mTOR inhibition rescues osteopenia in mice with systemic sclerosis

Chen, Chider; Akiyama, Kentaro; Wang, Dandan; Xu, Xiao; Li, Bei; Moshaverinia, Alireza; Brombacher, Frank; Sun, Lingyun; Shi, Songtao

doi:10.1083/jcb.2081oia234

Cited by 20 publications

(31 citation statements)

References 29 publications

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“…Histological analysis showed that deletion of Raptor in osteoclasts did not influence osteoblast activity, as indicated by consistent MAR and BFR in Rap Ctsk and WT mice. These results excluded the possibility that deletion of Raptor in osteoclasts promoted bone formation and increased bone mass indirectly through actions on osteoblasts, although mTORC1 may play an important but as yet undetermined role in osteoblasts (15,16,18). Further, reduced osteoclast activity, determined by decreased TRAP activity and Ctsk expression in Rap Ctsk mice, was the chief cause of the increased bone mass.…”

Section: Discussionmentioning

confidence: 74%

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Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice

Dai

Xie²,

Han³

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangMammalian target of rapamycin complex 1 (mTORC1) is involved in anabolic metabolism in both osteoblasts and chondrocytes, but the role of mTORC1 in osteoclast biology in vivo remains to be elucidated. In this study, we showed that deletion of regulatory-associated protein of mTOR (Raptor) in osteoclasts led to an increase in bone mass with decreased bone resorption. Raptordeficient bone marrow-derived macrophages exhibited lower mTORC1-S6K1 signaling and retarded osteoclast differentiation, as determined by the number of osteoclasts, tartrate-resistant acid phosphatase activity, and expression of osteoclast-specific genes. Enforced expression of constitutively active S6K1 rescued the impaired osteoclast differentiation in Raptor-deficient bone marrow-derived macrophages. Furthermore, pharmacological inhibition of mTORC1 signaling by rapamycin could also inhibit osteoclast differentiation and osteoclast-specific gene expression. Taken together, our findings demonstrate that mTORC1 plays a key role in the network of catabolic bone resorption in osteoclasts and may serve as a potential pharmacological target for the regulation of osteoclast activity in bone metabolic disorders.Bone is a rigid yet metabolically active organ that is molded, shaped, and repaired continuously (1). After bone is formed, bone undergoes a process known as remodeling by which bone is turned over throughout life (2). Bone remodeling acts as the predominant metabolic regulator of both the physical structure and physiological function of bone. Remodeling is a complex process involving osteoclasts, which are responsible for removing old mineralized matrix, and osteoblasts, which synthesize and secrete new bone matrix (1, 3). An imbalance in bone remodeling can induce perturbation of bone structure and function and potentially result in disease (1). In adults, most bone diseases, such as osteoporosis, rheumatoid arthritis, and periodontal disease, are the result of bone loss secondary to excess osteoclast activity (4). Prevention and treatment of these pathological disorders highlight the study of the underlying mechanisms by which osteoclasts differentiate from their precursors.Osteoclasts are tissue-specific giant multinucleated cells that differentiate from monocyte/macrophage precursor cells at or near the bone surface (1). It is known that the differentiation of osteoclasts is under the control of two important cytokines, receptor activator of nuclear factor B ligand (RANKL) 5 and M-CSF (3). RANKL and macrophage colony-stimulating factor (M-CSF) may activate a set of signaling pathways, including AKT and NF-B, that promote the differentiation, multinucleation, activation, and survival of osteoclasts (5). However, the * This work was supported in part by grants from the 973 Program from the Chinese Ministry of Science and Technology (2014CB964704 and 2015CB964503), the Science and Technology Commission of Shanghai (124119b0101), the National Natural Science Foundation of China (31371463, 81371121, and 81570950), Shan...

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Section: Discussionmentioning

confidence: 74%

“…In this study, we found that mTORC1 is a molecular node that is critical for osteoclast differentiation and bone metabolism. mTORC1 signaling has been reported to regulate bone anabolism in both osteoblasts and chondrocytes (12,(15)(16)(17)(18). However, evidence for the role of mTORC1 in osteoclast catabolism is limited.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice

Dai

Xie²,

Han³

et al. 2017

Journal of Biological Chemistry

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“…Simultaneously, rapamycin functions as a potent stimulator of osteoblastic differentiation of human embryonic stem cell (hESC), and it does so by inhibiting rapamycin‐sensitive mTOR signaling and promoting BMP/Smad signaling (Lee et al, ). Likewise, blockage of mTOR signaling by osteoblastic‐specific knockout or rapamycin treatment can rescue osteopenia phenotype in Fibrillin‐1 (Fbn1)‐deficient (Fbn1+/−) mice by improving osteoblastic differentiation and suppressing adipogenic differentiation of BMSCs (Chen et al, ). BEZ235, a newly developed dual PI3 K and mTOR inhibitor, has been reported to strongly promote osteoblastic differentiation in human MSCs by inhibiting PI3 K/mTOR signaling.…”

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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“…Age-related myocardial hypertrophy is known to be driven by increased protein synthesis; importantly, rapamycin prevents, and also reverses, myocardial hypertrophy in rodents (428), indicating that mTOR is involved in the process. Supported by recent work (64,71,72,442), another interesting possibility to explain the mechanim(s) involved in mammalian lifespan extension by mTORC1 inhibition is that mTORC1 can prevent tissue decay by ameliorating stem cell function.…”

Section: Mtor Sirtuins and Klotho: The Most Consistently Altered Tamentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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mTOR inhibition rescues osteopenia in mice with systemic sclerosis

Cited by 20 publications

References 29 publications

Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice

Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice

Mammalian target of rapamycin as a therapeutic target in osteoporosis

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

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