bone-related disorders.

2024-11-12 | GSE267039 | GEO

A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype

Project description:A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype

| PRJNA1046547 | ENA

PRDX1-TLR4-p65 axis inhibits RANKL-mediated osteoclast differentiation

Project description:PRDX1-TLR4-p65 axis inhibits RANKL-mediated osteoclast differentiation

| PRJNA1109386 | ENA

A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [PRDX KO]

Project description:A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [PRDX KO]

| PRJNA1046552 | ENA

Effect of RANKL on gene expression during osteoclast differentiation

Project description:To investigate effect of RANKL on osteoclast differentiation, bone marrow cells were cultured with M-CSF and RANKL.

2023-11-08 | GSE225883 | GEO

Genome-wide analysis of gene expression in osteoclast precursor cells cultured for 3 days with either M-CSF or M-CSF + RANKL

Project description:Genome wide expression analysis of murine bone marrow osteoclast precursor cells that were cultured for 3 days either with macrophage colony stimulating factor (M-CSF) alone to remain as monocytes or M-CSF + receptor activator of NF-kB (RANKL) to differentiate down the osteoclast lineage. Results provide important information on genes that are regulated by RANKL in order to drive commitment to the osteoclast lineage.

2019-04-05 | GSE129334 | GEO

Gene expression profiling during RANKL-mediated osteoclast differentiation

Project description:Gene expression profiling during RANKL-mediated osteoclast differentiation

| PRJNA735691 | ENA

Propionibacterium freudenreichii MJ2 inhibits RANKL-induced osteoclast differentiation and ameliorates rheumatoid arthritis in collagen-induced arthritis model

Project description:Osteoclast differentiation is crucial for bone absorption and osteoclast is involved in bone destruction in rheumatoid arthritis. The aim of this study was to investigate the inhibitory effect of MJ2 on osteoclast differentiation and to elucidate its mechanism. Murine macrophage cell line, Raw 264.7 cells and collagen-induced arthritis mouse model were used for in vitro and in vivo study, respectively. MJ2-treated cells significantly inhibited osteoclast differentiation and decreased arthritic score. Surface proteins (SP) extracted from MJ2 also showed inhibitory effect on osteoclast differentiation by upregulating lipocalin 2 (lcn2) expression. Specifically, heat shock protein 60 (hsp60) in SP was revealed as an active component of MJ2. Hsp60 inhibited binding of receptor activator of nuclear factor-κB ligand (RANKL) to receptor activator of nuclear factor κB (RANK). In conclusion, MJ2 inhibited osteoclast formation and differentiation through lcn2 and RANKL-binding property and the effective component of MJ2 might be hsp60 present in surface layer.

2022-09-18 | GSE213113 | GEO

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