scholarly journals Targeting S1PRs as a Therapeutic Strategy for Inflammatory Bone Loss Diseases—Beyond Regulating S1P Signaling

2021 ◽  
Vol 22 (9) ◽  
pp. 4411
Author(s):  
Hong Yu
Keyword(s):  
Bone Loss ◽  
Signaling Pathways ◽  
Soft Tissues ◽  
Alveolar Bone ◽  
Specific Inhibitor ◽  
Inflammatory Cells ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Cytokines And Chemokines ◽  
Underlying Mechanisms

As G protein coupled receptors, sphingosine-1-phosphate receptors (S1PRs) have recently gained attention for their role in modulating inflammatory bone loss diseases. Notably, in murine studies inhibiting S1PR2 by its specific inhibitor, JTE013, alleviated osteoporosis induced by RANKL and attenuated periodontal alveolar bone loss induced by oral bacterial inflammation. Treatment with a multiple S1PRs modulator, FTY720, also suppressed ovariectomy-induced osteoporosis, collagen or adjuvant-induced arthritis, and apical periodontitis in mice. However, most previous studies and reviews have focused mainly on how S1PRs manipulate S1P signaling pathways, subsequently affecting various diseases. In this review, we summarize the underlying mechanisms associated with JTE013 and FTY720 in modulating inflammatory cytokine release, cell chemotaxis, and osteoclastogenesis, subsequently influencing inflammatory bone loss diseases. Studies from our group and from other labs indicate that S1PRs not only control S1P signaling, they also regulate signaling pathways induced by other stimuli, including bacteria, lipopolysaccharide (LPS), bile acid, receptor activator of nuclear factor κB ligand (RANKL), IL-6, and vitamin D. JTE013 and FTY720 alleviate inflammatory bone loss by decreasing the production of inflammatory cytokines and chemokines, reducing chemotaxis of inflammatory cells from blood circulation to bone and soft tissues, and suppressing RANKL-induced osteoclast formation.

Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss

2012 ◽  
Vol 302 (11) ◽  
pp. E1440-E1449 ◽  
Author(s):  
Rethi Raghu Nadhanan ◽  
Suzanne M. Abimosleh ◽  
Yu-Wen Su ◽  
Michaela A. Scherer ◽  
Gordon S. Howarth ◽  
...  
Keyword(s):  
Bone Loss ◽  
Trabecular Bone ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Dark Agouti ◽  
Emu Oil ◽  
Gene Expression Studies ◽  
Underlying Mechanisms ◽  
Reduced Density

Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day−1·rat−1) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H2O + Sal, H2O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia ( days 3, 4, and 5 post-5-FU). Histological analysis showed that H2O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFα, osteoclast marker receptor activator of nuclear factor-κB, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss.

scholarly journals Antiperiodontitis Effects of Magnolia biondii Extract on Ligature-Induced Periodontitis in Rats

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 934 ◽  
Author(s):  
Hae Jin Lee ◽  
Dong-Ryung Lee ◽  
Bong-Keun Choi ◽  
Seung Hwan Yang
Keyword(s):  
Bone Loss ◽  
Tissue Damage ◽  
Alveolar Bone ◽  
Histopathological Examination ◽  
Nuclear Factor Κb ◽  
Alveolar Bone Loss ◽  
Gingival Tissue ◽  
Protective Effects ◽  
Tissue Destruction ◽  
Commercial Kits

Over the past decades, periodontitis has become a rising health problem and caused various diseases. In the many studies shows that some extracts and compound to the prevention and treatment of periodontitis. This study focuses on the effects of inhibition of gingival damage and alveolar bone loss. The aim of this study was to evaluate the protective effects of Magnolia biondii extract (MBE) against ligature-induced periodontitis in rats. A ligature was placed around the molar teeth for 8 weeks, and MBE was administered for 8 weeks. Gingival tissue damage and alveolar bone loss were measured by microcomputed tomography (CT) analysis and histopathological examination. Serum Interluekin-1 β (IL-1β), tumor necrosis factor-α (TNF-α), cyclooxygenases-2 (COX-2), and receptor activator of nuclear factor–κB ligand (RANKL) levels were investigated using commercial kits to confirm the antiperiodontitis effects of MBE. We confirmed that ligature-induced periodontitis resulted in gingival tissue damage and alveolar bone loss. However, treatment for 8 weeks with MBE protected from periodontal tissue damage and downregulated serum inflammatory cytokine factors and RANKL levels. These results suggest that MBE exerts antiperiodontitis effects by inhibiting gingival tissue destruction and alveolar bone loss through regulation of anti-inflammatory cytokines in periodontitis-induced rats.

