scholarly journals Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuri Yoshikawa ◽  
Takashi Izawa ◽  
Yusaku Hamada ◽  
Hiroko Takenaga ◽  
Ziyi Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mouse Model ◽  
Bone Metabolism ◽  
Temporomandibular Joint ◽  
Subchondral Bone ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Wild Type ◽  
Temporomandibular Joint Osteoarthritis ◽  
Signaling Axis

AbstractBone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[a]P was administered orally to wild-type and AhR−/− mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with μCT and histology. Exposure to B[a]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an AhR-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation.

scholarly journals Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 199
Author(s):  
Urara Tanaka ◽  
Shunichi Kajioka ◽  
Livia S. Finoti ◽  
Daniela B. Palioto ◽  
Denis F. Kinane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Resorption ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Osteoblastic Cell Line ◽  
Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

scholarly journals Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Murine Monoclonal Antibodies

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.

scholarly journals Serum Levels of miR-148a and miR-21-5p Are Increased in Type 1 Diabetic Patients and Correlated with Markers of Bone Strength and Metabolism

2018 ◽  
Vol 4 (4) ◽  
pp. 37 ◽  
Author(s):  
Giuseppina E. Grieco ◽  
Dorica Cataldo ◽  
Elena Ceccarelli ◽  
Laura Nigi ◽  
Giovanna Catalano ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Type 1 Diabetes ◽  
Bone Loss ◽  
Bone Metabolism ◽  
Bone Remodeling ◽  
Bone Mineral ◽  
Bone Fragility ◽  
Bone Homeostasis ◽  
Mineral Density

Type 1 diabetes (T1D) is characterized by bone loss and altered bone remodeling, resulting into reduction of bone mineral density (BMD) and increased risk of fractures. Identification of specific biomarkers and/or causative factors of diabetic bone fragility is of fundamental importance for an early detection of such alterations and to envisage appropriate therapeutic interventions. MicroRNAs (miRNAs) are small non-coding RNAs which negatively regulate genes expression. Of note, miRNAs can be secreted in biological fluids through their association with different cellular components and, in such context, they may represent both candidate biomarkers and/or mediators of bone metabolism alterations. Here, we aimed at identifying miRNAs differentially expressed in serum of T1D patients and potentially involved in bone loss in type 1 diabetes. We selected six miRNAs previously associated with T1D and bone metabolism: miR-21; miR-24; miR-27a; miR-148a; miR-214; and miR-375. Selected miRNAs were analyzed in sera of 15 T1D patients (age: 33.57 ± 8.17; BMI: 21.4 ± 1.65) and 14 non-diabetic subjects (age: 31.7 ± 8.2; BMI: 24.6 ± 4.34). Calcium, osteocalcin, parathormone (PTH), bone ALkaline Phoshatase (bALP), and Vitamin D (VitD) as well as main parameters of bone health were measured in each patient. We observed an increased expression of miR-148a (p = 0.012) and miR-21-5p (p = 0.034) in sera of T1D patients vs non-diabetic subjects. The correlation analysis between miRNAs expression and the main parameters of bone metabolism, showed a correlation between miR-148a and Bone Mineral Density (BMD) total body (TB) values (p = 0.042) and PTH circulating levels (p = 0.033) and the association of miR-21-5p to Bone Mineral Content-Femur (BMC-FEM). Finally, miR-148a and miR-21-5p target genes prediction analysis revealed several factors involved in bone development and remodeling, such as MAFB, WNT1, TGFB2, STAT3, or PDCD4, and the co-modulation of common pathways involved in bone homeostasis thus potentially assigning a role to both miR-148a and miR-21-5p in bone metabolism alterations. In conclusion, these results lead us to hypothesize a potential role for miR-148a and miR-21-5p in bone remodeling, thus representing potential biomarkers of bone fragility in T1D.

scholarly journals Extracellular ASC exacerbated the recurrent ischemic stroke in an NLRP3-dependent manner

2019 ◽  
Vol 40 (5) ◽  
pp. 1048-1060 ◽  
Author(s):  
Xiao-fei He ◽  
Yi-xuan Zeng ◽  
Ge Li ◽  
Yu-kun Feng ◽  
Cheng Wu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Mouse Model ◽  
Inflammatory Responses ◽  
Recurrent Stroke ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Wild Type ◽  
Infarct Area ◽  
Recurrent Strokes

Using a photothrombotic mouse model of single stroke, we show that a single stroke onset increases the nuclear factor-κB (NF-κB), NLR family CARD domain containing protein 4 (NLRC4), and absent in melanoma 2 (AIM2) inflammasomes, as well as the mRNA levels of NLRP3. Next, using a photothrombotic mouse model of recurrent stroke, we found that recurrent strokes increased the activation of NLRP3, exacerbated the brain damage and the pro-inflammatory response in wild type (WT) mice, but not in NLRP3 knockout ( NLRP3 KO) mice. Additionally, we found that apoptosis-associated speck-like protein containing a CARD (ASC) protein level surrounding the infarct area was comparatively increased, but that ASC specks outside of microglia in both the ipsilateral and contralateral of stroke site were decreased in NLRP3 KO mice relative to wild-type (WT) controls, and the number of ASC specks surrounding the second infarct area was positively correlated to the damage scores. Mechanistically, we found that recombinant ASC (RecASC) activated NLRP3 and induced pro-inflammatory responses, exacerbating the outcome of ischemic stroke, in WT mice, but not in NLRP3 KO mice. We therefore conclude that the NLRP3 inflammasome is activated by two attacks of stroke, which act together with ASC to exacerbate recurrent strokes.

