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.
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 June 4, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-tacrolimus-on-endoplasmic-reticulum-stress-mediated-osteoclastogenesis-in-a-collagen-induced-arthritis-mouse-model/