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Mol Ther ; 32(5): 1479-1496, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429926

RESUMO

Intense inflammatory response impairs bone marrow mesenchymal stem cell (BMSC)-mediated bone regeneration, with transforming growth factor (TGF)-ß1 being the most highly expressed cytokine. However, how to find effective and safe means to improve bone formation impaired by excessive TGF-ß1 remains unclear. In this study, we found that the expression of orphan nuclear receptor Nr4a1, an endogenous repressor of TGF-ß1, was suppressed directly by TGF-ß1-induced Smad3 and indirectly by Hdac4, respectively. Importantly, Nr4a1 overexpression promoted BMSC osteogenesis and reversed TGF-ß1-mediated osteogenic inhibition and pro-fibrotic effects. Transcriptomic and histologic analyses confirmed that upregulation of Nr4a1 increased the transcription of Wnt family member 4 (Wnt4) and activated Wnt pathway. Mechanistically, Nr4a1 bound to the promoter of Wnt4 and regulated its expression, thereby enhancing the osteogenic capacity of BMSCs. Moreover, treatment with Nr4a1 gene therapy or Nr4a1 agonist Csn-B could promote ectopic bone formation, defect repair, and fracture healing. Finally, we demonstrated the correlation of NR4A1 with osteogenesis and the activation of the WNT4/ß-catenin pathway in human BMSCs and fracture samples. Taken together, these findings uncover the critical role of Nr4a1 in bone formation and alleviation of inflammation-induced bone regeneration disorders, and suggest that Nr4a1 has the potential to be a therapeutic target for accelerating bone healing.


Assuntos
Regeneração Óssea , Inflamação , Células-Tronco Mesenquimais , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Osteogênese , Proteína Wnt4 , Células-Tronco Mesenquimais/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Osteogênese/genética , Regeneração Óssea/genética , Animais , Camundongos , Proteína Wnt4/metabolismo , Proteína Wnt4/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Regulação da Expressão Gênica , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Via de Sinalização Wnt , Masculino , Transcrição Gênica , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Modelos Animais de Doenças
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