Editorial

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Open AccessEditorial

Editorial: Special Issue on “Molecular Mechanisms Regulating Osteoclastogenesis”

by Giacomina Brunetti, Giorgio Mori and Maria Felicia Faienza

Int. J. Mol. Sci. 2020, 21(20), 7643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207643 - 15 Oct 2020

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Abstract

Bone is an active tissue that remodels continuously throughout life [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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10 pages, 1857 KiB

Open AccessArticle

Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

by Jin-Young Lee, Da-Ae Kim, Eun-Young Kim, Eun-Ju Chang, So-Jeong Park and Beom-Jun Kim

Int. J. Mol. Sci. 2021, 22(9), 4717; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094717 - 29 Apr 2021

Cited by 11 | Viewed by 2049

Abstract

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on [...] Read more.

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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13 pages, 1383 KiB

Open AccessArticle

Shedding “LIGHT” on the Link between Bone and Fat in Obese Children and Adolescents

by Giacomina Brunetti, Maria Felicia Faienza, Laura Piacente, Giuseppina Storlino, Angela Oranger, Gabriele D'Amato, Gianpaolo De Filippo, Silvia Colucci and Maria Grano

Int. J. Mol. Sci. 2020, 21(13), 4739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134739 - 03 Jul 2020

Cited by 7 | Viewed by 2167

Abstract

Obesity may affect bone health, but literature reports are contradictory about the correlation of body mass index (BMI) and bone markers. LIGHT, one of the immunostimulatory cytokines regulating the homeostasis of bone and adipose tissue, could be involved in obesity. The study involved [...] Read more.

Obesity may affect bone health, but literature reports are contradictory about the correlation of body mass index (BMI) and bone markers. LIGHT, one of the immunostimulatory cytokines regulating the homeostasis of bone and adipose tissue, could be involved in obesity. The study involved 111 obese subjects (12.21 ± 3.71 years) and 45 controls. Patients underwent the evaluation of bone status by quantitative ultrasonography (QUS). LIGHT amounts were evaluated in sera by ELISA, whereas its expression on peripheral blood cells was evaluated by flow cytometry. Osteoclastogenesis was performed by culturing peripheral blood mononuclear cells (PBMCs) with or without anti-LIGHT antibodies. Obese patients showed significant high BMI-standard deviation score (SDS), weight-SDS, and Homeostatic model assessment for insulin resistance (HOMA-IR) that negatively correlated with the reduced Amplitude Dependent Speed of Sound (AD-SoS)-Z-score and Bone Transmission Time (BTT-Z)-score. They displayed significantly higher serum levels of LIGHT compared with controls (497.30 ± 363.45 pg/mL vs. 186.06 ± 101.41 pg/mL, p < 0.001). LIGHT expression on monocytes, CD3+-T-cells, and neutrophils was also higher in obese patients than in the controls. Finally, in PBMC cultures, the addition of anti-LIGHT antibodies induced a significant osteoclastogenesis inhibition. Our study highlighted the high serum levels of LIGHT in obese children and adolescents, and its relationship with both the grade of obesity and bone impairment. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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12 pages, 1938 KiB

Open AccessArticle

IL-35 and RANKL Synergistically Induce Osteoclastogenesis in RAW264 Mouse Monocytic Cells

by Yosuke Kamiya, Takeshi Kikuchi, Hisashi Goto, Iichiro Okabe, Yuhei Takayanagi, Yuki Suzuki, Noritaka Sawada, Teppei Okabe, Yuki Suzuki, Shun Kondo, Jun-ichiro Hayashi and Akio Mitani

Int. J. Mol. Sci. 2020, 21(6), 2069; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062069 - 18 Mar 2020

Cited by 10 | Viewed by 2827

Abstract

Interleukin (IL)-35 is an immunosuppressive cytokine mainly produced by regulatory T cells. IL-35 mediates immunological functions by suppressing the inflammatory immune response. However, the role of IL-35 in bone-destructive diseases remains unclear, especially in terms of osteoclastogenesis. Therefore, the current study investigated the [...] Read more.

