Abnormal stress promotes intervertebral disc degeneration through WTAP/YTHDF2-dependent TIMP3 m6A modification.
J Cell Physiol
; 239(5): e31219, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38345407
ABSTRACT
Mechanical environment worsening is an important predisposing factor that accelerates intervertebral disc degeneration (IDD), but its specific regulatory mechanisms remain unclear. In this study, we reveal the molecular mechanisms of WTAP/YTHDF2-mediated m6A modification in abnormal stress-induced intervertebral disc (IVD) matrix degradation. WTAP expression in human nucleus pulposus cells was elevated under tension. Similarly, high WTAP expression was detected in severe degenerated human and rat nucleus pulposus tissues. Functionally, WTAP was found to increase the TIMP3 transcript methylation level under tension, resulting in YTHDF2 recognition, binding, and induction of its degradation. Reduction in TIMP3 caused increases in active matrix metalloproteinases, ultimately inducing extracellular matrix degradation in nucleus pulposus cells. Macroscopically, this promotes IDD. Additionally, in vitro and in vivo inhibition of WTAP expression or TIMP3 overexpression significantly increased stress resistance in the nucleus pulposus, thereby alleviating IDD. Our results show that abnormal stress disrupts IVD matrix stability through WTAP/YTHDF2-dependent TIMP3 m6A modification.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse Mecânico
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Adenosina
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Proteínas de Ligação a RNA
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Proteínas de Ciclo Celular
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Inibidor Tecidual de Metaloproteinase-3
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Degeneração do Disco Intervertebral
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Núcleo Pulposo
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Fatores de Processamento de RNA
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Cell Physiol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China