SPACIA1/SAAL1-Deficient Mice Show Reduced Disease Progression in Collagen-Induced Arthritis

Ryoji Fujii¹, Iwao Seki², Rie Komatsu¹, Tomomi Kohara², Miwa Takai², Tomoo Sato³, Koji Konomi², Hiroyuki Aono², Kazuo Yudoh¹, Kusuki Nishioka⁴ and Toshihiro Nakajima⁵, ¹Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa, Japan, ²Santen Pharmaceutical Co. Ltd., Nara, Japan, ³Molecular Medical Science, St. Marianna University School of Medicine, Kanagawa, Japan, ⁴Institute of Medical Science, Tokyo Medical University, Tokyo, Japan, ⁵Department of Locomotor Science/Future Medical Science, Institute of Medical Science, integrated Gene Editing Section (iGES), Tokyo Medical University, Tokyo, Japan

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Synovitis

Session Information

Date: Tuesday, November 10, 2015

Title: Rheumatoid Arthritis - Animal Models Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: SPACIA1/SAAL1 is a gene associated with abnormal synovial proliferation. We previously showed that SPACIA1/SAAL1 small interfering RNA inhibited the proliferation of rheumatoid arthritis synovial fibroblasts in vitro and that SPACIA1/SAAL1 transgenic mice exhibited early onset and rapid progression of collagen-induced arthritis (CIA). Therefore, SPACIA1/SAAL1 could be involved in the progression of synovitis. In the present study, we generated SPACIA1/SAAL1-deficient mice and investigated the gene’s potential as a druggable target.

Methods: To ablate the functional mouse SPACIA1/SAAL1 locus, we deleted its exon 4 in the C57BL/6 genome using the Cre/loxP system to cause a frameshift mutation. After backcross mating with the DBA/1J strain for 8 generations, we examined the effect of SPACIA1/SAAL1 in CIA. In SPACIA1/SAAL1-deficient and wild-type (control) mice, the serum levels of anti-type II collagen antibody and the bone destruction score were measured on day 56 after the first collagen injection.

Results: Heterozygous (SPACIA1^+/⁻) and homozygous (SPACIA1^−/−) mice systemically lacking SPACIA1/SAAL1 developed normally and did not show abnormalities. In the SPACIA1^−/− mice, the incidence of arthritis and its score were significantly reduced on days 35 and 56, respectively, when compared with values in wild-type mice. However, all tested mice developed CIA eventually. The mean anti-type II collagen antibody level and bone destruction score in the SPACIA1^−/− mice decreased by half compared with those in wild-type mice, but this difference was not significant.

Conclusion: Consistent with our previous study of CIA using SPACIA1/SAAL1 transgenic mice, this study also indicated that SPACIA1/SAAL1 may be involved in the progression of CIA. However, we conclude that there is almost no potential for SPACIA1/SAAL1 itself as a druggable target, although SPACIA could be related to regulation of crucial factors in CIA. We previously found that SPACIA1/SAAL1 is related to cyclin-dependent kinase 6 expression, at least in cultured rheumatoid arthritis synovial fibroblasts. We are currently studying downstream targets of SPACIA1/SAAL1, including cyclin-dependent kinase 6, to find potential druggable targets.

Disclosure: R. Fujii, None; I. Seki, None; R. Komatsu, None; T. Kohara, None; M. Takai, None; T. Sato, None; K. Konomi, None; H. Aono, None; K. Yudoh, None; K. Nishioka, None; T. Nakajima, None.

To cite this abstract in AMA style:

Fujii R, Seki I, Komatsu R, Kohara T, Takai M, Sato T, Konomi K, Aono H, Yudoh K, Nishioka K, Nakajima T. SPACIA1/SAAL1-Deficient Mice Show Reduced Disease Progression in Collagen-Induced Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/spacia1saal1-deficient-mice-show-reduced-disease-progression-in-collagen-induced-arthritis/. Accessed .

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