title: Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis.
abstract: OBJECTIVE
  The primary goal of this study was to test the disease-modifying effect of blocking a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 with a neutralizing monoclonal antibody (mAb) starting 4 weeks after destabilization of the medial meniscus (DMM) in the mouse. We also investigated whether ADAMTS-5 blockade reversed mechanical allodynia and decreased monocyte chemoattractant protein (MCP)-1 production by dorsal root ganglia (DRG) cells.
  
  
  METHODS
  Ten-week old male C57BL/6 mice underwent DMM surgery and were either left untreated or treated with anti-ADAMTS-5 mAb or IgG2c isotype control mAb starting 4 weeks after surgery. Knees were collected for histopathology 4 or 12 weeks later. Mechanical allodynia was monitored biweekly in the ipsilateral hind paw through 16 weeks. DRG were collected and cultured 8 weeks after DMM for analysis of MCP-1 production.
  
  
  RESULTS
  By 4 weeks after DMM, mild cartilage degeneration was evident in the medial compartment, small osteophytes were present, and subchondral bone sclerosis was established. By 16 weeks after surgery, significant cartilage deterioration was apparent on the medial tibial plateaux and medial femoral condyles, osteophyte size had increased, and subchondral bone sclerosis was maintained. Treatment with ADAMTS-5 mAb from week 4 to 16 after surgery slowed cartilage degeneration and osteophyte growth but did not affect subchondral bone sclerosis. Moreover, ADAMTS-5 blockade resulted in temporary reversal of mechanical allodynia, which correlated with decreased MCP-1 production by cultured DRG cells.
  
  
  CONCLUSIONS
  This study suggests therapeutic efficacy of an ADAMTS-5 mAb in the DMM model, when therapy starts early in disease.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA; Department of Biochemistry, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Miller
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Tran
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ishihara
authors.affiliation: Experimental Medicine Unit, Immunoinflammation Therapeutic Area, GlaxoSmithKline, Upper Merion, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Larkin
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA; Department of Biochemistry, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA. Electronic address: anne-marie_malfait@rush.edu.
authors.forename: A M
authors.initials: AM
authors.lastname: Malfait
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D000071116:ADAMTS5 Protein; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059225:Nociception / Q000187:drug effects*; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000503:physiopathology*; D013264:Stifle / Q000187:drug effects*; D000070600:Tibial Meniscus Injuries
chemical_list: D057134:Antibodies, Neutralizing; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse
keywords: ADAMTS-5; Mouse model; Osteoarthritis; Pain