scholarly journals α-Mangostin Inhibits LPS-Induced Bone Resorption by Restricting Osteoclastogenesis Via NF-κB and MAPK Signaling

2021 ◽  
Author(s):  
Wenkan Zhang ◽  
guangyao Jiang ◽  
xiaozhong zhou ◽  
leyi huang ◽  
jiahong meng ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Therapeutic Potential ◽  
Bone Destruction ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Receptor Activator ◽  
Cardioprotective Effects ◽  
And Function

Abstract Background: Excessive activation of osteoclasts is an important cause of imbalance in bone remodeling, which further leads to pathological bone destruction. This is a clear feature of many osteolytic diseases, such as rheumatoid arthritis, osteoporosis, and osteolysis around the prosthesis. Based on the fact that many natural compounds have therapeutic potential for treating these diseases by suppressing osteoclast formation and function, we proved that α-mangostin, a natural compound isolated from mango, might be a promising choice. α-mangostin was described had anti‐inflammatory, anticancer and cardioprotective effects. Methods: We evaluated the therapeutic effect of α-mangostin in the process of osteoclast formation and bone resorption. The receptor activator of NF-κB ligand (RANKL) induces the formation of osteoclasts in vitro, and the potential pathways of α-mangostin to inhibit the differentiation and function of osteoclasts were explored. A mouse model of LPS‐induced calvarial osteolysis was establish. Subsequently, micro-CT, histology, etc. were used to evaluate the effect of α-mangostin in preventing inflammatory osteolysis.Results: In our study, we found that α-mangostin could inhibit RANKL-induced osteoclastogenesis and reduced osteoclast‐related gene expression in vitro. Besides, F-actin ring immunofluorescence and resorption pit assay indicated that α-mangostin can also destroy the function of osteoclast. Furthermore, α-mangostin achieved these effects by disrupting the activation of NF-κB/MAPKs signaling pathways. In vivo, our data revealed that α-mangostin could protect mouse calvarial from osteolysis. Conclusions: Together, our study demonstrates that α-mangostin exhibit the ability of inhibiting steoclastogenesis both in vitro and in vivo, and may be a potential option for treating osteoclast‐related diseases.

scholarly journals Pantoprazole (PPZ) Inhibits RANKL-Induced Osteoclast Formation and Function In Vitro and Prevents Lipopolysaccharide- (LPS-) Induced Inflammatory Calvarial Bone Loss In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yu-Xi Li ◽  
Fu-Chao Chen ◽  
Ting Liu ◽  
Zhao-Peng Cai ◽  
Keng Chen ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Matrix ◽  
Bone Destruction ◽  
Mapk Signaling ◽  
Marker Genes ◽  
Calvarial Bone ◽  
Hematopoietic Stem ◽  
Increased Risk

Bone remodeling is a process delicately balanced between osteoclastic bone resorption and osteoblastic bone formation. Osteoclasts (OCs) are multinucleated giant cells formed through the fusion of monocytic precursors of the hematopoietic stem cells lineage. OCs are the exclusive cells responsible for the resorption and degradation of the mineralized bone matrix. Pantoprazole (PPZ), a proton pump inhibitor (PPI), is commonly prescribed to reduce excess gastric acid production for conditions such as gastroesophageal reflux disease and peptic ulcer disease. Studies have found contradictory effects of PPI therapy on bone metabolism due to the lack of understanding of the exact underlying mechanism. In this study, we found that PPZ inhibits receptor activator of nuclear factor-κB (NF-κB) ligand- (RANKL-) induced osteoclastogenesis from bone marrow monocytic/macrophage (BMMs) precursors and the bone-resorbing activity of mature OCs. Correspondingly, the expression of OC marker genes was also attenuated. At the molecular level, PPZ treatment was associated with reduced activation of the ERK MAPK signaling pathways crucial to OC differentiation. Additionally, the in vivo administration of PPZ protected mice against lipopolysaccharide- (LPS-) induced inflammatory calvarial bone erosion, as a result of the reduced number and activity of OCs on the calvarial bone surface. Although PPI use is associated with increased risk of osteoporosis and bone fractures, our study provides evidence for the direct inhibitory effect of PPZ on OC formation and bone resorption in vitro and in vivo, suggesting a potential therapeutic use of PPZ in the treatment of osteolytic disease with localized bone destruction.