scholarly journals Genetic or Enzymatic Disruption of Aromatase Inhibits the Growth of Ectopic Uterine Tissue

2002 ◽  
Vol 87 (7) ◽  
pp. 3460-3466 ◽  
Author(s):  
Zongjuan Fang ◽  
Sijun Yang ◽  
Bilgin Gurates ◽  
Mitsutoshi Tamura ◽  
Evan Simpson ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Mouse Model ◽  
Lesion Size ◽  
Dependent Manner ◽  
Wild Type ◽  
Uterine Tissue ◽  
Abdominal Organs ◽  
Letrozole Treatment ◽  
Key Enzyme ◽  
Dose Dependent

Aromatase P450 (P450arom) is the key enzyme for the biosynthesis of estrogen that is essential for the growth of human endometriosis, a pathology characterized by endometrium-like tissue on the peritoneal surfaces of abdominal organs manifest by pelvic pain and infertility. Surgically transplanted autologous uterine tissue to ectopic sites on the peritoneum in mice has been used as an animal model to study endometriosis. Using this mouse model, we evaluated the roles of the P450arom gene and aromatase enzyme activity in the growth of endometriosis represented by ectopic uterine tissues in mice. Endometriosis was induced surgically in the following groups of mice: 1) untreated transgenic mice with disrupted P450arom gene (ArKO); 2) ArKO mice treated with systemic estrogen; 3) untreated wild-type (WT) mice; 4) WT mice treated with estrogen; 5) WT mice treated with the aromatase inhibitor, letrozole; and 6) WT mice treated with letrozole and estrogen. Each group contained eight mice; +/+ littermates of ArKO mice were used as WT controls. Treatment with estrogen increased the size of ectopic uterine tissues in ArKO and WT mice significantly. The ectopic uterine lesions in untreated and estrogen-treated ArKO mice were strikingly smaller than those in untreated and estrogen-treated WT controls, respectively. Systemic treatment of WT mice with letrozole significantly decreased the lesion size in a dose-dependent manner. The addition of estrogen to letrozole treatment increased the ectopic lesion size, although these lesions were significantly smaller than those in mice treated with estrogen only. As tissue controls, the effects of these conditions on normally located (eutopic) uterine tissue were evaluated. The effects of disruption of the P450arom gene and treatments with letrozole and estrogen seemed to be more profound on ectopic tissues, suggesting that ectopic tissues might be more sensitive to estrogen for growth. We conclude that both an intact P450arom gene and the presence of aromatase enzyme activity are essential for the growth of ectopic uterine tissue in a mouse model of endometriosis.

scholarly journals Osteoking Decelerates Cartilage Degeneration in DMM-Induced Osteoarthritic Mice Model Through TGF-β/smad-dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Houfu Ling ◽  
Qinghe Zeng ◽  
Qinwen Ge ◽  
Jiali Chen ◽  
Wenhua Yuan ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Signaling Pathway ◽  
Subchondral Bone ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Common Disease ◽  
Dependent Manner ◽  
Wild Type ◽  
Bone Sclerosis

Osteoarthritis (OA) is a common disease characterized by cartilage degeneration. In recent years much attention has been paid to Traditional Chinese Medicine (TCM) since its treatments have shown efficacy for ameliorating cartilage degradation with mild side effects. Osteoking is a TCM prescription that has long been used in OA treatment. However, the exact mechanism of Osteoking are not fully elucidated. In the current study, destabilization of the medial meniscus (DMM)-induced OA mice was introduced as a wild type animal model. After 8 weeks of administration of Osteoking, histomorphometry, OARSI scoring, gait analysis, micro-CT, and immunohistochemical staining for Col2, MMP-13, TGFβRII and pSmad-2 were conducted to evaluate the chondroprotective effects of Osteoking in vivo. Further in vitro experiments were then performed to detect the effect of Osteoking on chondrocytes. TGFβRIICol2ER transgenic mice were constructed and introduced in the current study to validate whether Osteoking exerts its anti-OA effects via the TGF-β signaling pathway. Results demonstrated that in wild type DMM mice, Osteoking ameliorated OA-phenotype including cartilage degradation, subchondral bone sclerosis, and gait abnormality. Col2, TGFβRII, and pSmad-2 expressions were also found to be up-regulated after Osteoking treatment, while MMP-13 was down-regulated. In vitro, the mRNA expression of MMP-13 and ADAMTS5 decreased and the mRNA expression of Aggrecan, COL2, and TGFβRII were up-regulated after the treatment of Osteoking in IL-1β treated chondrocytes. The additional treatment of SB505124 counteracted the positive impact of Osteoking on primary chondrocytes. In TGFβRIICol2ER mice, spontaneous OA-liked phenotype was observed and treatment of Osteoking failed to reverse the OA spontaneous progression. In conclusion, Osteoking ameliorates OA progression by decelerating cartilage degradation and alleviating subchondral bone sclerosis partly via the TGF-β signaling pathway.

