scholarly journals 11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis

2018 ◽  
Vol 92 ◽  
pp. 104-113 ◽  
Author(s):  
R.S. Hardy ◽  
C. Fenton ◽  
A.P. Croft ◽  
A.J. Naylor ◽  
R. Begum ◽  
...  
Keyword(s):  
Bone Loss ◽  
Joint Destruction ◽  
Hydroxysteroid Dehydrogenase ◽  
Chronic Polyarthritis ◽  
Systemic Bone Loss

scholarly journals Effect of Angiotensin II on Bone Erosion and Systemic Bone Loss in Mice with Tumor Necrosis Factor-Mediated Arthritis

2020 ◽  
Vol 21 (11) ◽  
pp. 4145 ◽  
Author(s):  
Takahiko Akagi ◽  
Tomoyuki Mukai ◽  
Takafumi Mito ◽  
Kyoko Kawahara ◽  
Shoko Tsuji ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tumor Necrosis Factor ◽  
Bone Loss ◽  
Tumor Necrosis ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Bone Destruction ◽  
Ang Ii ◽  
Necrosis Factor ◽  
Systemic Bone Loss

Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), which regulates the cardiovascular system. The RAS is reportedly also involved in bone metabolism. The upregulation of RAS components has been shown in arthritic synovial tissues, suggesting the potential involvement of Ang II in arthritis. Accordingly, in the present study, we investigated the role of Ang II in bone erosion and systemic bone loss in arthritis. Ang II was infused by osmotic pumps in tumor necrosis factor-transgenic (TNFtg) mice. Ang II infusion did not significantly affect the severity of clinical and histological inflammation, whereas bone erosion in the inflamed joints was significantly augmented. Ang II administration did not affect the bone mass of the tibia or vertebra. To suppress endogenous Ang II, Ang II type 1 receptor (AT1R)-deficient mice were crossed with TNFtg mice. Genetic deletion of AT1R did not significantly affect inflammation, bone erosion, or systemic bone loss. These results suggest that excessive systemic activation of the RAS can be a risk factor for progressive joint destruction. Our findings indicate an important implication for the pathogenesis of inflammatory bone destruction and for the clinical use of RAS inhibitors in patients with rheumatoid arthritis.

scholarly journals Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice

2013 ◽  
Vol 74 (1) ◽  
pp. 220-226 ◽  
Author(s):  
Emmanuel Coste ◽  
Iain R Greig ◽  
Patrick Mollat ◽  
Lorraine Rose ◽  
Mohini Gray ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Joint Destruction ◽  
Luciferase Reporter ◽  
Collagen Induced Arthritis ◽  
Arthritis Model ◽  
Anti Inflammatory ◽  
Systemic Bone Loss

IntroductionInflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.MethodsThe inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis.ResultsThe ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.ConclusionsHere we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.

scholarly journals A8.3 Deficit of S100A4 Prevents Joint Destruction and Systemic Bone Loss in hTNFtg Mouse Model

2013 ◽  
Vol 72 (Suppl 1) ◽  
pp. A58.1-A58
Author(s):  
Michal Tomcik ◽  
Christina Böhm ◽  
Carina Scholtysek ◽  
Lucie Andres Cerezo ◽  
Wolfgang Baum ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mouse Model ◽  
Joint Destruction ◽  
Systemic Bone Loss

THU0114 The Loss of S100A4 Prevents Joint Destruction and Systemic Bone Loss in hTNFtg Mouse Model

2013 ◽  
Vol 72 (Suppl 3) ◽  
pp. A201.1-A201
Author(s):  
M. Tomcik ◽  
C. Böhm ◽  
C. Scholtysek ◽  
L. Andres Cerezo ◽  
W. Baum ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mouse Model ◽  
Joint Destruction ◽  
Systemic Bone Loss

scholarly journals Synthesis and theoretical activity of three steroid-derivatives on both aromatase and 17β-hydroxysteroid dehydrogenase Type 1 enzymes

2019 ◽  
Vol 9 (2) ◽  
pp. 3898-3906
Keyword(s):  
Breast Cancer ◽  
Blood Pressure ◽  
Bone Loss ◽  
Hydroxysteroid Dehydrogenase ◽  
Secondary Effects ◽  
Cancer Breast ◽  
Docking Model ◽  
Common Malignancy

Breast cancer is the most common malignancy in the worldwide. It is noteworthy, that several drugs are used for cancer breast; nevertheless, some these drugs can produce secondary effects such as changes in blood pressure, bone loss and others. The objective of this investigation was synthesizing three steroid derivatives (compounds 4, 5 and 6) to evaluate their theoretical activity against both aromatase (2W3D) and 17β-Hydroxysteroid dehydrogenase Type 1 (3BH4) enzymes using fisetin and exemestane as control in a docking model. The data found indicate that compound 5 could exert a greater interaction with the 2WD4 and 3BH4 proteins in comparison with fisetin, exemestane and compounds 4 or 6. In conclusion, this compound could be a good candidate as both aromatase and 17β-hydroxysteroid dehydrogenase enzymes inhibitor.

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