Background/Purpose: Angiotensin II (Ang II) is known to function on various organs including kidneys, adrenal glands as well as the nervous and cardiovascular systems through its specific receptors, called Ang II type I receptor (AT1R), type II receptor and Mas receptor. In addition, recent studies have revealed that Ang II affects the skeletal system as well. The presence and up-regulation of receptors for Ang II and angiotensin converting enzyme, a key enzyme for the generation of Ang II, have been previously shown in the synovial tissue in patients with rheumatoid arthritis, suggesting the potential involvement of Ang II in the disease process. However, the details are not yet clear. The purpose of this study is to determine whether and how Ang II exacerbates TNF-induced bone destruction using a murine arthritis model.

Methods: To investigate the effect of exogenous Ang II, Ang II (1 μg/kg/min) was infused by osmotic pumps from 12 to 16 weeks of age in wild-type and human TNF-transgenic (hTNF-tg) mice. As controls, H₂O was infused by osmotic pumps in each genotype. The swelling of the paws was graded as arthritis score once per week until 16 weeks of age. The bone property of the talus of the hind paws was analyzed by micro-computed tomography (CT) to assess the extent of bone erosion. Inflammation, bone erosion, and osteoclast formation were evaluated by histological analysis. To examine the role of endogenous AT1R on the erosive bone destruction, AT1R deficient (AT1R-KO) mice were crossed with hTNF-tg. Inflammation and bone erosion were evaluated as described above.

Results: Micro-CT and histological analyses revealed that systemic administration of Ang II significantly augmented bone erosion on hind paws in hTNF-tg mice. Ang II increased the number of osteoclasts around the talus. The severity of clinical arthritis and the histological degree of inflammatory cell infiltration were not affected by Ang II infusion. Interestingly, genetic deletion of AT1R also resulted in more severe bone destruction in hTNF-tg mice without affecting the clinical severity of arthritis.

Conclusion: Both systemic administration of Ang II and genetic deletion of AT1R exacerbated bone destruction in hTNF-tg mice. These results suggest that Ang II is likely to be involved in the TNF-induced bone destruction, and the binding of Ang II to the receptors other than AT1R may be important in the process. Our findings have important implication for the present clinical use of AT1R blockers in patients with rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/angiotensin-ii-type-i-receptor-deficiency-exacerbates-erosive-bone-destruction-of-htnf-transgenic-arthritis-mice/