Interleukin (IL)-35 is an immunosuppressive cytokine mainly produced by regulatory T cells. IL-35 mediates immunological functions by suppressing the inflammatory immune response. However, the role of IL-35 in bone-destructive diseases remains unclear, especially in terms of osteoclastogenesis. Therefore, the current study investigated the synergistic effect of IL-35 on osteoclastogenesis that is involved the pathogeneses of periodontitis and rheumatoid arthritis. Osteoclastic differentiation and osteoclastogenesis of RAW264 (RAW) cells induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) and IL-35 were evaluated by tartrate-resistant acid phosphate staining, hydroxyapatite resorption assays, and quantitative polymerase chain reaction. The effect of IL-35 on RANKL-stimulated signaling pathways was assessed by Western blot analysis. Costimulation of RAW cells by RANKL and IL-35 induced osteoclastogenesis significantly compared with stimulation by RANKL alone. Phosphorylations of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase tended to be increased by RANKL and IL-35 compared with RANKL or IL-35 alone. Additionally, the osteoclastogenesis induced by RANKL and IL-35 was suppressed by inhibition of ERK. In this study, IL-35 and RANKL induced osteoclastogenesis synergistically. Previous reports have shown that IL-35 suppresses the differentiation of osteoclasts. Therefore, IL-35 might play dual roles of destruction and protection in osteoclastogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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13 pages, 2880 KiB

Open AccessArticle

IL-33 Inhibits TNF-α-Induced Osteoclastogenesis and Bone Resorption

by Fumitoshi Ohori, Hideki Kitaura, Saika Ogawa, Wei-Ren Shen, Jiawei Qi, Takahiro Noguchi, Aseel Marahleh, Yasuhiko Nara, Adya Pramusita and Itaru Mizoguchi

Int. J. Mol. Sci. 2020, 21(3), 1130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031130 - 08 Feb 2020

Cited by 42 | Viewed by 3918

Abstract

Interleukin (IL)-33 is a member of the IL-1 family, which acts as an alarmin. Several studies suggested that IL-33 inhibited osteoclastogenesis and bone resorption. Tumor necrosis factor-α (TNF-α) is considered a direct inducer of osteoclastogenesis. However, there has been no report regarding the [...] Read more.

Interleukin (IL)-33 is a member of the IL-1 family, which acts as an alarmin. Several studies suggested that IL-33 inhibited osteoclastogenesis and bone resorption. Tumor necrosis factor-α (TNF-α) is considered a direct inducer of osteoclastogenesis. However, there has been no report regarding the effect of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. The objective of this study is to investigate the role of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. In an in vitro analysis of osteoclastogenesis, osteoclast precursors, which were derived from bone marrow cells, were treated with or without IL-33 in the presence of TNF-α. Tartrate-resistant acid phosphatase (TRAP) staining solution was used to assess osteoclast formation. In an in vivo analysis of mouse calvariae, TNF-α with or without IL-33 was subcutaneously administrated into the supracalvarial region of mice daily for 5 days. Histological sections were stained for TRAP, and osteoclast numbers were determined. Using micro-CT reconstruction images, the ratio of bone destruction area on the calvariae was evaluated. The number of TRAP-positive cells induced by TNF-α was significantly decreased with IL-33 in vitro and in vivo. Bone resorption was also reduced. IL-33 inhibited IκB phosphorylation and NF-κB nuclear translocation. These results suggest that IL-33 inhibited TNF-α-induced osteoclastogenesis and bone resorption. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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14 pages, 3142 KiB

Open AccessArticle

Inhibitory Effects of N-[2-(4-acetyl-1-piperazinyl) phenyl]-2-(2-chlorophenoxy) acetamide on Osteoclast Differentiation In Vitro via the Downregulation of TRAF6

by Zhihao Chen, Eunjin Cho, Jinkyung Lee, Sunwoo Lee and Tae-Hoon Lee

Int. J. Mol. Sci. 2019, 20(20), 5196; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205196 - 20 Oct 2019

Cited by 14 | Viewed by 2632

Abstract

Osteoclasts are poly-nuclear cells that resorb mineral components from old or damaged bone tissue. Primary mononuclear cells are activated by receptor activator of nuclear factor kappa-Β ligand (RANKL) and differentiate into large multinucleated cells. Dysregulation of osteoclast differentiation can lead to pathological bone [...] Read more.