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

2020 ◽  
Vol 21 (3) ◽  
pp. 1130 ◽  
Author(s):  
Fumitoshi Ohori ◽  
Hideki Kitaura ◽  
Saika Ogawa ◽  
Wei-Ren Shen ◽  
Jiawei Qi ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Nuclear Translocation ◽  
Bone Marrow Cells ◽  
Bone Destruction ◽  
Osteoclast Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Ct Reconstruction ◽  
Tnf Α

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.

scholarly journals Overexpression of γ-Glutamyltransferase in Transgenic Mice Accelerates Bone Resorption and Causes Osteoporosis

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2708-2715 ◽  
Author(s):  
Kiyoshi Hiramatsu ◽  
Yutaro Asaba ◽  
Sunao Takeshita ◽  
Yuji Nimura ◽  
Sawako Tatsumi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Transgenic Mice ◽  
Bone Destruction ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Expression Cloning ◽  
Nuclear Factor ◽  
Receptor Activator

We previously identified γ-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. To examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages to receptor activator of nuclear factor-κB ligand, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased receptor activator of nuclear factor-κB ligand expression in marrow stromal cells and also stimulated osteoclastogenesis from bone marrow macrophages at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction and provides a new target for therapeutic intervention.

Myeloma bone disease and proteasome inhibition therapies

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1098-1104 ◽  
Author(s):  
Evangelos Terpos ◽  
Orhan Sezer ◽  
Peter Croucher ◽  
Meletios-Athanassios Dimopoulos
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Disease ◽  
Proteasome Inhibitors ◽  
Bone Destruction ◽  
Osteoclast Formation ◽  
Bone Specific Alkaline Phosphatase ◽  
Myeloma Bone Disease

AbstractBone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor-κB ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin. The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points.

scholarly journals Jatrorrhizine Hydrochloride Suppresses RANKL-Induced Osteoclastogenesis and Protects against Wear Particle-Induced Osteolysis

2018 ◽  
Vol 19 (11) ◽  
pp. 3698 ◽  
Author(s):  
Hui Li ◽  
Jing Wang ◽  
Qiwen Sun ◽  
Gang Chen ◽  
Shengnan Sun ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Chinese Herb ◽  
Major Complication ◽  
Wear Particle ◽  
Osteoclast Formation ◽  
Marker Genes

Wear particle-induced aseptic prosthetic loosening is a major complication associated with total joint arthroplasty (TJA). A growing body of evidence suggests that receptor activator of nuclear factor κ-B ligand (RANKL)-stimulated osteoclastogenesis and bone resorption are responsible for peri-implant loosening. Thus, agents which attenuate excessive osteoclast differentiation and function have been considered to offer therapeutic potential for prolonging the life of TJA implants. Jatrorrhizine hydrochloride (JH), a major protoberberine alkaloid isolated from the traditional Chinese herb Coptis chinensis, has been reported to have antimicrobial, antitumor, and antihypercholesterolemic and neuroprotective activities. However, its effects on osteoclast biology remain unknown. Here, we found that JH inhibited RANKL-induced osteoclast formation and bone resorption in vitro and exerted protection against titanium (Ti) particle-induced osteolysis in vivo. Biochemical analysis demonstrated that JH suppressed RANKL-induced activation of MAPKs (p38 and ERK) which down-regulated the production of NFATc1 and NFATc1-regulated osteoclastic marker genes, such as TRAP, CTR and CTSK. Collectively, our findings suggest that JH may be a promising anti-osteoclastogenesis agent for treating periprosthetic osteolysis or other osteoclast-related osteolytic diseases.

