Effect of Tacrolimus on Endoplasmic Reticulum Stress-Mediated Osteoclastogenesis in a Collagen-Induced Arthritis Mouse Model

Won-Seok Lee¹, Yun Jung Choi², Myong-Joo Hong³, Chang-Hoon Lee^4,5, Myeung Su Lee⁶, Young Sun Suh⁷, Sang-Il Lee⁸ and Wan-Hee Yoo⁹, ¹Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine of Chonbuk National University Hospital-Chonbuk National University, jeonju, South Korea, ²Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine of Chonbuk National University Hospital-Chonbuk National University, JeonJu, South Korea, ³Internal Medicine, Presbyterian Medical center, Jeonju, South Korea, ⁴Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan, Chonbuk, South Korea, ⁵Rheumatology, Department of Internal Medicine, School of medicine, Wonkwang university, Iksan, Chonbuk, South Korea, ⁶Internal Medicine, School of Medicine, Wonkwang University, Iksan, Chonbuk, South Korea, ⁷Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea, ⁸Division of Rheumatology, Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, South Korea, ⁹Division of Rhuematology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine of Chonbuk National University Hospital-Chonbuk National University, Jeonju, South Korea

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: ER Stress

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: Although the effects of tacrolimus on T cells are well known, its direct effects on osteoclastogenesis remain unclear. We previously revealed that thapsigargin (TG)-induced endoplasmic reticulum (ER) stress modulates receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis in vitro. We have also shown that tacrolimus downregulates ER-mediated osteoclastogenesis in vitro. We examined whether the regulatory effect of tacrolimus on ER stress-mediated osteoclastogenesis and inflammation could be detected in collagen-induced arthritis (CIA).

Methods: CIA was induced by immunization of female Lewis rats with an emulsion of bovine type II collagen and incomplete Freund’s adjuvant. Tacrolimus at doses of 3.2 mg/kg or a placebo formulation were orally administered to rats for 28 days from the day after immunization. The histopathological changes in osteolysis and the expression of specific ER stress-mediated inflammatory signaling pathway biomarkers (IRE1α, GRP78/Bip, c-Fos, and NF-κB) were examined. In addition, pro-inflammatory cytokines and osteoclastogenic molecules (RANKL and M-CSF) were assessed in the knee and ankle joints in the CIA mouse model. Changes in bone mass and structure were assessed based on micro-CT scans of ankle and knee joints.

Results: In the mouse model, tacrolimus administration resulted in a dramatic amelioration of osteolysis and a significant reduction in ER stress intensity. Simultaneously, tacrolimus lessened inflammatory cell infiltration, reduced osteoclastogenesis capability, and reduced the inflammatory response via reduced levels of IRE1α, GRP78/Bip, c-Fos, and NF-κB. Based on the Micro-CT analysis, bone erosion on the hind paw in CIA was augmented compared with that of CIA + tacrolimus mice.

Conclusion: These findings suggest that tacrolimus has the potential to inhibit the progression of joint damage by inhibiting ER stress and has anti-inflammatory effects in established rheumatoid arthritis.

Disclosure: W. S. Lee, None; Y. J. Choi, None; M. J. Hong, None; C. H. Lee, None; M. S. Lee, None; Y. S. Suh, None; S. I. Lee, None; W. H. Yoo, None.

To cite this abstract in AMA style:

Lee WS, Choi YJ, Hong MJ, Lee CH, Lee MS, Suh YS, Lee SI, Yoo WH. Effect of Tacrolimus on Endoplasmic Reticulum Stress-Mediated Osteoclastogenesis in a Collagen-Induced Arthritis Mouse Model [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/effect-of-tacrolimus-on-endoplasmic-reticulum-stress-mediated-osteoclastogenesis-in-a-collagen-induced-arthritis-mouse-model/. Accessed .

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