Osteoclasts are poly-nuclear cells that resorb mineral components from old or damaged bone tissue. Primary mononuclear cells are activated by receptor activator of nuclear factor kappa-Β ligand (RANKL) and differentiate into large multinucleated cells. Dysregulation of osteoclast differentiation can lead to pathological bone loss and destruction. Many studies have focused on the development of new molecules to regulate RANKL-mediated signaling. In this study, N-[2-(4-acetyl-1-piperazinyl)phenyl]-2-(2-chlorophenoxy) acetamide (PPOA-N-Ac-2-Cl) led to a significant decrease in the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells in a dose-dependent manner, without inducing significant cytotoxicity. PPOA-N-Ac-2-Cl affected the expression of osteoclast-specific marker genes, such as TRAF6, c-fos, DC-STAMP, NFATc1, MMP9, CtsK, and TRAP (Acp5), during RANKL-mediated osteoclastogenesis. Moreover, PPOA-N-Ac-2-Cl significantly attenuated the protein levels of CtsK, a critical protease involved in bone resorption. Accordingly, bone resorption activity and F-actin ring formation decreased in the presence of PPOA-N-Ac-2-Cl. In conclusion, this study shows that PPOA-N-Ac-2-Cl acts as an inhibitor of osteoclast differentiation and may serve as a potential candidate agent for the treatment of osteoclast-related bone diseases by virtue of attenuating bone resorption. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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Review

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25 pages, 1586 KiB

Open AccessReview

by Hideki Kitaura, Aseel Marahleh, Fumitoshi Ohori, Takahiro Noguchi, Wei-Ren Shen, Jiawei Qi, Yasuhiko Nara, Adya Pramusita, Ria Kinjo and Itaru Mizoguchi

Int. J. Mol. Sci. 2020, 21(14), 5169; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145169 - 21 Jul 2020

Cited by 161 | Viewed by 10922

Abstract

The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type. Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone [...] Read more.

The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type. Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone resorption. In osteolytic diseases such as rheumatoid arthritis, periodontitis, and osteoporosis, the balance is lost and changes in favor of bone resorption. Therefore, it is vital to elucidate the mechanisms of osteoclast formation and bone resorption. It has been reported that osteocytes express Receptor activator of nuclear factor κΒ ligand (RANKL), an essential factor for osteoclast formation. RANKL secreted by osteocytes is the most important factor for physiologically supported osteoclast formation in the developing skeleton and in pathological bone resorption such as experimental periodontal bone loss. TNF-α directly enhances RANKL expression in osteocytes and promotes osteoclast formation. Moreover, TNF-α enhances sclerostin expression in osteocytes, which also increases osteoclast formation. These findings suggest that osteocyte-related cytokines act directly to enhance osteoclast formation and bone resorption. In this review, we outline the most recent knowledge concerning bone resorption-related cytokines and discuss the osteocyte as the master regulator of bone resorption and effector in osteoclast formation. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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29 pages, 4535 KiB

Open AccessReview

Mechanisms Underlying Bone Loss Associated with Gut Inflammation

by Ke Ke, Manoj Arra and Yousef Abu-Amer

Int. J. Mol. Sci. 2019, 20(24), 6323; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246323 - 15 Dec 2019

Cited by 14 | Viewed by 4946

Abstract

Patients with gastrointestinal diseases frequently suffer from skeletal abnormality, characterized by reduced bone mineral density, increased fracture risk, and/or joint inflammation. This pathological process is characterized by altered immune cell activity and elevated inflammatory cytokines in the bone marrow microenvironment due to disrupted [...] Read more.

Patients with gastrointestinal diseases frequently suffer from skeletal abnormality, characterized by reduced bone mineral density, increased fracture risk, and/or joint inflammation. This pathological process is characterized by altered immune cell activity and elevated inflammatory cytokines in the bone marrow microenvironment due to disrupted gut immune response. Gastrointestinal disease is recognized as an immune malfunction driven by multiple factors, including cytokines and signaling molecules. However, the mechanism by which intestinal inflammation magnified by gut-residing actors stimulates bone loss remains to be elucidated. In this article, we discuss the main risk factors potentially contributing to intestinal disease-associated bone loss, and summarize current animal models, illustrating gut-bone axis to bridge the gap between intestinal inflammation and skeletal disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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