Homer proteins modulate RANKL-induced NFATc1 signaling in osteoclast differentiation and bone metabolism

2016 ◽  
Author(s):  
Yu-Mi Yang ◽  
Aran Son ◽  
Jung Yun Kang ◽  
Dong Min Shin
Keyword(s):  
Bone Metabolism ◽  
Osteoclast Differentiation ◽  
Homer Proteins

scholarly journals Homer2 and Homer3 modulate RANKL-induced NFATc1 signaling in osteoclastogenesis and bone metabolism

2019 ◽  
Vol 242 (3) ◽  
pp. 241-249 ◽  
Author(s):  
Aran Son ◽  
Namju Kang ◽  
Sue Young Oh ◽  
Ki Woo Kim ◽  
Shmuel Muallem ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Nuclear Translocation ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Signaling Proteins ◽  
Nuclear Factor ◽  
Bone Homeostasis ◽  
Activated T Cells ◽  
Multinucleated Cells ◽  
Homer Proteins

The receptor activator of nuclear factor-kappa B ligand (RANKL) induces osteoclastogenesis by induction of Ca2+ oscillation, calcineurin activation and translocation into the nucleus of nuclear factor of activated T cells type c1 (NFATc1). Homer proteins are scaffold proteins. They regulate Ca2+ signaling by modulating the activity of multiple Ca2+ signaling proteins. Homers 2 and 3, but not Homer1, also independently affect the interaction between NFATc1 and calcineurin. However, to date, whether and how the Homers are involved in osteoclastogenesis remains unknown. In the present study, we investigated Homer2 and Homer3 roles in Ca2+ signaling and NFATc1 function during osteoclast differentiation. Deletion of Homer2/Homer3 (Homer2/3) markedly decreased the bone density of the tibia, resulting in bone erosion. RANKL-induced osteoclast differentiation is greatly facilitated in Homer2/3 DKO bone marrow-derived monocytes/macrophages (BMMs) due to increased NFATc1 expression and nuclear translocation. However, these findings did not alter RANKL-induced Ca2+ oscillations. Of note, RANKL treatment inhibited Homer proteins interaction with NFATc1, but it was restored by cyclosporine A treatment to inhibit calcineurin. Finally, RANKL treatment of Homer2/3 DKO BMMs significantly increased the formation of multinucleated cells. These findings suggest a novel potent mode of bone homeostasis regulation through osteoclasts differentiation. Specifically, we found that Homer2 and Homer3 regulate NFATc1 function through its interaction with calcineurin to regulate RANKL-induced osteoclastogenesis and bone metabolism.

scholarly journals Influence of activating Fcgamma receptors on osteoclast differentiation and bone metabolism

2012 ◽  
Vol 10 (S3) ◽  
Author(s):  
Michaela Seeling ◽  
Jan Peter Tuckermann ◽  
Jean Pierre David ◽  
Georg Schett ◽  
Falk Nimmerjahn
Keyword(s):  
Bone Metabolism ◽  
Osteoclast Differentiation ◽  
Fcgamma Receptors

scholarly journals Deletion of Gb3 Synthase in Mice Resulted in the Attenuation of Bone Formation via Decrease in Osteoblasts

2019 ◽  
Vol 20 (18) ◽  
pp. 4619 ◽  
Author(s):  
Kazunori Hamamura ◽  
Kosuke Hamajima ◽  
Shoyoku Yo ◽  
Yoshitaka Mishima ◽  
Koichi Furukawa ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Bone Metabolism ◽  
Osteoclast Differentiation ◽  
Mrna Levels ◽  
Bone Surface ◽  
Micro Computed Tomography ◽  
Differentiation Markers ◽  
Double Labeling ◽  
Globo Series

