The neurofibromatosis type I gene promotes autophagy via mTORC1 signalling pathway to enhance new bone formation after fracture

Tan, Qian; Wu, Jiangyan; Liu, Yaoxi; Liu, Kun; Tang, Jin; Ye, Weihua; Zhu, Guoqiang; Mei, Haibo; Yang, Ge

doi:10.1111/jcmm.15767

Cited by 7 publications

(9 citation statements)

References 25 publications

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“…However, to the best of our knowledge, few studies have reported the effects of NF1 on autophagy in BMSCs. Tan et al ( 20 ) revealed that autophagic activity and osteogenic differentiation were significantly enhanced in NF1 -overexpressing BMSCs, consistent with the results of the present study. However, Tan et al ( 20 ) only established NF1 -overexpression BMSC models, which are different from the clinical situation in patients with NF1 mutations, where the function of NF1 is insufficient ( 8 ).…”

Section: Discussionsupporting

confidence: 93%

“…Tan et al ( 20 ) revealed that autophagic activity and osteogenic differentiation were significantly enhanced in NF1 -overexpressing BMSCs, consistent with the results of the present study. However, Tan et al ( 20 ) only established NF1 -overexpression BMSC models, which are different from the clinical situation in patients with NF1 mutations, where the function of NF1 is insufficient ( 8 ). Therefore, a cell model with inhibited expression of NF1 can simulate the pathological conditions of NF1 more closely compared with one with overexpression of NF1 .…”

Section: Discussionsupporting

confidence: 93%

“…The PI3K/AKT/mTOR pathway is also considered to be a classical signaling pathway for autophagy activation ( 18 ), such that mTORC1 is the main gatekeeper to autophagy that connects environmental cues to metabolic processes in order to preserve cellular homoeostasis ( 19 ). In a recent study, Tan et al ( 20 ) revealed that overexpression of NF1 gene enhanced the osteogenic differentiation of BMSCs by promoting autophagy and that mTORC1 signaling was involved in this process. However, this previous study only established NF1 -overexpression BMSC models, which is different from the clinical situation in patients with NF1 , where the function of the NF1 gene is typically insufficient ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

“…In a recent study, Tan et al ( 20 ) revealed that overexpression of NF1 gene enhanced the osteogenic differentiation of BMSCs by promoting autophagy and that mTORC1 signaling was involved in this process. However, this previous study only established NF1 -overexpression BMSC models, which is different from the clinical situation in patients with NF1 , where the function of the NF1 gene is typically insufficient ( 20 ). Therefore, a cell model with the inhibited expression of NF1 would simulate the pathological conditions of NF1 more closely compared with one modeling the overexpression of NF1 .…”

Section: Introductionmentioning

confidence: 99%

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Autophagy is involved in neurofibromatosis type I gene‑modulated osteogenic differentiation in human bone mesenchymal stem cells

Zhu

Lin

et al. 2021

Exp Ther Med

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Neurofibromatosis type I (NF1) is an autosomal dominant genetic disease that is caused by mutations in the NF1 gene. Various studies have previously demonstrated that the mTOR complex 1 signaling pathway is essential for the NF1-modulated osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, the mTOR signaling pathway plays a notable role in autophagy. The present study hypothesized that NF1 could modulate the osteogenic differentiation of BMSCs by regulating the autophagic activities of BMSCs. In the present study, human BMSCs were cultured in an osteogenic induction medium. The expression of the NF1 gene was either knocked down or overexpressed by transfection with a specific small interfering RNA (siRNA) targeting NF1 or the pcDNA3.0 NF1-overexpression plasmid, respectively. Autophagic activities of BMSCs (Beclin-1, P62, LC3B I, and LC3B II) were determined using western blotting, electron microscopy, acridine orange (AO) staining and autophagic flux/lysosomal detection by fluorescence microscopy. In addition, the autophagy activator rapamycin (RAPA) and inhibitor 3-methyladenine (3-MA) were used to investigate the effects of autophagy on NF1-modulated osteogenic differentiation in BMSCs. Inhibiting NF1 with siRNA significantly decreased the expression levels of autophagy markers Beclin-1 and LC3B-II, in addition to osteogenic differentiation markers osterix, runt-related transcription factor 2 and alkaline phosphatase. By contrast, overexpressing NF1 with pcDNA3.0 significantly increased their levels. Transmission electron microscopy, AO staining and autophagic flux/lysosomal detection assays revealed that the extent of autophagosome formation was significantly decreased in the NF1-siRNA group but significantly increased in the NF1-pcDNA3.0 group when compared with the NC-siRNA and pcDNA3.0 groups, respectively. In addition, the activity of the PI3K/AKT/mTOR pathway [phosphorylated (p)-PI3K, p-AKT, p-mTOR and p-p70S6 kinase] was significantly upregulated in the NF1-siRNA group compared with the NC-siRNA group, and significantly inhibited in the NF1-pcDNA3.0 group, compared with the pcDNA3.0 group. The knockdown effects of NF1-siRNA on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy activator RAPA, while the overexpression effects of NF1-pcDNA3.0 on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy inhibitor 3-MA. In conclusion, results from the present study suggest at the involvement of autophagy in the NF1-modulated osteogenic differentiation of BMSCs. Furthermore, NF1 may partially regulate the autophagic activity of BMSCs through the PI3K/AKT/mTOR signaling pathway.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Autophagy is involved in neurofibromatosis type I gene‑modulated osteogenic differentiation in human bone mesenchymal stem cells

