AB0729 DIFFERENTIAL GENDER EFFECT ON RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE AND POTENTIAL STEROID HORMONE MECHANISMS IN SKG MICE
Authors: S. J. Hong, M. Kim, Y. A. Lee
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that causes arthritis of multiple joints. This disease affects not only joints but also other organs. One of the most common extra-articular manifestations is interstitial lung disease, which involves inflammation starting in the interstitium and eventually progressing to fibrosis. Risk factors for developing RA associated ILD (RA-ILD) include smoking, older age, male gender, high levels of anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF). RA occurs 2-3 times more frequently in women than in men, whereas RA-ILD has a higher incidence in men with RA. This gender difference seems to be linked with the alteration of gender hormone metabolism through the estrogen receptor (ER), aromatase and vitamin D receptor (VDR). <h3>Objectives:</h3> The purpose of this study is to investigate whether there are differences in the occurrence of arthritis and ILD based on gender, similar to that observed in human RA, using SKG mouse model. Furthermore, we aimed to investigate the underlying mechanism of how steroid hormones and aromatase contribute to gender-based variations in the incidence of RA-ILD. <h3>Methods:</h3> RA-ILD was induced by injecting 3 mg of curdlan into peritoneal cavity of nine-week-old SKG mice (female, n=14; male, n=13) at 0 and 2 weeks. On a weekly basis, arthritis score, gross photographs of paws, and measurement of body weight were performed. After 21th week of curdlan treatment, the mice were sacrificed for sampling blood and tissues. Hematoxylin &amp; eosin (H&amp;E) and Masson's trichrome staining, RT-qPCR and Western blot analyses were performed to assess lung inflammation and fibrosis. Particularly, Western blot was used to assess the expression levels of ER, aromatase and VDR proteins. <h3>Results:</h3> In the histological observation, the more severe interstitial lung disease was observed more in male mice than in female mice. On the other hand, infiltration of inflammatory cells in the joint tissue was more pronounced in female mice. Additionally, there were increased expression of pro-inflammatory cytokines such as IL-6 and TNF-α in the lung tissues of male mice, along with the elevated expression of fibrosis markers such as fibronectin, collagen type I α 1 chain (COL1A1), α-smooth muscle actin (α-SMA) and mucin-1 (MUC-1). The levels of estrogen-related proteins such as ERα, aromatase and VDR were also noticeably increased in male mice compared with female mice. Elevated expression of aromatase, ERα, and VDR in inflammatory male lung tissue as well. <h3>Conclusion:</h3> Sex differences in clinical manifestations were observed in the RA-ILD animal model using SKG mice. Lung inflammation and fibrosis were more severe in male mice compared to female mice, whereas arthritis was noticeably induced in female mice than male. Male mice lung had higher levels of estrogen-related proteins, including ERα, aromatase, and VDR, in comparison to female mice. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>