mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation

Yan, Bo; Zhang, Zhongmin; Jin, Dadi; Cai, Chen; Jia, Chunhong; Li, Wen; Wang, Ting; Li, Shengfa; Zhang, Haiyan; Huang, Bin; Lai, Pinglin; Wang, Hua; Liu, Anling; Zeng, Chun; Cai, Daozhang; Jiang, Yu; Bai, Xia

doi:10.1038/ncomms11151

Cited by 102 publications

(123 citation statements)

References 53 publications

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“…In our 2D and 3DCI assays of Activin-A-stimulated FOP-iMSCs, mTOR inhibitors clearly decreased both GAG/DNA and the expression levels of chondrogenesis markers (Figure 3 and Supplemental Figure 4), indicating that mTOR inhibition did not simply affect proliferation or survival, but modified the differentiation of chondrocytes, since data from both assays were corrected by the number of cells (DNA amount) and the expression of a housekeeping gene (β-actin), respectively. On the other hand, another report showed that hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes blocked chondrocyte differentiation (72). These reports suggest that a well-coordinated, but complicated, regulation of mTORC1 activity is crucial for chondrocyte differentiation during development.…”

Section: Discussionmentioning

confidence: 97%

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

Hino

Horigome

Nishio³

et al. 2017

Journal of Clinical Investigation

140

164

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Section: Discussionmentioning

confidence: 97%

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

Hino

Horigome

Nishio³

et al. 2017

Journal of Clinical Investigation

140

164

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“…A recent study suggested that mTOR signaling in B cells could indirectly regulate osteoclast formation through regulation of ␤-catenin and RANKL/osteoprotegerin (OPG) (9) and another study showed everolimus can restrain the paracrine pro-osteoclast activity of breast cancer cells (19). mTOR signaling may also play an important role in osteoclast survival and differentiation of osteoclast progenitors (8,20,21). In this study, we found that mTORC1 regulates osteoclast differentiation and formation in a cell-autonomous manner with a conditional knockout mice model.…”

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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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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“…Disruption of mTORC1 signaling through the biallelic deletion of Raptor in chondrocytes inhibits chondrocyte functions, leading to impaired skeletal growth (37). In addition, genetic inactivation of the mTORC1 inhibitor TSC1 gene in chondrocytes causes chondrodysplasia in mice (38), suggesting that the fine-tuning of mTORC1 signaling is essential for longitudinal bone growth.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

Bartolomeo

Cinque

Leonibus

et al. 2017

Journal of Clinical Investigation

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The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs

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mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation

Cited by 102 publications

References 53 publications

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

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

mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

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