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-κB 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.
Highlights
The mechanistic/mammalian target of rapamycin is a kinase belonging to the phosphoinositide 3-kinase-related kinase (PIKK) family of protein kinase. mTOR is composed of two forms of distinct complexes designated as mTOR complex 1 and mTORC2 (Brown et al, 1994; Sabatini et al, 1994)
tartrate-resistant acid phosphatase (TRAP)-positive cells were increased in proportion to the culture period up to 4 days (Figure 1A). quantitative polymerase chain reaction (qPCR) analysis revealed that the expression of all osteoclastic marker genes, including cathepsin K (Ctsk), calcitonin receptor (Calcr), and acid phosphatase 5 (Acp5), was drastically increased during culture from 0 to 4 days (Figure 1B–D)
In accordance with the upregulation of Hamartin (Tsc1) expression, the phosphorylation level of p70S6 kinase (p70S6K), a downstream effector of mTOR complex 1 (mTORC1) signaling, was markedly abolished in osteoclasts 2 days after RANKL stimulation (Figure 1I), indicating a possible inverse correlation between Hamartin (Tsc1) expression and p70S6K phosphorylation during osteoclastogenesis. These results suggest that mTORC1 activity in vitro is reduced during osteoclast differentiation in a Hamartin (Tsc1)-dependent manner
Summary
The mechanistic/mammalian target of rapamycin (mTOR) is a kinase belonging to the phosphoinositide 3-kinase-related kinase (PIKK) family of protein kinase. mTOR is composed of two forms of distinct complexes designated as mTOR complex 1 (mTORC1) and mTORC2 (Brown et al, 1994; Sabatini et al, 1994). MTOR is composed of two forms of distinct complexes designated as mTOR complex 1 (mTORC1) and mTORC2 (Brown et al, 1994; Sabatini et al, 1994). It is widely implicated in various cellular functions such as growth, proliferation, survival, autophagy, differentiation, and cytoskeletal organization (Sabatini, 2017). The Rictor subunit belongs to mTORC2 (Jacinto et al, 2004). Global deletion of mTOR, Raptor, and Rictor results in embryonic lethality, cell-specific deletion strategies show that mTOR is implicated in the pathogenesis of various diseases, including cancer, obesity, and cardiovascular disease (Murakami et al, 2004; Guertin et al, 2006; Shiota et al, 2006)
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