Glycosphingolipids are known to play a role in developing and maintaining the integrity of various organs and tissues. Among glycosphingolipids, there are several reports on the involvement of gangliosides in bone metabolism. However, there have been no reports on the presence or absence of expression of globo-series glycosphingolipids in osteoblasts and osteoclasts, and the involvement of their glycosphingolipids in bone metabolism. In the present study, we investigated the presence or absence of globo-series glycosphingolipids such as Gb3 (globotriaosylceramide), Gb4 (globoside), and Gb5 (galactosyl globoside) in osteoblasts and osteoclasts, and the effects of genetic deletion of Gb3 synthase, which initiates the synthesis of globo-series glycosphingolipids on bone metabolism. Among Gb3, Gb4, and Gb5, only Gb4 was expressed in osteoblasts. However, these glycosphingolipids were not expressed in pre-osteoclasts and osteoclasts. Three-dimensional micro-computed tomography (3D-μCT) analysis revealed that femoral cancellous bone mass in Gb3 synthase-knockout (Gb3S KO) mice was lower than that in wild type (WT) mice. Calcein double labeling also revealed that bone formation in Gb3S KO mice was significantly lower than that in WT mice. Consistent with these results, the deficiency of Gb3 synthase in mice decreased the number of osteoblasts on the bone surface, and suppressed mRNA levels of osteogenic differentiation markers. On the other hand, osteoclast numbers on the bone surface and mRNA levels of osteoclast differentiation markers in Gb3S KO mice did not differ from WT mice. This study demonstrated that deletion of Gb3 synthase in mice decreases bone mass via attenuation of bone formation.

scholarly journals The phytochemical plumbagin reciprocally modulates osteoblasts and osteoclasts

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Avinash M. Yadav ◽  
Manali M. Bagade ◽  
Soni Ghumnani ◽  
Sujatha Raman ◽  
Bhaskar Saha ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Biological Activities ◽  
Osteoclast Differentiation ◽  
Bioactive Compound ◽  
Oxygen Species ◽  
Hormonal Changes ◽  
Mineral Density ◽  
Osteoblast Activity

Abstract Bone metabolism is essential for maintaining bone mineral density and bone strength through a balance between bone formation and bone resorption. Bone formation is associated with osteoblast activity whereas bone resorption is linked to osteoclast differentiation. Osteoblast progenitors give rise to the formation of mature osteoblasts whereas monocytes are the precursors for multi-nucleated osteoclasts. Chronic inflammation, auto-inflammation, hormonal changes or adiposity have the potential to disturb the balance between bone formation and bone loss. Several plant-derived components are described to modulate bone metabolism and alleviate osteoporosis by enhancing bone formation and inhibiting bone resorption. The plant-derived naphthoquinone plumbagin is a bioactive compound that can be isolated from the roots of the Plumbago genus. It has been used as traditional medicine for treating infectious diseases, rheumatoid arthritis and dermatological diseases. Reportedly, plumbagin exerts its biological activities primarily through induction of reactive oxygen species and triggers osteoblast-mediated bone formation. It is plausible that plumbagin’s reciprocal actions – inhibiting or inducing death in osteoclasts but promoting survival or growth of osteoblasts – are a function of the synergy with bone-metabolizing hormones calcitonin, Parathormone and vitamin D. Herein, we develop a framework for plausible molecular modus operandi of plumbagin in bone metabolism.

scholarly journals Pharmacological Topics of Bone Metabolism: Antiresorptive Microbial Compounds That Inhibit Osteoclast Differentiation, Function, and Survival

2008 ◽  
Vol 106 (4) ◽  
pp. 547-554 ◽  
Author(s):  
Je-Tae Woo ◽  
Takayuki Yonezawa ◽  
Byung-Yoon Cha ◽  
Toshiaki Teruya ◽  
Kazuo Nagai
Keyword(s):  
Bone Metabolism ◽  
Osteoclast Differentiation

scholarly journals Persistent increase of osteoprotegerin levels after cortisol normalization in patients with Cushing's syndrome

2010 ◽  
Vol 162 (1) ◽  
pp. 85-90 ◽  
Author(s):  
Valentina Camozzi ◽  
Francesca Sanguin ◽  
Nora Albigier ◽  
Carla Scaroni ◽  
Franco Mantero ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Cushing’S Syndrome ◽  
Osteoclast Differentiation ◽  
Serum Levels ◽  
Cushing's Syndrome ◽  
Mineral Density ◽  
Receptor Activator ◽  
Before And After ◽  
Design And Methods ◽  
Gonadal Status

