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 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 Bone Resorption Induced by Titanium Implantation Through Activation of Osteoclast Formation via C3a

2020 ◽  
Author(s):  
Xiaohan Liu ◽  
Siwen Li ◽  
Yuan Meng ◽  
Yu Fan ◽  
Ce Shi ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Inflammatory Responses ◽  
Titanium Implant ◽  
Osteoclast Formation ◽  
Alternative Pathways ◽  
Tnf Α ◽  
Differentiation And Proliferation ◽  
Pro Inflammatory Cytokines

Abstract Titanium implantation is widely used for dental replacement with advantages of excellent mechanical strength, corrosion resistance, chemical stability and biocompatibility. Some patients, however, are subject to the failure of implantation due to bone resorption, which closely related to the inflammatory responses without clear mechanisms. In this study, first we found that there were inflammatory responses and increases of osteoclasts in the surrounding tissues near by the titanium implant. Further, data revealed that the C3 was increased in the serum and surrounding tissues near by the titanium implant, and activated by classical and alternative pathways. Next, we recognized that the C3a/C3aR, no C3b played an important role in stimulating secretions of pro-inflammatory cytokines of TNF-α and MMP9 via transcription factors NF-kB and NFATc1. This cascade of responses to titanium implant leaded the differentiation and proliferation of osteoclasts in vivo and in vitro, bone resorption of surrounding tissues of Ti implant. These suggest that the cleaved C3a fragment plays predominant roles in the activation of osteoclast. Therefore, the blocking C3a activation should provide potential to prevent bone resorption and prolong the survival of biomaterial implants.

scholarly journals 3-Hydroxyolean-12-en-27-oic Acids Inhibit RANKL-Induced Osteoclastogenesis in Vitro and Inflammation-Induced Bone Loss in Vivo

2020 ◽  
Vol 21 (15) ◽  
pp. 5240
Author(s):  
Wonyoung Seo ◽  
Suhyun Lee ◽  
Phuong Thao Tran ◽  
Thi Quynh-Mai Ngo ◽  
Okwha Kim ◽  
...  
Keyword(s):  
Bone Destruction ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Marker Genes ◽  
Tartrate Resistant Acid Phosphatase ◽  
Specific Marker ◽  
Nuclear Factor ◽  
Activated T Cells

Olean-12-en-27-oic acids possess a variety of pharmacological effects. However, their effects and underlying mechanisms on osteoclastogenesis remain unclear. This study aimed to investigate the anti-osteoclastogenic effects of five olean-12-en-27-oic acid derivatives including 3α,23-isopropylidenedioxyolean-12-en-27-oic acid (AR-1), 3-oxoolean-12-en-27-oic acid (AR-2), 3α-hydroxyolean-12-en-27-oic acid (AR-3), 23-hydroxy-3-oxoolean-12-en-27-oic acid (AR-4), and aceriphyllic acid A (AR-5). Among the five olean-12-en-27-oic acid derivatives, 3-hydroxyolean-12-en-27-oic acid derivatives, AR-3 and AR-5, significantly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced mature osteoclast formation by reducing the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, F–actin ring formation, and mineral resorption activity. AR-3 and AR-5 decreased RANKL-induced expression levels of osteoclast-specific marker genes such as c-Src, TRAP, and cathepsin K (CtsK) as well as c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Mice treated with either AR-3 or AR-5 showed significant protection of the mice from lipopolysaccharide (LPS)-induced bone destruction and osteoclast formation. In particular, AR-5 suppressed RANKL-induced phosphorylation of JNK and ERK mitogen-activated protein kinases (MAPKs). The results suggest that AR-3 and AR-5 attenuate osteoclast formation in vitro and in vivo by suppressing RANKL-mediated MAPKs and NFATc1 signaling pathways and could potentially be lead compounds for the prevention or treatment of osteolytic bone diseases.

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.

