Mammalian target of rapamycin as a therapeutic target in osteoporosis

Shen, Gengyang; Ren, Hui; Qiu, Ting; Zhang, Zhida; Zhao, Wenhua; Yu, Xiang; Huang, Jinjing; Tang, Jingjing; Liang, De; Yao, Zhensong; Yang, Zhidong; Jiang, Xiaobing

doi:10.1002/jcp.26161

Cited by 30 publications

(39 citation statements)

References 178 publications

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“…The increased levels of mTOR in our patient group may be due to increased protein synthesis secondary to fracture and trauma. In summary, the current literature agrees on the vital role of mTOR signaling for bone hemostasis [21].…”

Section: Discussionsupporting

confidence: 55%

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Does the mammalian target of rapamycin and sestrin 1 protein signaling have a role in bone fracture healing?

2019

Turk J Med Sci

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Background/aim: Fracture healing is a complex physiological process that involves a well-orchestrated series of biological events. The mammalian target of rapamycin (mTOR) and sestrin 1 (SESN 1) play a central role in cell metabolism, proliferation, and survival. The aim of our study is to present serum mTOR and SESN 1 levels by comparing patients with or without bone fractures. It is also a guide for further research on the roles of these proteins in fracture healing. Materials and methods: A total of 34 patients (10 females, 24 males) with bone fractures and 32 controls (10 females, 22 males) participated in this study. After collecting serum venous blood samples, the quantitative sandwich ELISA technique was used for the determination of serum mTOR and SESN 1 levels. Results: The mean serum mTOR level was significantly higher in the fracture group compared to the control group (P = 0.001). However, SESN 1 levels did not significantly differ between groups (P = 0.913). Conclusion: We found that serum mTOR levels increased on the first day after fracture compared to the control group. However, we obtained no significant difference between groups in terms of SESN 1 levels. This study may guide further clinical studies investigating the potential role of mTOR signaling in the bone healing process.

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Section: Discussionsupporting

confidence: 55%

“…On the other hand, there is still debate about the effect of mTOR in osteogenesis. The negative and positive effects of mTOR inhibition on osteogenesis were also reported [21,22]. Interestingly, the activation of mTOR signaling has also been found to promote osteoblast differentiation [21].…”

Section: Discussionmentioning

confidence: 93%

Does the mammalian target of rapamycin and sestrin 1 protein signaling have a role in bone fracture healing?

2019

Turk J Med Sci

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“…Functions of mTORC2 are less well studied and include organization of the actin cytoskeleton 26 , control of ion transport 27 , and anti-apoptotic properties via stimulation of the AKT-FOXO pathway 28 . Direct involvement of specific branches of the mTOR signaling network in regulation of mammalian life-span 29 , cellular senescence 25,30 , and vascular smooth muscle and osteoblast differentiation 5,6,31,32 opens a perspective for therapeutic mTOR targeting in aging-related pathologies of the bone-vascular axis. The macrolide Rapamycin (Rapa) is a complex modulator of mTOR signaling since it effectively blocks most but not all mTORC1 functions 21 without inhibitory effects on mTORC2, aside from a few exceptions 33 .…”

mentioning

confidence: 99%

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Schaub

Gürgen

Maus

et al. 2019

Sci Rep

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Vascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC). Deregulated MSC differentiation and maladaptive cell fate programs associated with age and metabolic diseases may exacerbate arteriosclerosis due to excessive transformation to osteoblast-like calcifying cells. Targeting mTOR, a central controller of differentiation and cell fates, could offer novel therapeutic perspectives. In a cell culture model for osteoblastic differentiation of pluripotent human MSC we found distinct roles for mTORC1 and mTORC2 in the regulation of differentiation towards calcifying osteoblasts via cell fate programs in a temporally-controlled sequence. Activation of mTORC1 with induction of cellular senescence and apoptosis were hallmarks of transition to a calcifying phenotype. Inhibition of mTORC1 with Rapamycin elicited reciprocal activation of mTORC2, enhanced autophagy and recruited anti-apoptotic signals, conferring protection from calcification. Pharmacologic and genetic negative interference with mTORC2 function or autophagy both abolished regenerative programs but induced cellular senescence, apoptosis, and calcification. Overexpression of the mTORC2 constituent rictor revealed that enhanced mTORC2 signaling without altered mTORC1 function was sufficient to inhibit calcification. Studies in mice reproduced the in vitro effects of mTOR modulation with Rapamycin on cell fates in vascular cells in vivo. Amplification of mTORC2 signaling promotes protective cell fates including autophagy to counteract osteoblast differentiation and calcification of MSC, representing a novel mTORC2 function. Regenerative approaches aimed at modulating mTOR network activation patterns hold promise for delaying age-related vascular diseases and treatment of accelerated arteriosclerosis in chronic metabolic conditions.

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“…By contrast, ALA, ω‐7 LCMUFAs and MCFAs could inhibit NF‐κB cascade, and repression of NF‐κB cascade attenuates osteoclastogenesis by enhancing both cell death and differentiation . Moreover, PI3K/mTOR pathway could be downregulated by EPA or LXA 4 but upregulated by PA and thus involved in BMMSC differentiation, osteoblast function and osteocyte formation during bone metabolism …”

Section: Signalling Pathyways Involved In Fatty Acids‐modulated Bone mentioning

confidence: 98%

Therapeutic potentials and modulatory mechanisms of fatty acids in bone

et al. 2019

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Bone metabolism is a lifelong process that includes bone formation and resorption. Osteoblasts and osteoclasts are the predominant cell types associated with bone metabolism, which is facilitated by other cells such as bone marrow mesenchymal stem cells (BMMSCs), osteocytes and chondrocytes. As an important component in our daily diet, fatty acids are mainly categorized as long‐chain fatty acids including polyunsaturated fatty acids (LCPUFAs), monounsaturated fatty acids (LCMUFAs), saturated fatty acids (LCSFAs), medium‐/short‐chain fatty acids (MCFAs/SCFAs) as well as their metabolites. Fatty acids are closely associated with bone metabolism and associated bone disorders. In this review, we summarized the important roles and potential therapeutic implications of fatty acids in multiple bone disorders, reviewed the diverse range of critical effects displayed by fatty acids on bone metabolism, and elucidated their modulatory roles and mechanisms on specific bone cell types. The evidence supporting close implications of fatty acids in bone metabolism and disorders suggests fatty acids as potential therapeutic and nutritional agents for the treatment and prevention of metabolic bone diseases.

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Mammalian target of rapamycin as a therapeutic target in osteoporosis

Cited by 30 publications

References 178 publications

Does the mammalian target of rapamycin and sestrin 1 protein signaling have a role in bone fracture healing?

Does the mammalian target of rapamycin and sestrin 1 protein signaling have a role in bone fracture healing?

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Therapeutic potentials and modulatory mechanisms of fatty acids in bone

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