ObjectiveOsteoprotegerin (OPG) has been identified as a decoy receptor that inhibits osteoclast differentiation and, more recently, as a paracrine regulator of vascular calcification. OPG is suppressed by glucocorticoids (GC); however, results from experimental and clinical studies are not univocal. The aim of this study was to evaluate OPG and bone metabolism in patients with Cushing's syndrome (CS) before and after cure.Design and methodsTwenty-six patients with CS (all women, mean age: 39.1±11.9 years) and 24 age- and gonadal status-matched healthy women were studied for bone mineral density, bone metabolism, OPG, and receptor activator of nuclear factor-kB ligand at baseline. Twelve patients were also studied 6–18 months after surgery, with persistent normalization of cortisol levels.ResultsOPG was significantly higher and osteocalcin (OC) was significantly lower in CS patients than in controls (OPG: 4.17±1.23 vs 2.95±0.79 pmol/l, P=0.00001; OC: 15.0±6.1 vs 18.8±6.8 ng/ml, P=0.04 in CS and controls respectively). After cure, we found no difference in OPG levels, despite a significant increase in OC levels (from 16.4±11 to 37.2±15 ng/ml, P=0.03).ConclusionPatients with CS showed increased OPG serum levels that remained unchanged after recovery, despite a restoration of bone formation. We speculate that high levels of OPG could reflect the persistent damage of the GCs on cardiovascular system.

scholarly journals The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κB Ligand–Induced Osteoclastogenesis by Suppressing Protein Kinase-C α/βII Phosphorylation

2021 ◽  
Vol 12 ◽  
Author(s):  
Kyosuke Sakaida ◽  
Kazuhiro Omori ◽  
Masaaki Nakayama ◽  
Hiroki Mandai ◽  
Saki Nakagawa ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Bone Metabolism ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Common Disease ◽  
Mouse Bone Marrow ◽  
Nuclear Factor ◽  
Receptor Activator

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

scholarly journals OP0241 IL9 MODULATION OF OSTEOCLASTS DIFFERENTIATION AND IMPACTS ON BONE METABOLISM

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 152.1-152
Author(s):  
M. Saad ◽  
S. Rauber ◽  
G. Schett ◽  
A. Ramming
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Metabolism ◽  
Mouse Models ◽  
Intracellular Signaling ◽  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Microcomputed Tomography ◽  
Tartrate Resistant Acid Phosphatase ◽  
Resolution Of Inflammation

Background:Osteoclasts are multinucleated cells originating from the monocytes/macrophage lineage and require receptor activator of NF-κB ligand (RANK-L) and macrophage-colony-stimulating factor (M-CSF) for their development. They play a major role in bone remodeling by degrading the calcified bone matrix. They are considered as one of the culprits in bone destruction in many inflammatory diseases e.g. rheumatoid arthritis and osteoporosis. In previous work by our group, it was observed that IL-9 mediated the resolution of inflammation in rheumatoid arthritis and hence protected against bone degradation in animal models. Despite this protection was particularly associated to the resolution of inflammation, our data also supported the hypothesis of a direct signalling of IL-9 to osteoclasts.Objectives:The aim of this study was to investigate the modulating effect of IL-9 on osteoclasts and on the bone metabolism.Methods:Osteoclasts differentiation was studied in the mouse models of antigen induced arthritis (AIA) and KBxN serum induced arthritis (SIA) in the presence and absence of IL-9 by histomorphometric analysis and microcomputed tomography scans (µCT). Osteoclasts were generated from bone marrow derived monocytes of BALB/c mice with M-CSF, RANKL and IL-9, which were added in varying concentrations to induce osteoclast differentiation. Tartrate-resistant acid phosphatase (TRAP) staining was performed to follow the differentiation steps from monocytes into multinucleated osteoclasts and to determine the effects of IL-9 on osteoclastogenesis. Additionally, we performed RNA-seq and seahorse analysis to detect IL-9 dependent, differentially expressed genes and metabolites. Intracellular signaling as induced by IL9R activation was followed by western blot analysis.Results:IL-9 KO mice showed higher numbers of osteoclasts as compared to wild-type mice in the mouse models of AIA and SIA. Microcomputed tomography showed pronounced loss of the trabecular network and bone volume as signs of inflammation-induced osteopenia in Il9−/− mice. We found that osteoclasts express high levels of IL-9R. Next, monocytes were differentiated into osteoclasts in the presence of different concentrations of recombinant IL-9. Cells cultured in the presence of IL-9 showed significantly impaired differentiation into osteoclasts. We observed phosphorylation of STAT3 and STAT5 in cultured osteoclasts in dependency of IL-9. Furthermore, the presence of IL-9 during osteoclast differentiation impacted the gene expression levels of characteristic osteoclast related genes such as NFATc1, Cathepsin K and TRAP. Furthermore, IL-9 showed a major impact on mitochondrial respiration rate and glycolysis as assessed by Seahorse assays.Conclusion:IL-9 exerted direct effects on osteoclast differentiation and modulated the expression of several genes that are related to osteoclast differentiation and function.Disclosure of Interests:mina saad: None declared, Simon Rauber: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen

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