title: Suppression of arthritis-induced bone erosion by a CRAC channel antagonist.
abstract: OBJECTIVE
  We have shown in vitro and in vivo that osteoclast maturation requires calcium-release activated calcium (CRAC) channels. In inflammatory arthritis, osteoclasts mediate severe and debilitating bone erosion. In the current study, we assess the value of CRAC channels as a therapeutic target to suppress bone erosion in acute inflammatory arthritis.
  
  
  METHODS
  Collagen-induced arthritis (CIA) was induced in mice. The CRAC channel inhibitor 3,4-dichloropropionaniline (DCPA) and a placebo was administered 1 day prior to collagen II booster to induce arthritis. Effects on swelling, inflammatory cell invasion in joints, serum cytokines and bone erosion were measured.
  
  
  RESULTS
  Assays, by blinded observers, of arthritis severity showed that DCPA, 21 mg/kg/day, suppressed arthritis development over 3 weeks. Bone and cartilage damage in sections of animal feet was reduced approximately 50%; overall swelling of joints was reduced by a similar amount. Effects on bone density by µCT showed clear separation in DCPA-treated CIA animals from CIA without treatment, while differences between controls without CIA and CIA treated with DCPA differed by small amounts and in most cases were not statistically different. Response was not related to anticollagen titres. There were no adverse effects in the treated group on animal weight or activity, consistent with low toxicity. The effect was maximal 12-17 days after collagen booster, during the rapid appearance of arthritis in untreated CIA. At 20 days after treatment (day 40), differences in arthritis score were reduced and tumour necrosis factor α, interleukin (IL)-1, or IL-6 in the serum of the animals were similar in treated and untreated animals.
  
  
  CONCLUSIONS
  DCPA, a novel inhibitor of CRAC channels, suppresses bone erosion associated with acute arthritis in mice and might represent a new treatment modality for acute arthrits.
authors.affiliation: Departments of Pathology and of Cell Biology , The Pittsburgh VA Medical Center and the University of Pittsburgh , Pittsburgh , USA.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Blair
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology and the Department of Medical Genetics & Molecular Biochemistry , Temple University School of Medicine , Philadelphia, Pennsylvania , USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Soboloff
authors.affiliation: Departments of Pathology and of Microbiology, Immunology & Cell Biology , West Virginia University School of Medicine , Morgantown, West Virginia , USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Robinson
authors.affiliation: Departments of Pathology and of Cell Biology , The Pittsburgh VA Medical Center and the University of Pittsburgh , Pittsburgh , USA.
authors.forename: Irina L
authors.initials: IL
authors.lastname: Tourkova
authors.affiliation: Departments of Pathology and of Cell Biology , The Pittsburgh VA Medical Center and the University of Pittsburgh , Pittsburgh , USA.
authors.forename: Quitterie C
authors.initials: QC
authors.lastname: Larrouture
authors.affiliation: Departments of Pathology and of Cell Biology , The Pittsburgh VA Medical Center and the University of Pittsburgh , Pittsburgh , USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Witt
authors.affiliation: Department of Microbiology, Immunology & Cell Biology, and the Mary Babb Randolph Cancer Center , West Virginia University School of Medicine , Morgantown, West Virginia , USA.
authors.forename: Ida
authors.initials: I
authors.lastname: Holaskova
authors.affiliation: Department of Microbiology, Immunology & Cell Biology, and the Mary Babb Randolph Cancer Center , West Virginia University School of Medicine , Morgantown, West Virginia , USA.
authors.forename: Rosana
authors.initials: R
authors.lastname: Schafer
authors.affiliation: Department of Microbiology, Immunology & Cell Biology, and the Mary Babb Randolph Cancer Center , West Virginia University School of Medicine , Morgantown, West Virginia , USA.
authors.forename: Meenal
authors.initials: M
authors.lastname: Elliott
authors.affiliation: Department of Pediatrics , University of Iowa Carver College of Medicine , Iowa City ,.
authors.forename: Raphael
authors.initials: R
authors.lastname: Hirsch
authors.affiliation: Department of Microbiology, Immunology & Cell Biology, and the Mary Babb Randolph Cancer Center , West Virginia University School of Medicine , Morgantown, West Virginia , USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Barnett
keywords: Arthritis; Bone Mineral Density; Cytokines; Treatment
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