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. 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 formation of Ang II, have been previously described in the synovial tissue in patients with rheumatoid arthritis (RA), suggesting the potential involvement of Ang II in the disease process. However, the details are not yet clear. The purpose of this study was to determine whether hypertensive stimulus Ang II further exacerbates TNF-induced bone destruction and systemic bone loss in a murine arthritis model.

Methods: To evaluate the role of Ang II in osteoclastogenesis, we conducted primary bone marrow-derived macrophages (BMMs) culture and co-culture with primary osteoblasts. In the BMMs culture, cells were treated with Ang II in the presence of RANKL. In the co-culture, cells were treated with Ang II in the presence of prostaglandin E2 and vitamin D. The formation of osteoclasts was examined by tartrate-resistant acid phosphatase (TRAP) staining. To investigate in vivo effect of Ang II, Ang II (1 μg/kg/min) was infused by osmotic pumps from 12 to 16 weeks of age in wild-type and TNF-transgenic (TNF-tg) mice. As controls, saline was infused by osmotic pumps in wild-type and TNF-tg mice. The swelling of the paws was graded as arthritis score once per week until 16 weeks of age. The bone property of talus and tibia was analyzed by micro-computed tomography (CT) to assess the extent of bone loss.

Results:  In the BMMs culture, the number of TRAP-positive osteoclasts was not affected by Ang II stimulation, whereas, in the co-culture with osteoblasts, the number of osteoclasts was increased by Ang II treatment in a concentration-dependent manner. This result suggests that Ang II augments osteoclastogenesis through acting on osteoblastic cells not directly on BMMs. In vivo administration of Ang II significantly raised the systolic blood pressure in both wild-type and TNF-tg mice. Arthritis scores in TNF-tg mice were not altered by the Ang II infusion. Micro-CT analysis revealed that erosive bone destruction on the talus was significantly more severe in Ang II-infused TNF-tg mice compared to saline-infused TNF-tg mice. Bone volume per total volume in the trabecular bone of proximal tibia was significantly lower in TNF-tg mice than in wild-type mice, and further diminished by the Ang II infusion­­­­.

Conclusion:  Ang II infusion exacerbated bone destruction and systemic bone loss without significant alteration in the severity of arthritis. These findings suggest that Ang II attributes to the bone destructive mechanisms mainly by increasing osteoclastogenesis with the minor effect on the inflammation in the murine arthritis model. Ang II could be a therapeutic target to protect the inflammatory bone destruction in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/angiotensin-ii-exacerbates-bone-destruction-in-tnf-transgenic-arthritis-mice/