scholarly journals Biological Effects of β-Glucans on Osteoclastogenesis

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1982
Author(s):  
Wataru Ariyoshi ◽  
Shiika Hara ◽  
Ayaka Koga ◽  
Yoshie Nagai-Yoshioka ◽  
Ryota Yamasaki
Keyword(s):  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Biological Effects ◽  
Osteoclast Differentiation ◽  
Treatment Strategies ◽  
Alcaligenes Faecalis ◽  
Osteoclast Formation ◽  
Osteoclast Precursors

Although the anti-tumor and anti-infective properties of β-glucans have been well-discussed, their role in bone metabolism has not been reviewed so far. This review discusses the biological effects of β-glucans on bone metabolisms, especially on bone-resorbing osteoclasts, which are differentiated from hematopoietic precursors. Multiple immunoreceptors that can recognize β-glucans were reported to be expressed in osteoclast precursors. Coordinated co-stimulatory signals mediated by these immunoreceptors are important for the regulation of osteoclastogenesis and bone remodeling. Curdlan from the bacterium Alcaligenes faecalis negatively regulates osteoclast differentiation in vitro by affecting both the osteoclast precursors and osteoclast-supporting cells. We also showed that laminarin, lichenan, and glucan from baker’s yeast, as well as β-1,3-glucan from Euglema gracilisas, inhibit the osteoclast formation in bone marrow cells. Consistent with these findings, systemic and local administration of β-glucan derived from Aureobasidium pullulans and Saccharomyces cerevisiae suppressed bone resorption in vivo. However, zymosan derived from S. cerevisiae stimulated the bone resorption activity and is widely used to induce arthritis in animal models. Additional research concerning the relationship between the molecular structure of β-glucan and its effect on osteoclastic bone resorption will be beneficial for the development of novel treatment strategies for bone-related diseases.

scholarly journals Immunological Reaction in TNF-α-Mediated Osteoclast Formation and Bone ResorptionIn VitroandIn Vivo

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Hideki Kitaura ◽  
Keisuke Kimura ◽  
Masahiko Ishida ◽  
Haruka Kohara ◽  
Masako Yoshimatsu ◽  
...  
Keyword(s):  
T Cells ◽  
Bone Metabolism ◽  
Stromal Cells ◽  
Fas Ligand ◽  
Bone Marrow Cells ◽  
Bone Destruction ◽  
Osteoclast Formation ◽  
Bone Diseases

Tumor necrosis factor-α(TNF-α) is a cytokine produced by monocytes, macrophages, and T cells and is induced by pathogens, endotoxins, or related substances. TNF-αmay play a key role in bone metabolism and is important in inflammatory bone diseases such as rheumatoid arthritis. Cells directly involved in osteoclastogenesis include macrophages, which are osteoclast precursor cells, osteoblasts, or stromal cells. These cells express receptor activator of NF-κB ligand (RANKL) to induce osteoclastogenesis, and T cells, which secrete RANKL, promote osteoclastogenesis during inflammation. Elucidating the detailed effects of TNF-αon bone metabolism may enable the identification of therapeutic targets that can efficiently suppress bone destruction in inflammatory bone diseases. TNF-αis considered to act by directly increasing RANK expression in macrophages and by increasing RANKL in stromal cells. Inflammatory cytokines such as interleukin- (IL-) 12, IL-18, and interferon-γ(IFN-γ) strongly inhibit osteoclast formation. IL-12, IL-18, and IFN-γinduce apoptosis in bone marrow cells treated with TNF-α  in vitro, and osteoclastogenesis is inhibited by the interactions of TNF-α-induced Fas and Fas ligand induced by IL-12, IL-18, and IFN-γ. This review describes and discusses the role of cells concerned with osteoclast formation and immunological reactions in TNF-α-mediated osteoclastogenesisin vitroandin vivo.

