Dataset Information

MTORC1 Activation in Osteoclasts Prevents Bone Loss in a Mouse Model of Osteoporosis.

ABSTRACT: The mechanistic/mammalian target of rapamycin (mTOR) is widely implicated in the pathogenesis of various diseases, including cancer, obesity, and cardiovascular disease. Bone homeostasis is maintained by the actions of bone-resorbing osteoclasts and bone-forming osteoblasts. An imbalance in the sophisticated regulation of osteoclasts and osteoblasts leads to the pathogenesis as well as etiology of certain metabolic bone diseases, including osteoporosis and osteopetrosis. Here, we identified mTOR complex 1 (mTORC1) as a pivotal mediator in the regulation of bone resorption and bone homeostasis under pathological conditions through its expression in osteoclasts. The activity of mTORC1, which was indicated by the phosphorylation level of its downstream target p70S6 kinase, was reduced during osteoclast differentiation, in accordance with the upregulation of Hamartin (encoded by tuberous sclerosis complex 1 [Tsc1]), a negative regulator of mTORC1. Receptor activator of nuclear factor-?B ligand (RANKL)-dependent osteoclastogenesis was impaired in Tsc1-deficient bone marrow macrophages. By contrast, osteoclastogenesis was markedly enhanced by Raptor deficiency but was unaffected by Rictor deficiency. The deletion of Tsc1 in osteoclast lineage cells in mice prevented bone resorption and bone loss in a RANKL-induced mouse model of osteoporosis, although neither bone volume nor osteoclastic parameter was markedly altered in these knockout mice under physiological conditions. Therefore, these findings suggest that mTORC1 is a key potential target for the treatment of bone diseases.

SUBMITTER: Hiraiwa M

PROVIDER: S-EPMC6585391 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

mTORC1 Activation in Osteoclasts Prevents Bone Loss in a Mouse Model of Osteoporosis.

Hiraiwa Manami M Ozaki Kakeru K Yamada Takanori T Iezaki Takashi T Park Gyujin G Fukasawa Kazuya K Horie Tetsuhiro T Kamada Hikari H Tokumura Kazuya K Motono Mei M Kaneda Katsuyuki K Hinoi Eiichi E

Frontiers in pharmacology 20190613

The mechanistic/mammalian target of rapamycin (mTOR) is widely implicated in the pathogenesis of various diseases, including cancer, obesity, and cardiovascular disease. Bone homeostasis is maintained by the actions of bone-resorbing osteoclasts and bone-forming osteoblasts. An imbalance in the sophisticated regulation of osteoclasts and osteoblasts leads to the pathogenesis as well as etiology of certain metabolic bone diseases, including osteoporosis and osteopetrosis. Here, we identified mTOR ...[more]

PMID: 31263418

Similar Datasets

Project description:BackgroundOsteoporosis (OP), a systemic skeletal disease common in aged population, is an important public health problem worldwide. Animal models are important tools for understanding OP. In ovariectomy (OVX) or orchiectomy (ORX) OP models, lumbar vertebrae are often used for evaluating of the OP progression. However, unlike the bipeds, the lumbar vertebrae are not weight loading bones in quadruped animal, but the head-bearing cervical vertebrae take much higher stress. So, we compared the murine cervical vertebrae with lumbar vertebrae for OP assessment.MethodsOVX and ORX mouse models were established on C57BL/6J mice. Serum estradiol, testosterone and bone related biomarkers were verified. Bone quantity and quality were determined using micro computed tomography (micro-CT) analysis. Hard tissue sections were prepared, stained for histomorphological analyzing, and micro-indentation measured for bone mechanical property evaluation.ResultsIn OVX and ORX mice, serum estradiol or testosterone levels reduced, bone resorption level and related biomarkers elevated, indicated the successful generation of the OP models. In the early stage, the trabecular bone mineral density (BMD) of cervical vertebrae was already reduced 16.1% (OVX) and 21.7% (ORX) one-month post-gonadectomy, respectively; while this decline in the fifth lumbar vertebra were only 5% and 7.4%, respectively. Six months post-gonadectomy, the reduction of BMD in cervical vertebrae and the fifth lumbar vertebra were 31.2% & 36.1% and 28.5% & 30.7% respectively. In biomechanical aspects, cervical spines showed worse Vickers hardness (HV) and elastic modulus than lumbar spine in six-month OVX and ORX mice.ConclusionsWe provide a new OP early-stage evaluation mouse model based on the cervical spine. Through the radiographic, biological and biomechanical assessments, the mouse cervical spine is more suitable for bone remodeling evaluation in OP models than the conventional lumbar vertebrae, especially for early-stage OP study.

Project description:Periodontal disease (PD) is a prevalent inflammatory disease with the most severe consequence being the loss of the alveolar bone and teeth. We therefore aimed to evaluate the effects of telmisartan (TELM), an angiotensin II type 1 receptor (Agtr1) antagonist, on the PD-induced alveolar bone loss, in Wistar (W) and Spontaneous Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk, and 10 mg/kg TELM was concomitantly administered for 15 days. The hemimandibles were subjected to microtomography, ELISA was used for detecting tumor necrosis factor (TNF-?), interleukin-1? (IL-1?), interleukin-6 (IL-6), CXCL3, and CCL2, while qRT-PCR was used for analyzing expression of components of renin-angiotensin system (RAS) (Agt, Ace, Agt1r, Agt2r, Ace2, and Masr), and bone markers (Runx2, Osx, Catnb, Alp, Col1a1, Opn, Ocn, Bsp, Bmp2, Trap, Rank, Rankl, CtsK, Mmp-2, Mmp-9, and osteoclast-associated receptor (Oscar)). The SHR + PD group showed greater alveolar bone loss than the W + PD group, what was significantly inhibited by treatment with TELM, especially in the SHR group. Additionally, TELM reduced the production of TNF-?, IL-1?, and CXCL3 in the SHR group. The expression of Agt increased in the groups with PD, while Agtr2 reduced, and TELM reduced the expression of Agtr1 and increased the expression of Agtr2, in W and SHRs. PD did not induce major changes in the expression of bone formation markers, except for the expression of Alp, which decreased in the PD groups. The bone resorption markers expression, Mmp9, Ctsk, and Vtn, was higher in the SHR + PD group, compared to the respective control and W + PD group. However, TELM attenuated these changes and increased the expression of Runx2 and Alp. Our study suggested that TELM has a protective effect on the progression of PD, especially in hypertensive animals, as evaluated by the resorption of the lower alveolar bone. This can be partly explained by the modulation in the expression of Angiotensin II receptors (AT1R and AT2R), reduced production of inflammatory mediators, the reduced expression of resorption markers, and the increased expression of the bone formation markers.

Dataset Information

MTORC1 Activation in Osteoclasts Prevents Bone Loss in a Mouse Model of Osteoporosis.

Publications

mTORC1 Activation in Osteoclasts Prevents Bone Loss in a Mouse Model of Osteoporosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets