CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts

Greenblatt, Matthew B.; Park, Kwang Hwan; Oh, Han; Kim, Jung-Min; Shin, Dong Yeon; Lee, Jae Myun; Lee, Jin Woo; Singh, Anju; Lee, Ki young; Hu, Dorothy; Xiao, Changchun; Charles, Julia F.; Penninger, Josef; Lotinun, Sutada; Baron, Roland; Ghosh, Sankar; Shim, Jae Hyuck

doi:10.1084/jem.20150407

Cited by 63 publications

(55 citation statements)

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“…Raptor deletion in osteoclasts impaired bone resorption, which is important for bone modeling during bone development (3,24), which may disturb the normal developmental process and, ultimately, induce decreased body weight. This phenomenon was found in other mouse models too (25,26).…”

Section: Discussionsupporting

confidence: 67%

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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: Discussionsupporting

confidence: 67%

“…Cell Culture and Osteoclast Differentiation-For osteoclast differentiation analysis, 4-week-old mice were used to obtain BMMs from whole bone marrow following a method described previously (26,35). Briefly, bone marrow was washed out from the femora and tibiae and centrifuged at 500 ϫ g for 10 min.…”

Section: Mtorc1 Regulates Osteoclast Differentiationmentioning

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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“…Importantly, these results indicated that the overall conformation of the NOD2 protein is not compromised when fused to GAL4DBD and thus allows isolation of valid partners in Y2H. Several putative NIPs (PPP1R12C, LDOC1, ANKHD1, CHMP5 or IKBIP) were previously reported to be linked with the NF-κB signaling pathway, confirming their interest as potential candidates [30, 38–41]. Others were involved in cellular trafficking, protein sorting or cytoskeletal architecture (CHMP5, DOCK7, VIM, SDCCAG3, KRT15, DCTN1, and GOLGB1) [42–47] or as regulators of cell signaling (PPP2R3B, TRIM41) [48, 49].…”

Section: Resultssupporting

confidence: 57%

Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins

et al. 2016

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NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, inducing gene transcription and synthesis of proteins required to initiate a balanced immune response. Mutations in NOD2 have been associated with an increased risk of Crohn’s Disease (CD), a disabling inflammatory bowel disease (IBD). Because NOD2 signaling plays a key role in CD, it is important to further characterize the network of protein interacting with NOD2. Using yeast two hybrid (Y2H) screens, we identified new NOD2 interacting proteins (NIP). The primary interaction was confirmed by coimmunoprecipitation and/or bioluminescence resonance energy transfer (BRET) experiments for 11 of these proteins (ANKHD1, CHMP5, SDCCAG3, TRIM41, LDOC1, PPP1R12C, DOCK7, VIM, KRT15, PPP2R3B, and C10Orf67). These proteins are involved in diverse functions, including endosomal sorting complexes required for transport (ESCRT), cytoskeletal architecture and signaling regulation. Additionally, we show that the interaction of 8 NIPs is compromised with the 3 main CD associated NOD2 mutants (R702W, G908R and 1007fs). Furthermore, to determine whether these NOD2 protein partners could be encoded by IBD susceptibility genes, a transmission disequilibrium test (TDT) was performed on 101 single nucleotide polymorphisms (SNPs) and the main corresponding haplotypes in genes coding for 15 NIPs using a set of 343 IBD families with 556 patients. Overall this work did not increase the number of IBD susceptibility genes but extends the NOD2 protein interaction network and suggests that NOD2 interactome and signaling depend upon the NOD2 mutation profile in CD.

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“…A very recent study of mice with an osteoclast-driven deletion of the NF-κB inhibitor CHMP5 has suggested the phenotype of exuberant BPagetic^periosteal remodelling in these mice results from an interaction of ephrinB2 in osteoclasts with EphB4 in osteoblasts [63]. In this work, high ephrinB2 mRNA levels were noted in cultured osteoclasts from these mice, likely a simple reflection of greater osteoclast numbers (also indicated by high mRNA levels of osteoclast markers).…”

Section: Ephrinb2 As a Mediator Of Pth And Igf-i Anabolic Actionssupporting

confidence: 57%

EphrinB2 Signalling in Osteoblast Differentiation, Bone Formation and Endochondral Ossification

Vrahnas

Sims

2015

Curr Mol Bio Rep

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The main functions of the osteoblast lineage (preosteoblasts, osteoblasts and osteocytes) are the production of bone matrix (osteoid), its mineralisation and the support of osteoclast formation. EphrinB2 and its contact-dependent receptor, EphB4, are stably expressed through all these stages of the lineage, and their expression of ephrinB2 is stimulated by parathyroid hormone (PTH), an agent that stimulates bone formation. Recent work has shown that the ephrinB2/EphB4 interaction is required for late stages of osteoblast differentiation and PTH action. Furthermore, specific deletion of ephrinB2 within the osteoblast lineage delays the process of bone mineralisation resulting in impaired bone strength and its response to anabolic PTH in both trabecular and periosteal bone. EphrinB2 and EphB4 are also expressed in growth plate chondrocytes, cells that also support osteoclast formation in development and fracture healing. This review will discuss the roles of forward and reverse signalling through EphB4 and ephrinB2, respectively, in bone growth and remodelling.

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CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts

Abstract: Greenblatt et al. show that deletion of CHMP5 in osteoclasts leads to increased bone resorption coupled with exuberant osteoblast activity, resembling an early onset form of human Paget’s Disease of Bone

Cited by 63 publications

References 58 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

Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins

EphrinB2 Signalling in Osteoblast Differentiation, Bone Formation and Endochondral Ossification

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