Agrimophol suppresses RANKL-mediated osteoclastogenesis through Blimp1-Bcl6 axis and prevents inflammatory bone loss in mice.
Int Immunopharmacol
; 90: 107137, 2021 Jan.
Article
em En
| MEDLINE
| ID: mdl-33199235
ABSTRACT
Excessive activity of osteoclasts causes many bone-related diseases, such as rheumatoid arthritis and osteoporosis. Agrimophol (AGR), a phenolic compound, originated from Agrimonia pilosa Ledeb. In prior studies, AGR is reported to possess schistosomicidal and mycobactericidal activities. However, no reports covered its anti-osteoclastogenesis characteristic. In this study, we found that AGR inhibited RANKL-induced osteoclastogenesis, bone-resorption, F-actin ring formation, and the mRNA expression of osteoclast-associated genes such as CTSK, TRAP, MMP-9, and ATP6v0d2 in vitro. In addition, AGR suppressed RANKL-induced expression of c-Fos and NFATc1. However, AGR treatment did not affect NF-κB activation and MAPKs phosphorylation in RANKL-stimulated BMMs, which implicated that AGR might not influence the initial expression of NFATc1 mediated by NF-κB and MAPKs signaling. Our results further indicated that AGR did not alter phosphorylation levels of GSK3ß and the expression of calcineurin, which implicated that AGR treatment might not interfere with phosphorylation and de-phosphorylation of NFATc1 mediated by GSK3ß and calcineurin, respectively. B-lymphocyte-induced maturation protein-1 (Blimp1), which was regarded as a transcriptional repressor of negative regulators of osteoclastogenesis, was markedly attenuated in the presence of AGR, leading to the enhanced expression of B-cell lymphoma 6 (Bcl-6). Meanwhile, Blimp1 knockdown in BMMs by siRNA strongly enhanced the expression of Bcl6 and reduced NFATc1 induction by RANKL. These findings suggested that AGR inhibited RANKL-induced osteoclast differentiation through Blimp1-Bcl-6 signaling mediated modulation of NFATc1 and its target genes. Consistent with these in vitro results, AGR exhibited a protective influence in an in vivo mouse model of LPS-induced bone loss by suppressing excessive osteoclast activity and attenuating LPS-induced bone destruction. Hence, these results identified that AGR could be considered as a potential therapeutic agent against bone lysis disease.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoclastos
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Osteogênese
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Fenóis
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Reabsorção Óssea
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Diferenciação Celular
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Proteínas Proto-Oncogênicas c-bcl-6
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Ligante RANK
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Fator 1 de Ligação ao Domínio I Regulador Positivo
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article