scholarly journals Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo

2021 ◽  
Vol 22 (23) ◽  
pp. 12921
Author(s):  
Irina Giralt ◽  
Gabriel Gallo-Oller ◽  
Natalia Navarro ◽  
Patricia Zarzosa ◽  
Guillem Pons ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Positive Effects ◽  
Novel Therapeutic Strategies ◽  
And Function ◽  
Myogenic Markers ◽  
First Time ◽  
Dickkopf 1 ◽  
Proliferation And Invasion

The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.

scholarly journals Chitosan oligosaccharide inhibits skull resorption induced by lipopolysaccharides in mice

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ke Guo ◽  
Zong Lin Liu ◽  
Wen Chao Wang ◽  
Wei Feng Xu ◽  
Shi Qi Yu ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Therapeutic Potential ◽  
Bone Destruction ◽  
Osteoclast Formation ◽  
Water Soluble ◽  
Tartrate Resistant Acid Phosphatase ◽  
Chitosan Oligosaccharide ◽  
Micro Computed Tomography ◽  
Bone Damage ◽  
Dose Dependent Decrease

Abstract Background Low-molecular-weight chitosan oligosaccharide (LMCOS), a chitosan degradation product, is water-soluble and easily absorbable, rendering it a popular biomaterial to study. However, its effect on bone remodelling remains unknown. Therefore, we evaluated the effect of LMCOS on lipopolysaccharide (LPS)-induced bone resorption in mice. Methods Six-week-old male C57BL/6 mice (n = five per group) were randomly divided into five groups: PBS, LPS, LPS + 0.005% LMCOS, LPS + 0.05% LMCOS, and LPS + 0.5% LMCOS. Then, the corresponding reagents (300 μL) were injected into the skull of the mice. To induce bone resorption, LPS was administered at 10 mg/kg per injection. The mice were injected three times a week with PBS alone or LPS without or with LMCOS and sacrificed 2 weeks later. The skull was removed for micro-computed tomography, haematoxylin-eosin staining, and tartrate-resistant acid phosphatase staining. The area of bone damage and osteoclast formation were evaluated and recorded. Results LMCOS treatment during LPS-induced skull resorption led to a notable reduction in the area of bone destruction; we observed a dose-dependent decrease in the area of bone destruction and number of osteoclasts with increasing LMCOS concentration. Conclusions Our findings showed that LMCOS could inhibit skull bone damage induced by LPS in mice, further research to investigate its therapeutic potential for treating osteolytic diseases is required.

scholarly journals The Therapeutic Potential of Naringenin: A Review of Clinical Trials

2019 ◽  
Vol 12 (1) ◽  
pp. 11 ◽  
Author(s):  
Bahare Salehi ◽  
Patrick Fokou ◽  
Mehdi Sharifi-Rad ◽  
Paolo Zucca ◽  
Raffaele Pezzani ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Biological Activities ◽  
In Vivo Studies ◽  
Citrus Fruits ◽  
Delivery Methods ◽  
Cardioprotective Effects ◽  
Compromised Patients ◽  
Cardioprotective Action

Naringenin is a flavonoid belonging to flavanones subclass. It is widely distributed in several Citrus fruits, bergamot, tomatoes and other fruits, being also found in its glycosides form (mainly naringin). Several biological activities have been ascribed to this phytochemical, among them antioxidant, antitumor, antiviral, antibacterial, anti-inflammatory, antiadipogenic and cardioprotective effects. Nonetheless, most of the data reported have been obtained from in vitro or in vivo studies. Although some clinical studies have also been performed, the main focus is on naringenin bioavailability and cardioprotective action. In addition, these studies were done in compromised patients (i.e., hypercholesterolemic and overweight), with a dosage ranging between 600 and 800 μM/day, whereas the effect on healthy volunteers is still debatable. In fact, naringenin ability to improve endothelial function has been well-established. Indeed, the currently available data are very promising, but further research on pharmacokinetic and pharmacodynamic aspects is encouraged to improve both available production and delivery methods and to achieve feasible naringenin-based clinical formulations.

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