scholarly journals Osteoprotegerin-Deficient Male Mice as a Model for Severe Alveolar Bone Loss: Comparison With RANKL-Overexpressing Transgenic Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 773-782 ◽  
Author(s):  
Masanori Koide ◽  
Yasuhiro Kobayashi ◽  
Tadashi Ninomiya ◽  
Midori Nakamura ◽  
Hisataka Yasuda ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Nuclear Factor Κb ◽  
Alveolar Bone Loss ◽  
Male Mice ◽  
Periodontal Tissues ◽  
Cortical Areas ◽  
Immunohistochemical Analyses ◽  
Transgenic Male

Periodontitis, an inflammatory disease of periodontal tissues, is characterized by excessive alveolar bone resorption. An increase in the receptor activator of nuclear factor-κB ligand (RANKL) to osteoprotegerin (OPG) ratio is thought to reflect the severity of periodontitis. Here, we examined alveolar bone loss in OPG-deficient (OPG−/−) mice and RANKL-overexpressing transgenic (RANKL-Tg) mice. Alveolar bone loss in OPG−/− mice at 12 weeks was significantly higher than that in RANKL-Tg mice. OPG−/− but not RANKL-Tg mice exhibited severe bone resorption especially in cortical areas of the alveolar bone. An increased number of osteoclasts was observed in the cortical areas in OPG−/− but not in RANKL-Tg mice. Immunohistochemical analyses showed many OPG-positive signals in osteocytes but not osteoblasts. OPG-positive osteocytes in the cortical area of alveolar bones and long bones were abundant in both wild-type and RANKL-Tg mice. This suggests the resorption in cortical bone areas to be prevented by OPG produced locally. To test the usefulness of OPG−/− mice as an animal model for screening drugs to prevent alveolar bone loss, we administered an antimouse RANKL antibody or risedronate, a bisphosphonate, to OPG−/− mice. They suppressed alveolar bone resorption effectively. OPG−/− mice are useful for screening therapeutic agents against alveolar bone loss.

scholarly journals Rac1 signaling regulates LPS-induced mouse mastitis via inhibition of NLRP3, NF-κB and MAPK signaling pathways

2020 ◽  
Author(s):  
Chaoqun Wang ◽  
Aimin Jiang ◽  
Wang Jingjing ◽  
Xiao Liu ◽  
Han Zhen ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Signaling Pathways ◽  
Inflammatory Responses ◽  
Bovine Mastitis ◽  
Specific Inhibitor ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
New Drugs ◽  
Mitogen Activated Protein Kinase ◽  
Pcr Analysis

Abstract Background Bovine mastitis characterized by mammary gland inflammatory responses, is the most frequent and costly diseases in dairy cattle. Researchers have been seeking effective treatments for this disease, but still not very successful. Ras-related C3 botulinum toxin substrate 1 (Rac1) is implicated in various cellular functions, including apoptosis, ROS production and inflammatory responses, and presents an attractive therapeutic target for many diseases. However, the effects of Rac1 signaling on mastitis remain unclear. The aim of this study is to investigate the effects of Rac1 signaling on mastitis via inhibition by Rac1 specific inhibitor NSC23766 based on a murine model of lipoplysaccharide (LPS)-induced mastitis. Methods Murine mastitis model was established by perfusion of LPS, hematoxylin-eosin (H & E) staining was employed to explore the mechanisms in mouse model, qRT- PCR analysis, Western blotting analysis. Results The results revealed that NSC23766 significantly decreased the damage of mammary gland by LPS, reduced myeloperoxidase activities, and the productions of IL-1β, IL-6, TNF-α and MCP-1 gene expression in the mammary glands with LPS perfusion. Moreover, western blot analysis showed that NSC23766 inhibited the phosphoryation of p65, IκBα, ERK, and p38, and suppressed the expression of NLRP3. Conclusion These findings suggested that administration of NSC23766 prevented the development of mastitis by inhibiting NLRP3, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Accordingly, this study may provide research basis for the development of new drugs against mastitis, and NSC23766 might be a potential therapeutic drugs for mastitis.

scholarly journals Mitogen-Activated Protein Kinase 2 Signaling Shapes Macrophage Plasticity in Aggregatibacter actinomycetemcomitans-Induced Bone Loss

