Association of Bone Loss with the Upregulation of Survival-Related Genes and Concomitant Downregulation of Mammalian Target of Rapamycin and Osteoblast Differentiation-Related Genes in the Peripheral Blood of Late Postmenopausal Osteoporotic Women

Tchetina, Elena V.; Maslova, K.; Krylov, M. Yu.; Myakotkin, Valery A.

doi:10.1155/2015/802694

Cited by 7 publications

(5 citation statements)

References 56 publications

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“…This became apparent in our other studies of a significant downregulation of mTOR gene expression in the blood of the postmenopausal osteoporotic patients ([62], Tchetina et al, paper in preparation).…”

Section: Discussionmentioning

confidence: 78%

Differences in Mammalian Target of Rapamycin Gene Expression in the Peripheral Blood and Articular Cartilages of Osteoarthritic Patients and Disease Activity

et al. 2013

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The gene expression of mTOR, autophagy-related ULK1, caspase 3, CDK-inhibitor p21, and TNF α was measured in the peripheral blood of osteoarthritic (OA) patients at different stages of the disease aiming to establish a gene expression profile that might indicate the activity of the disease and joint destruction. Whole blood of 65 OA outpatients, 27 end-stage OA patients, 27 healthy volunteers, and knee articular cartilages of 28 end-stage OA patients and 26 healthy subjects were examined. OA outpatients were subjected to clinical testing, ultrasonography, and radiographic and WOMAC scoring. Protein levels of p70-S6K, p21, and caspase 3 were quantified by ELISA. Gene expression was measured using real-time RT-PCR. Upregulation of mTOR gene expression was observed in PBMCs of 42 OA outpatients (“High mTOR expression subset”) and in PBMCs and articular cartilages of all end-stage OA patients. A positive correlation between mTOR gene expression in PBMCs and cartilage was observed in the end-stage OA patients. 23 OA outpatients in the “Low mTOR expression subset” exhibited significantly lower mTOR gene expression in PBMCs compared to healthy controls. These “Low mTOR” subset subjects experienced significantly more pain upon walking, and standing and increased total joint stiffness versus “High mTOR” subset, while the latter more often exhibited synovitis. The protein concentrations of p70-S6K, p21, and caspase 3 in PBMCs were significantly lower in the “Low” subset versus “High” subset and end-stage subjects. Increases in the expression of mTOR in PBMCs of OA patients are related to disease activity, being associated with synovitis more than with pain.

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Section: Discussionmentioning

confidence: 78%

Differences in Mammalian Target of Rapamycin Gene Expression in the Peripheral Blood and Articular Cartilages of Osteoarthritic Patients and Disease Activity

et al. 2013

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“…7 ), a previous pharmacological study has also shown that rapamycin led to increased bone remodeling and bone loss in healthy male rats 58 . Clinically, it has been observed that in osteoporotic women with elevated osteoclast activity and bone resorption, mTOR expression was lower by three-fold in their peripheral blood cells, which include circulating osteoclast precursors 59 . Sirolimus has been shown to increase bone resorptive marker in renal transplant patients, leading to high bone turnover osteopenia 60 .…”

Section: Discussionmentioning

confidence: 99%

mTORC1 impedes osteoclast differentiation via calcineurin and NFATc1

Huynh

Wan

2018

Commun Biol

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Rapamycins are immunosuppressant and anti-cancer drugs that inhibit the kinase mTOR. Clinically, they often cause bone pain, bone necrosis, and high bone turnover, yet the mechanisms are unclear. Here we show that mTORC1 activity is high in osteoclast precursors but downregulated upon RANKL treatment. Loss-of-function genetic models reveal that while early Raptor deletion in hematopoietic stem cells blunts osteoclastogenesis due to compromised proliferation/survival, late Raptor deletion in osteoclast precursors instead augments osteoclastogenesis. Gain-of-function genetic models by TSC1 deletion in HSCs or osteoclast precursors cause constitutive mTORC1 activation, impairing osteoclastogenesis. Pharmacologically, rapamycin treatment at low but clinically relevant doses exacerbates osteoclast differentiation and bone resorption, leading to bone loss. Mechanistically, RANKL inactivates mTORC1 via calcineurin-mediated mTORC1 dephosphorylation, consequently activating NFATc1 by reducing mTORC1-mediated NFATc1 phosphorylation. These findings uncover biphasic roles of mTORC1 in osteoclastogenesis, dosage-dependent effects of rapamycin on bone, and a previously unrecognized calcineurin–mTORC1–NFATc1 phosphorylation-regulatory signaling cascade.

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“…Recently, anticancer synergy with the use of mTOR signaling inhibitors have been postulated in osteosarcoma treatment, suggesting that mTOR inhibition may also have a positive impact on bone (Moriceau et al, ). More importantly, preclinical studies have revealed that mTOR signaling is associated with bone loss (Spencer, Utting, Etheridge, Arnett, & Genever, ; Tchetina, Maslova, Krylov, & Myakotkin, ). However, more basic and clinical studies in elucidating the role of mTOR signaling in osteoporosis therapy are still required.…”

Section: Implications Of Mtor Signaling In Osteoporosismentioning

confidence: 99%

Mammalian target of rapamycin as a therapeutic target in osteoporosis

Shen

Ren²,

Qiu

et al. 2017

Journal Cellular Physiology

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The mechanistic target of rapamycin (mTOR) plays a key role in sensing and integrating large amounts of environmental cues to regulate organismal growth, homeostasis, and many major cellular processes. Recently, mounting evidences highlight its roles in regulating bone homeostasis, which sheds light on the pathogenesis of osteoporosis. The activation/inhibition of mTOR signaling is reported to positively/negatively regulate bone marrow mesenchymal stem cells (BMSCs)/osteoblasts-mediated bone formation, adipogenic differentiation, osteocytes homeostasis, and osteoclasts-mediated bone resorption, which result in the changes of bone homeostasis, thereby resulting in or protect against osteoporosis. Given the likely importance of mTOR signaling in the pathogenesis of osteoporosis, here we discuss the detailed mechanisms in mTOR machinery and its association with osteoporosis therapy.

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Association of Bone Loss with the Upregulation of Survival-Related Genes and Concomitant Downregulation of Mammalian Target of Rapamycin and Osteoblast Differentiation-Related Genes in the Peripheral Blood of Late Postmenopausal Osteoporotic Women

Cited by 7 publications

References 56 publications

Differences in Mammalian Target of Rapamycin Gene Expression in the Peripheral Blood and Articular Cartilages of Osteoarthritic Patients and Disease Activity

Differences in Mammalian Target of Rapamycin Gene Expression in the Peripheral Blood and Articular Cartilages of Osteoarthritic Patients and Disease Activity

mTORC1 impedes osteoclast differentiation via calcineurin and NFATc1

Mammalian target of rapamycin as a therapeutic target in osteoporosis

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