title: Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis.
abstract: OBJECTIVE
  Through its location on nociceptors, acid-sensing ion channel 3 (ASIC-3) is activated by decreases in pH and plays a significant role in musculoskeletal pain. We recently showed that decreases in pH activate ASIC-3 located on fibroblast-like synoviocytes (FLS), which are key cells in the inflammatory process. The purpose of this study was to test whether ASIC-3-deficient mice with arthritis have altered inflammation and pain relative to controls.
  
  
  METHODS
  Collagen antibody-induced arthritis (CAIA) was generated by injection of an anti-type II collagen antibody cocktail. Inflammation and pain parameters in ASIC-3(-/-) and ASIC-3(+/+) mice were assessed. Disease severity was assessed by determining clinical arthritis scores, measuring joint diameters, analyzing joint histology, and assessing synovial gene expression by quantitative polymerase chain reaction analysis. Cell death was assessed with a Live/Dead assay of FLS in response to decreases in pH. Pain behaviors in the mice were measured by examining withdrawal thresholds in the joints and paws and by measuring their physical activity levels.
  
  
  RESULTS
  Surprisingly, ASIC-3(-/-) mice with CAIA demonstrated significantly increased joint inflammation, joint destruction, and expression of interleukin-6 (IL-6), matrix metalloproteinase 3 (MMP-3), and MMP-13 in joint tissue as compared to ASIC-3(+/+) mice. ASIC-3(+/+) FLS showed enhanced cell death when exposed to pH 6.0 in the presence of IL-1β, which was abolished in ASIC-3(-/-) FLS. Despite enhanced disease severity, ASIC-3(-/-) mice did not develop mechanical hypersensitivity of the paw and showed greater levels of physical activity.
  
  
  CONCLUSIONS
  Our findings are consistent with the hypothesis that ASIC-3 plays a protective role in the inflammatory arthritides by limiting inflammation through enhanced synoviocyte cell death, which reduces disease severity, and through the production of pain, which reduces joint use.
authors: Department of Physical Therapy and Rehabilitation Science, University of Iowa Carver College of Medicine, Iowa City 52242, USA. kathleen-sluka@uiowa.edu
authors: Kathleen A
authors: KA
authors: Sluka
authors: Lynn A
authors: LA
authors: Rasmussen
authors: Meghan M
authors: MM
authors: Edgar
authors: James M
authors: JM
authors: O'Donnell
authors: Roxanne Y
authors: RY
authors: Walder
authors: Sandra J
authors: SJ
authors: Kolker
authors: David L
authors: DL
authors: Boyle
authors: Gary S
authors: GS
authors: Firestein
mesh_terms: D062565:Acid Sensing Ion Channels / Q000172:deficiency*; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D001522:Behavior, Animal; D016923:Cell Death; D002470:Cell Survival; D005260:Female; D015870:Gene Expression; D006614:Hindlimb; D006930:Hyperalgesia; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold; D012720:Severity of Illness Index; D013585:Synovitis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology
chemical_list: C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D015850:Interleukin-6; D020782:Matrix Metalloproteinases