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Bethany A. Herbert ◽  
Heidi M. Steinkamp ◽  
Matthias Gaestel ◽  
Keith L. Kirkwood
Keyword(s):  
Protein Kinase ◽  
Bone Loss ◽  
Periodontal Disease ◽  
Alveolar Bone ◽  
Aggregatibacter Actinomycetemcomitans ◽  
Osteoclast Formation ◽  
Mitogen Activated Protein Kinase ◽  
Micro Computed Tomography ◽  
Content Type ◽  
Mitogen Activated Protein

ABSTRACT Aggregatibacter actinomycetemcomitans is associated with aggressive periodontal disease, which is characterized by inflammation-driven alveolar bone loss. A. actinomycetemcomitans activates the p38 mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase 2 (MK2) stress pathways in macrophages that are involved in host responses. During the inflammatory process in periodontal disease, chemokines are upregulated to promote recruitment of inflammatory cells. The objective of this study was to determine the role of MK2 signaling in chemokine regulation during A. actinomycetemcomitans pathogenesis. Utilizing a murine calvarial model, Mk2 +/+ and Mk2 −/− mice were treated with live A. actinomycetemcomitans bacteria at the midsagittal suture. MK2 positively regulated the following macrophage RNA: Emr1 (F4/80), Itgam (CD11b), Csf1r (M-CSF Receptor), Itgal (CD11a), Tnf, and Nos2. Additionally, RNA analysis revealed that MK2 signaling regulated chemokines CCL3 and CCL4 in murine calvarial tissue. Utilizing the chimeric murine air pouch model, MK2 signaling differentially regulated CCL3 and CCL4 in the hematopoietic and nonhematopoietic compartments. Bone resorption pits in calvaria, observed by micro-computed tomography, and osteoclast formation were decreased in Mk2 −/− mice compared to Mk2 +/+ mice after A. actinomycetemcomitans treatment. In conclusion, these data suggest that MK2 in macrophages contributes to regulation of chemokine signaling during A. actinomycetemcomitans-induced inflammation and bone loss.

Antcamphin M Inhibits TLR4-Mediated Inflammatory Responses by Upregulating the Nrf2/HO-1 Pathway and Suppressing the NLRP3 Inflammasome Pathway in Macrophages

2019 ◽  
Vol 47 (07) ◽  
pp. 1611-1626 ◽  
Author(s):  
Wei-Hsiu Liu ◽  
Li-Shian Shi ◽  
Min-Chieh Chung ◽  
Tsu-Chung Chang ◽  
Shih-Yu Lee
Keyword(s):  
Signaling Pathways ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Heme Oxygenase 1 ◽  
Prostaglandin E ◽  
Related Factor ◽  
Potential Candidate ◽  
Cytokines And Chemokines ◽  
Anti Inflammatory ◽  
Underlying Mechanisms

The medicinal mushroom Antrodia cinnamomea has been demonstrated to have anti-inflammatory properties. However, the bioactive compounds in A. cinnamomea need further investigation. The present study aimed to understand the mechanism of action of antcamphin M, an ergostanoid isolated from A. cinnamomea mycelium and to clarify its underlying mechanisms of action. RAW264.7 cells were pretreated with the indicated concentrations of antcamphin M, prior to stimulation with lipopolysaccharide (LPS). Cell viability, production of nitric oxide (NO), prostaglandin E2 (PGE[Formula: see text], cytokines, and chemokines, as well as the inflammation-related signaling pathways were investigated. The study revealed that antcamphin M significantly decreased the LPS-induced production of NO, PGE2, pro-inflammatory cytokines, and keratinocyte chemoattractant CXCL1 (KC), along with the levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins without significant cytotoxicity, indicating it had a better anti-inflammatory activity than that of gisenoside Rb1 and Rg1. Additionally, antcamphin M significantly inhibited the activation of MAPKs (p38, ERK, and JNK), NF[Formula: see text]B, and components of the NLRP3 inflammasome (NLRP3, ASC, and caspase-1) signaling pathways and also increased the levels of nuclear factor erythroid-2-related factor (Nrf2) and heme oxygenase-1 (HO-1). These findings suggest that antcamphin M possesses potent anti-inflammatory activities and could be a potential candidate for the development of anti-inflammatory drugs.

scholarly journals The roles of osteocytes in alveolar bone destruction in periodontitis

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaofei Huang ◽  
Mengru Xie ◽  
Yanling Xie ◽  
Feng Mei ◽  
Xiaofeng Lu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Remodeling ◽  
Alveolar Bone ◽  
Bone Cells ◽  
Bone Destruction ◽  
Alveolar Bone Loss ◽  
Receptor Activator ◽  
Local Destruction ◽  
Underlying Mechanisms

