title: Increased RANKL-mediated osteoclastogenesis by interleukin-1β and endoplasmic reticulum stress.
abstract: OBJECTIVE
  The mechanism by which IL-1β and thapsigargin (TG)-induced endoplasmic reticulum (ER) stress modulate the receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis remains elusive. Thus, we investigated the osteoclast-specific and ER signals in osteoclastogenesis of bone marrow-derived cells.
  
  
  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 4-phenylbutyric acid (PBA), an ER stress-reducing drug. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with a dentine slice. The molecular mechanism of IL-1β and ER stress in osteoclastogenesis was investigated in BMCs transfected with siRNA for GRP78, PERK and IRE1 using reverse transcription-polymerase chain reaction and immunoblotting for osteoclast-specific and ER stress signaling molecules.
  
  
  RESULTS
  IL-1β and ER stress induced by TG-augmented the formation of osteoclasts, which was significantly inhibited by PBA and was mediated with osteoclast-specific signals, including c-Fos, NFATc1, and ER stress- associated signaling pathways, such as PERK, IRE1, GRP78, and eIF2α. siRNA-mediated knockdown of ER stress signals inhibited the expression of NFATc1 and c-Fos, thus reducing IL-1β and/or TG-induced formation of osteoclasts.
  
  
  CONCLUSIONS
  Osteoclastogenesis by IL-1β and/or ER stress is mainly associated with upregulation of eIF2α, GRP78, PERK and IRE1. These results suggest that the signaling pathway of ER stress-induced osteoclast formation might be a new therapeutic target to prevent inflammatory and destructive arthritic disease such as RA and diverse osteoporosis.
authors: Department of Internal Medicine, Medical School and Research Institute of Clinical Medicine, Chonbuk National University and Chonbuk, National University Hospital, Jeonju, Jeonbuk 561-712, South Korea.
authors: Eun-Gyeong
authors: EG
authors: Lee
authors: Department of Internal Medicine, Medical School and Research Institute of Clinical Medicine, Chonbuk National University and Chonbuk, National University Hospital, Jeonju, Jeonbuk 561-712, South Korea.
authors: Myung-Soon
authors: MS
authors: Sung
authors: Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston RI 02881, United States of America.
authors: Han-Gyul
authors: HG
authors: Yoo
authors: Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-712, South Korea.
authors: Han-Jung
authors: HJ
authors: Chae
authors: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea.
authors: Hang-Rae
authors: HR
authors: Kim
authors: Department of Internal Medicine, Medical School and Research Institute of Clinical Medicine, Chonbuk National University and Chonbuk, National University Hospital, Jeonju, Jeonbuk 561-712, South Korea. Electronic address: ywhim@jbnu.ac.kr.
authors: Wan-Hee
authors: WH
authors: Yoo
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D002454:Cell Differentiation; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D010654:Phenylbutyrates; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717248:Hspa5 protein, mouse; D053583:Interleukin-1beta; D010654:Phenylbutyrates; D053245:RANK Ligand; D019284:Thapsigargin; C075773:4-phenylbutyric acid
keywords: 4-phenylbutyric acid; Endoplasmic reticulum stress; IL-1β; Osteoclast; Thapsigargin