Zhu

Lin

et al. 2021

Exp Ther Med

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“…Zhao et al demonstrated that autophagy regulates hypoxia-induced osteoclastogenesis, and the activation of autophagy under hypoxic conditions is caused by the HIF-1 α -dependent upregulated expression of BNIP3 [ 15 ]. In neurofibromatosis type I (NF1) overexpressing BMSCs, NF1 overexpression promotes new bone formation after fracture by enhancing autophagy and inhibiting mTORC1 signaling, indicating that promoting autophagy can promote new bone formation [ 38 ]. Unfortunately, at present, we have not measured the mineral density of the femoral head and more autophagy-related proteins (such as p62); meanwhile, we cannot determine which active ingredients in Gujiansan exert a therapeutic effect on SANFH and which active ingredient or ingredients exert a regulatory effect on autophagy in SANFH.…”

Section: Discussionmentioning

confidence: 99%

Gujiansan Ameliorates Avascular Necrosis of the Femoral Head by Regulating Autophagy via the HIF-1α/BNIP3 Pathway

Han

Chai

Zhang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. Clinically, the traditional Chinese medicine compound Gujiansan has been widely used in the treatment of steroid-induced avascular necrosis of the femoral head (SANFH). The present study aimed to investigate the mechanisms underlying the therapeutic effect of Gujiansan. Methods. A rat model of SANFH was established by the injection of dexamethasone (DEX) at a high dosage of 25 mg/kg/d. Then, Gujiansan was intragastrically administered for 2 weeks, 4 weeks, and 8 weeks, and histological examination of the femoral head was performed. The expression levels of related mRNAs and proteins were analyzed by qRT-PCR, Western blotting, and immunohistochemistry, and the levels of bone biochemical markers and cytokines were detected with ELISA kits. Results. Gujiansan administration ameliorated SANFH and induced the expression of hypoxia-inducible factor-1α (HIF-1α), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), LC3, and Beclin-1 in the rat model in a dose- and time-dependent manner, and Gujiansan promoted osteocalcin secretion at the femoral head. In addition, Gujiansan increased the levels of bone formation- and bone resorption-specific markers (osteocalcin (OC), bone-specific alkaline phosphatase (BAP), tartrate resistant acid phosphatase-5b (TRACP-5b), N-terminal telopeptides of type I collagen (NTX-1), and C-terminal telopeptide of type I collagen (CTX-1)) and decreased the levels of proinflammatory cytokines (TNF-α, IL-6, and CRP) in a dose- and time-dependent manner. Conclusions. Gujiansan accelerates the formation of a new bone, promotes the absorption of the damaged bone, inhibits the inflammatory response, induces autophagy of the femoral head via the HIF-1α/BNIP3 pathway, and ultimately ameliorates SANFH.

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Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications

Ayub,

Hasan,

Mahmud

et al. 2024

Med Oncol

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The neurofibromatosis type I gene promotes autophagy via mTORC1 signalling pathway to enhance new bone formation after fracture

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 25 publications

Autophagy is involved in neurofibromatosis type I gene‑modulated osteogenic differentiation in human bone mesenchymal stem cells

Autophagy is involved in neurofibromatosis type I gene‑modulated osteogenic differentiation in human bone mesenchymal stem cells

Gujiansan Ameliorates Avascular Necrosis of the Femoral Head by Regulating Autophagy via the HIF-1α/BNIP3 Pathway

Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications

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