scholarly journals Mycobacterium indicus pranii therapy induces tumor regression in MyD88- and TLR2-dependent manner

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Pawan Kumar ◽  
Gobardhan Das ◽  
Sangeeta Bhaskar
Keyword(s):  
Tumor Regression ◽  
Tumor Burden ◽  
Antitumor Efficacy ◽  
Dependent Manner ◽  
Wild Type ◽  
Signaling Axis ◽  
B16f10 Tumor ◽  
Mycobacterium Indicus Pranii ◽  
Antigen Presenting ◽  
Tlr2 Signaling

Abstract Objectives Mycobacterium indicus pranii (MIP) is an atypical mycobacterium species with potent antitumor efficacy. Macrophages and dendritic cells (DCs) are antigen-presenting cells, playing key roles in the activation of antitumor immunity. We have previously shown the potent activation of macrophages and DCs by MIP, which is mediated by MyD88–TLR2 signaling axis. In the present study, we further examined the role of MyD88 and TLR2 in MIP-mediated tumor regression. Results Wild-type and MyD88−/− mice were implanted with B16F10 tumor cells, treated with MIP or phosphate-buffered saline (PBS) and monitored for tumor growth. As expected, MIP therapy led to significant tumor regression in wild-type mice. However, antitumor efficacy of MIP was lost in MyD88−/− animals. Both PBS-treated (control) and MIP-treated MyD88−/− mice developed tumors with comparable volume. Since MyD88 relays TLR engagement signals, we analyzed the antitumor efficacy of MIP in TLR2−/− and TLR4−/− mice. It was observed that MIP therapy reduced tumor burden in wild-type and TLR4−/− mice but not in TLR2−/− mice. Tumor volume in MIP-treated TLR2−/− mice were comparable with those in PBS-treated wild-type animals. These results implicated the MyD88–TLR2 signaling axis in the antitumor efficacy of MIP.

scholarly journals β2-adrenergic signal transduction plays a detrimental role in subchondral bone loss of temporomandibular joint in osteoarthritis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Kai Jiao ◽  
Li-Na Niu ◽  
Qi-hong Li ◽  
Gao-tong Ren ◽  
Chang-ming Zhao ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Bone Loss ◽  
Temporomandibular Joint ◽  
Subchondral Bone

scholarly journals Bentonite diminishes DON-induced changes in bone development in mink dams

2016 ◽  
Vol 60 (3) ◽  
pp. 349-355 ◽  
Author(s):  
Ewa Tomaszewska ◽  
Siemowit Muszyński ◽  
Piotr Dobrowolski ◽  
Krzysztof Kostro ◽  
Iwona Taszkun ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Development ◽  
Control Group ◽  
Geometrical Parameters ◽  
Lactation Period ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Pregnancy And Lactation ◽  
Induced Changes ◽  
Dose Dependent

AbstractIntroduction: The aim of this study was to determine the effect of deoxynivalenol (DON), given alone or with bentonite (which eliminates mycotoxicity) in the diet of mink dams throughout mating, pregnancy, and lactation period to pelt harvesting, on the mechanical properties and geometry of their long bones.Material and Methods: The minks were randomly assigned into two groups: a control group (not supplemented with DON, n = 15) and a group fed naturally DON-contaminated wheat and divided into three sub-groups (each sub-group n = 15), depending on bentonite dose: 0 M – sub-group fed naturally DON-contaminated wheat at a concentration of 3.7 mg kg−1 alone; 2 M – sub-group fed naturally DON-contaminated wheat at a concentration of 3.7 mg kg−1 and bentonite at a concentration of 2 kg 1000 kg−1; 0.5 M – sub-group fed naturally DON-contaminated wheat at a concentration of 3.7 mg kg−1 and bentonite at a concentration of 0.5 kg 1000 kg−1.Results: The DON treatment reduced the length of the femur compared to the control group and reduced the bone weight dependently on the amount of bentonite supplementation. However, DON treatment reduced the MRWT and CI of the femur, irrespective of the bentonite supplementation, compared to the control. The total BTD and BMC decreased in all DON-treated groups (irrespective of the bentonite supplementation). Furthermore, the densitometric analysis showed that the main changes in BMD and BMC indicated bone loss in the proximal and distal parts of bone covering the trabecular bone; whereas when bentonite was given at the dose of 2 kg 1000 kg−1 an increase in the whole BMD and BMC was observed in the femoral midshaft.Conclusion: Analysis of the geometrical parameters seems to indicate that endosteal resorption was delayed after bentonite supplementation. The addition of bentonite diminished the DON action on bone homeostasis in the mink dams. Thus bentonite could prevent DON-induced bone loss in a dose-dependent manner.

Sign in / Sign up

Export Citation Format

Share Document