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Oxidative stress induces downregulation of TP53INP2 and suppresses osteogenic differentiation of BMSCs during osteoporosis through the autophagy degradation pathway.
Yang, Yuehua; Sun, Yuan; Mao, Wei-Wei; Zhang, Haonan; Ni, Binbin; Jiang, Leisheng.
Afiliação
  • Yang Y; Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. 1665 Kongjiang Road, Shanghai, 200092, China; Department of Orthopedics, The Fifth Affiliated Hospital, Southern Medical University, No. 566 Congcheng Avenue, Conghua District, Guangzhou, 510900,
  • Sun Y; Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. 1665 Kongjiang Road, Shanghai, 200092, China.
  • Mao WW; Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665, Kongjiang Road, Shanghai, 200092, PR China.
  • Zhang H; Department of Orthopedics, The Fifth Affiliated Hospital, Southern Medical University, No. 566 Congcheng Avenue, Conghua District, Guangzhou, 510900, PR China.
  • Ni B; Department of Orthopaedics, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: nibinbin@xinhuamed.com.cn.
  • Jiang L; Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: jiangleisheng@xinhuamed.com.cn.
Free Radic Biol Med ; 166: 226-237, 2021 04.
Article em En | MEDLINE | ID: mdl-33636337
Oxidative stress plays an important role in the pathogenesis of osteoporosis and impaired bone formation. However, the mechanisms behind which oxidative stress represses bone formation remains unclear. TP53INP2, a target of the tumor suppressor p53, is ubiquitously expressed in various cell types including BMSCs and contributes to autophagosome formation by recruiting ubiquitinated substrates to autophagosomes for degradation. However, little is known about its function in BMSCs and its relation to osteoporosis. In this study, first, we verified that the expression of TP53INP2 was persistently decreased in BMSCs derived from osteoporosis patients and OVX mice, and that the antioxidant N-acetylcysteine could ameliorate this decreased TP53INP2 level in vitro. Second, we identified that the mRNA and protein levels of TP53INP2 decreased in BMSCs under H2O2 induced oxidative stress in a dose-dependent manner, with resultant co-location of LC3 and TP53INP2. Additionally, the autophagy-lysosome system was involved in the degradation process of TP53INP2 and applying autophagy inhibitors (Baf-A1) could significantly increase the TP53INP2 levels in murine and human BMSCs under oxidative stress. Third, gain- and loss-of-function assays revealed that knockdown of TP53INP2 inhibited osteogenic differentiation of BMSCs, while overexpression of TP53INP2 promoted osteogenic differentiation of BMSCs in vitro. Further analysis demonstrated that TP53INP2 promoted osteogenic differentiation of BMSCs by activating Wnt/ß-cantenin signaling. DKK1, an inhibitor of Wnt signaling, resulted in osteogenic defects of BMSCs that had over-expressed TP53INP2. Lithium, a Wnt/ß-catenin activator, improved the mineralization ability in TP53INP2-knockdown BMSCs. Moreover, restoring TP53INP2 levels recovered OVX-derived BMSCs osteogenic differentiation and attenuated bone loss in OVX mice. Taken together, our study indicated that oxidative stress-induced downregulation of TP53INP2 suppressed osteogenic differentiation of BMSCs during osteoporosis and was mediated by the autophagy degradation pathway. These findings may introduce a novel therapeutic target for osteoporosis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoporose / Células-Tronco Mesenquimais Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Free Radic Biol Med Assunto da revista: BIOQUIMICA / MEDICINA Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoporose / Células-Tronco Mesenquimais Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Free Radic Biol Med Assunto da revista: BIOQUIMICA / MEDICINA Ano de publicação: 2021 Tipo de documento: Article