Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Akagi T

PROVIDER: S-EPMC7312645 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Akagi Takahiko T Mukai Tomoyuki T Mito Takafumi T Kawahara Kyoko K Tsuji Shoko S Fujita Shunichi S Uchida Haruhito A HA Morita Yoshitaka Y

International journal of molecular sciences 20200610 11

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 ...[more]

PMID: 32532031

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Project description:To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).Tumor necrosis factor ? (TNF?) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNF?(-/-) , Toll-like receptor-deficient (TLR-7(-/-) ), interferon (IFN)-?/?/? receptor-knockout (IFNAR(-/-) ), and B cell-deficient (?mt) mice treated with pristane. Flow cytometry was used to examine TNF? production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction.BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNF? overproduction. BM from mice with a type I IFN-mediated lupus syndrome induced by pristane showed similar abnormalities. TNF? was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNF? production was abolished in pristane-treated TLR-7(-/-) and ?mt mice but was restored in ?mt mice by infusing normal plasma. Pristane-treated WT and IFNAR(-/-) mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7(-/-) and TNF?(-/-) mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated WT mice but was normal in BM from pristane-treated TNF?(-/-) mice.Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNF? driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNF? production mediating glomerulonephritis and hematologic involvement, respectively.

Dataset Information

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

Publications

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

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