AbstractPeriodontitis, a bacterium-induced inflammatory disease that is characterized by alveolar bone loss, is highly prevalent worldwide. Elucidating the underlying mechanisms of alveolar bone loss in periodontitis is crucial for understanding its pathogenesis. Classically, bone cells, such as osteoclasts, osteoblasts and bone marrow stromal cells, are thought to dominate the development of bone destruction in periodontitis. Recently, osteocytes, the cells embedded in the mineral matrix, have gained attention. This review demonstrates the key contributing role of osteocytes in periodontitis, especially in alveolar bone loss. Osteocytes not only initiate physiological bone remodeling but also assist in inflammation-related changes in bone remodeling. The latest evidence suggests that osteocytes are involved in regulating bone anabolism and catabolism in the progression of periodontitis. The altered secretion of receptor activator of NF-κB ligand (RANKL), sclerostin and Dickkopf-related protein 1 (DKK1) by osteocytes affects the balance of bone resorption and formation and promotes bone loss. In addition, the accumulation of prematurely senescent and apoptotic osteocytes observed in alveolar bone may exacerbate local destruction. Based on their communication with the bloodstream, it is noteworthy that osteocytes may participate in the interaction between local periodontitis lesions and systemic diseases. Overall, further investigations of osteocytes may provide vital insights that improve our understanding of the pathophysiology of periodontitis.

scholarly journals IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss

2005 ◽  
Vol 201 (10) ◽  
pp. 1677-1687 ◽  
Author(s):  
Maria Grazia Ruocco ◽  
Shin Maeda ◽  
Jin Mo Park ◽  
Toby Lawrence ◽  
Li-Chung Hsu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Osteoclast Survival

Transcription factor, nuclear factor κB (NF-κB), is required for osteoclast formation in vivo and mice lacking both of the NF-κB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IκB kinase (IKK) complex that mediate NF-κB activation, IKKα and IKKβ, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKβ subunit as a transducer of signals from receptor activator of NF-κB (RANK) to NF-κB. Although IKKα is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKβ is required for osteoclastogenesis in vitro and in vivo. IKKβ also protects osteoclasts and their progenitors from tumor necrosis factor α–induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.

scholarly journals Nicorandil Inhibits Osteoclast Formation Base on NF-κB and p-38 MAPK Signaling Pathways and Relieves Ovariectomy-Induced Bone Loss

2021 ◽  
Vol 12 ◽  
Author(s):  
Shenggui Xu ◽  
Xiankun Cao ◽  
Zhenxing Yu ◽  
Wenxin He ◽  
Yichuan Pang ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Biological Effects ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Mineral Density ◽  
Mapk Activation ◽  
Bone Disorders

Osteolytic bone disorders are characterized by an overall reduction in bone mineral density which enhances bone ductility and vulnerability to fractures. This disorder is primarily associated with superabundant osteoclast formation and bone resorption activity. Nicorandil (NIC) is a vasodilatory anti-anginal drug with ATP-dependent potassium (KATP) channel openings. However, NIC is adopted to manage adverse cardiovascular and coronary events. Recent research has demonstrated that NIC also possesses anti-inflammatory peculiarity through the regulation of p38 MAPK and NF-κB signaling pathways. Both MAPK and NF-κB signaling pathways play pivotal roles in RANKL-induced osteoclast formation and bone resorption function. Herein, we hypothesized that NIC may exert potential biological effects against osteoclasts, and revealed that NIC dose-dependently suppressed bone marrow macrophage (BMM) precursors to differentiate into TRAP + multinucleated osteoclasts in vitro. Furthermore, osteoclast resorption assays demonstrated anti-resorptive effects exhibited by NIC. NIC had no impact on osteoblast differentiation or mineralization function. Based on Biochemical analyses, NIC relieved RANKL-induced ERK, NF-κB and p38 MAPK signaling without noticeable effects on JNK MAPK activation. However, the attenuation of NF-κB and p38 MAPK activation was sufficient to hamper the downstream induction of c-Fos and NFATc1 expression. Meanwhile, NIC administration markedly protected mice from ovariectomy (OVX)-induced bone loss through in vivo inhibition of osteoclast formation and bone resorption activity. Collectively, this work demonstrated the potential of NIC in the management of osteolytic bone disorders mediated by osteoclasts.

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