Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts

Kneissel, Michaela; Luong-Nguyen, Ngoc-Hong; Baptist, Myma; Cortesi, Reto; Zumstein-Mecker, Sabine; Κοσσίδα, Σοφία; O’Reilly, Terry; Lane, Heidi A.; Šuša, Mira

doi:10.1016/j.bone.2004.07.013

Cited by 149 publications

(107 citation statements)

References 34 publications

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“…On the one hand, rapamycin treatment yielded a significant reduction in the number of TRAP-positive cells at the metaphyseal front. This agrees with the decreased number of osteoclasts and osteoclast activity recently reported in adult rats receiving everolimus [31]. On the other hand, the arrangement of capillary sprouts among slender longitudinal septa in the primary spongiosa was clearly distorted after rapamycin treatment, with many vascular channels running parallel to the chondro-osseous junction.…”

Section: Discussionsupporting

confidence: 90%

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

et al. 2007

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Rapamycin is a potent immunosuppressant with antitumoral properties widely used in the field of renal transplantation. To test the hypothesis that the antiproliferative and antiangiogenic activity of rapamycin interferes with the normal structure and function of growth plate and impairs longitudinal growth, 4-week-old male rats (n=10/ group) receiving 2 mg/kg per day of intraperitoneal rapamycin (RAPA) or vehicle (C) for 14 days were compared. Rapamycin markedly decreased bone longitudinal growth rate (94±3 vs. 182±3 μm/day), body weight gain (60.2±1.4 vs. 113.6±1.9 g), food intake (227.8±2.6 vs. 287.5±3.4 g), and food efficiency (0.26±0.00 vs. 0.40± 0.01 g/g). Signs of altered cartilage formation such as reduced chondrocyte proliferation (bromodeoxiuridine-labeled cells 32.9±1.4 vs. 45.2±1.1%), disturbed maturation and hypertrophy (height of terminal chondrocytes 26±0 vs. 29±0 μm), and decreased cartilage resorption (18.7±0.5 vs. 31.0±0.8 tartrate-resistant phosphatase alkaline reactive cells per 100 terminal chondrocytes), together with morphological evidence of altered vascular invasion, were seen in the growth plate of RAPA animals. This study indicates that rapamycin can severely impair body growth in fastgrowing rats and distort growth-plate structure and dynamics. These undesirable effects must be kept in mind when rapamycin is administered to children.

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Section: Discussionsupporting

confidence: 90%

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

et al. 2007

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“…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. This is consistent with the observation that an mTOR inhibitor could rescue bone loss partly through suppression of bone resorption in ovariectomized rats (11) and protect bone health in postmenopausal women with breast cancer (12,22). Meanwhile, Xian et al (23) reported that rapamycin decreased bone mass in WT mice, which may be caused by the fact that the effects of rapamycin on osteoblasts masked those on osteoclasts.…”

Section: Discussionsupporting

confidence: 82%

“…Everolimus, a derivative of rapamycin, has been reported to have beneficial effects on bone when used as an anticancer ancillary in postmenopausal women with breast cancer (11,12). Although the underlying mechanism of the protective effects of everolimus on bone is still unclear, osteoclasts may be its target, considering that blocking of mTORC1 in osteoblasts results in decreased bone mass in mice (4).…”

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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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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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“…26,27 Interestingly, the expression of cathepsin-k in osteoclasts is regulated by MITF 28 and is significantly reduced by mTOR inhibitors. 29 MITF and cathepsin-k are also expressed in melanocytes and melanomas, 30 where mTOR is also activated and critical for the regulation of apoptosis. 31,32 All these data taken together, it is possible to hypothesize that MITF and cathepsink are in fact under the control of mTOR pathway, and could serve as further molecular markers for evaluating mTOR pathway activation in lymphangioleiomyomatosis.…”

Section: Recently Kenerson Et Almentioning

confidence: 99%

Cathepsin-k expression in pulmonary lymphangioleiomyomatosis

Chilosi

Pea²,

Martignoni

et al. 2009

Modern Pathology

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Lymphangioleiomyomatosis is a rare and progressive lung cystic disease, caused by the infiltration of lung parenchyma by mesenchymal cells characterized by co-expression of contractile proteins and melanocytic markers. The pathogenesis of lymphangioleiomyomatosis is determined by mutations affecting tuberous sclerosis complex (TSC) genes, with eventual deregulation of the Rheb/mTOR/p70S6K pathway, and the potential therapeutic activity of mTOR inhibitors is currently under investigation. To better understand the molecular mechanisms involved in the pathogenesis of lymphangioleiomyomatosis, we investigated the expression of cathepsin-k (a papain-like cysteine protease with high matrix-degrading activity). The rationale of this choice was based on the recent demonstration that mTOR inhibitors can regulate major functional activities of osteoclasts, including the expression of cathepsin-k. The immunohistochemical study included 12 cases of lymphangioleiomyomatosis. Twelve angiomyolipomas and several lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema) were investigated as controls. In all lymphangioleiomyomatosis cases, strong cathepsin-k immunoreactivity was demonstrated, restricted to lymphangioleiomyomatosis cells. Similar expression levels were observed in renal angiomyolipomas. These observations extend the knowledge regarding the immunophenotypic profile of lymphangioleiomyomatosis cells, and provide a useful new marker for diagnosis in difficult cases (eg, in small transbronchial biopsies). The strong expression of such a potent papain-like cysteine protease in lymphangioleiomyomatosis cells can significantly contribute to the progressive remodelling of lung parenchyma observed in this deadly disease, with eventual formation of lung cysts. It is possible to speculate that mTOR inhibitors may exert part of their action by limiting the destructive remodelling of lung structure.

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Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts

Cited by 149 publications

References 34 publications

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

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

Cathepsin-k expression in pulmonary lymphangioleiomyomatosis

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