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 The Prenyl Group Contributes to Activities of Phytoestrogen 8-Prenynaringenin in Enhancing Bone Formation and Inhibiting Bone Resorption In Vitro

Endocrinology ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 1202-1214 ◽  
Author(s):  
Lei-Guo Ming ◽  
Xiang Lv ◽  
Xiao-Ni Ma ◽  
Bao-Feng Ge ◽  
Ping Zhen ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Mrna Expression ◽  
Bone Marrow Cells ◽  
Osteoclast Differentiation ◽  
Cathepsin K ◽  
Active Role ◽  
Osteoclast Formation ◽  
Calcium Deposition ◽  
Tartrate Resistant Acid Phosphatase

Abstract Previous studies have found that 8-prenylflavonoids have a higher osteogenic activity than do flavonoids, which suggested that the 8-prenyl group may play an active role in bone-protective properties. To address this hypothesis, activities of 8-prenylnaringenin (PNG) and naringenin (NG) in osteoblast and osteoclast differentiation and function were compared in vitro. PNG was found to have a stronger ability than NG to improve osteoblast differentiation and osteogenic function in cultured rat calvarial osteoblasts, as demonstrated by levels of alkaline phosphatase activity, osteocalcin, calcium deposition, and the number and area of mineralized bone nodules, as well as mRNA expression of osteogenesis-related genes Bmp-2, OSX, and Runx-2. In addition, although expression of osteoclastogenic inducer receptor activator of nuclear factor kappa-B ligand (RANKL) was not affected, that of osteoclastogenesis inhibitor osteoprotegerin (OPG) and consequently the OPG/RANKL ratio were increased, more potently by PNG than NG. PNG was also found to have a higher potency than NG in inhibiting the osteoclast formation in rabbit bone marrow cells and their resorptive activity, as revealed by lower numbers of osteoclasts formed, lower numbers and areas of bone resorption pits, and lower mRNA expression levels of tartrate-resistant acid phosphatase and cathepsin K. Furthermore, PNG induced apoptosis of mature osteoclasts at a higher degree and at an earlier time than did NG. These results indicate that the 8-prenyl group plays an important role and contributes to the higher bone-protective activity of PNG in comparison with NG.

scholarly journals Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 619
Author(s):  
Hyun-Jung Park ◽  
Malihatosadat Gholam-Zadeh ◽  
Sun-Young Yoon ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Ring Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Actin Ring ◽  
Collagen Crosslinks ◽  
Trap Staining ◽  
Src Activation

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p–Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

scholarly journals Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

2021 ◽  
Vol 22 (1) ◽  
pp. 434
Author(s):  
Yuria Jang ◽  
Hong Moon Sohn ◽  
Young Jong Ko ◽  
Hoon Hyun ◽  
Wonbong Lim
Keyword(s):  
Nuclear Translocation ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Point Mutations ◽  
Tartrate Resistant Acid Phosphatase ◽  
Mice Model ◽  
Gsk 3Β ◽  
Rank Signaling

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.

scholarly journals 1,25-Dihydroxy-19-nor-vitamin D2, a Vitamin D Analog with Reduced Bone Resorbing Activity In Vitro

2000 ◽  
Vol 11 (10) ◽  
pp. 1857-1864
Author(s):  
L. SHANNON HOLLIDAY ◽  
STEPHEN L. GLUCK ◽  
EDUARDO SLATOPOLSKY ◽  
ALEX J. BROWN
Keyword(s):  
Vitamin D ◽  
Acid Phosphatase ◽  
Bone Resorption ◽  
Vitamin D Receptor ◽  
Intrinsic Activity ◽  
Tartrate Resistant Acid Phosphatase ◽  
Mouse Bone Marrow ◽  
Bone Resorbing Activity

Abstract. 1,25-Dihydroxy-19-nor-vitamin D2 (19-norD2), a new analog of 1,25(OH)2D3, suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)2D3. Although 19-norD2 has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)2D3, it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD2 on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD2 and 1,25(OH)2D3 (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD2, as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)2D3-stimulated osteoclasts (P < 0.05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD2 in cultures was approximately 20% greater than 1,25(OH)2D3, not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD2 and 1,25(OH)2D3. In summary, 19-norD2 is less effective than 1,25(OH)2D3 in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD2 compared with 1,25(OH)2D3.

Sign in / Sign up

Export Citation Format

Share Document