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AB0103 Tacrolimus Inhibit IL-1β and ER Stress-Induced, Rankl-Mediated Osteoclastogenesis by Inhibiting Perk, Ire1, Grp78, Eif2a, C-Fos and Nfatc1
  1. W.-S. Lee1,
  2. E.-G. Lee1,
  3. M.-S. Sung1,
  4. C.-H. Lee2,
  5. M.-S. Lee2,
  6. W.-H. Yoo1
  1. 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
  2. 2Department of Internal Medicine, School of medicine, Wonkwang university, Iksan, Korea, Republic Of

Abstract

Background Tacrolimus (TAC) is a T cell specific, anti-inflammatory agent that has been used as a therapeutic agent for rheumatoid arthritis (RA). IL-1β and thapsigargin (TG)-induced endoplasmic reticulum (ER) stress modulate the receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis.

Objectives This study was investigated to define the effects of TAC on IL-1β and ER stress-induced, RANKL-mediated osteoclastogenesis and its mechanisms.

Methods Bone marrow cells (BMCs) were obtained from 5-week-old male ICR mice and cultured to be differentiated into osteoclasts with M-CSF and RANKL in the presence or absence of IL-1β, TG, or TAC. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with dentine slice. The molecular mechanisms of the above effects of TAC on osteoclastogenesis were investigated by using RT-PCR and immunoblotting for osteoclast specific and ER stress signaling molecules, including PERK, IRE1, GRP78, eIF2α, c-Fos and NFATc1.

Results IL-1β and TG-induced ER stress increased the formation of osteoclasts by up-regulating the osteoclast specific signals (c-Fos, NFATc1) and ER stress-associated signaling pathways (PERK, IRE1, GRP78, and eIF2α). TAC significantly inhibited IL-1β and ER stress-induced, RANKL-mediated osteoclastogenesis by down-regulating above signal pathways, dose-dependently.

Conclusions TAC inhibited IL-1β and ER stress-induced, RANKL-mediated osteoclastogenesis by inhibiting intracellular signaling pathways, including PERK, IRE1, GRP78, c-Fos and NFATc1. These results suggest that TAC might have disease modifying effects by inhibition of inflammation and ER stress-induced osteoclastogenesis in the inflammatory joint diseases, such as RA.

Disclosure of Interest None declared

DOI 10.1136/annrheumdis-2014-eular.4216

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