title: Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice.
abstract: OBJECTIVE
  To determine the importance of the enzymatic activity of ADAMTS-4 in normal growth and development and to evaluate the role of ADAMTS-4 in the progression of osteoarthritis (OA).
  
  
  METHODS
  We generated catalytic domain-deleted ADAMTS-4-transgenic mice and performed extensive gross and histologic analyses of various organs. The mice were challenged by surgical induction of joint instability leading to OA, to determine the importance of the enzymatic activity of ADAMTS-4 in the progression of the disease. The response of wild-type (WT) and ADAMTS-4-knockout (ADAMTS-4-KO) articular cartilage to interleukin-1 and retinoic acid challenge in vitro was also evaluated.
  
  
  RESULTS
  ADAMTS-4-KO mice up to 1 year of age exhibited no gross or histologic abnormalities in 36 tissue sites examined. Despite evidence of ADAMTS-4 expression and activity in growth plates of WT mice, catalytic silencing of this proteinase caused no abnormalities in skeletal development, growth, or remodeling. There was no effect of ADAMTS-4 knockout on the progression or severity of OA 4 weeks or 8 weeks after surgical induction of joint instability. Enzymatic cleavage of aggrecan at the TEGE(373-374)ARGS site was clearly evident after exposure of articular cartilage from ADAMTS-4-KO mice to inflammatory cytokines.
  
  
  CONCLUSIONS
  Although expression of the ADAMTS-4 gene has been found in many tissues throughout the body, deletion of enzymatic activity did not appear to have any effect on normal growth and physiology. Our study provides evidence that ADAMTS-4 is the primary aggrecanase in murine growth plates; however, deletion of its enzymatic activity did not affect normal long bone remodeling. Our results also lead to the hypothesis that, in the mouse, ADAMTS-4 is not the primary enzyme responsible for aggrecan degradation at the TEGE(373-374)ARGS site. The elucidation of the relative importance of ADAMTS-4 in the pathologic process of human OA will require examination of human OA tissues and evidence of disease modification in patients following therapeutic intervention.
authors.affiliation: Wyeth Research, Cambridge, Massachusetts 02140, USA.
authors.forename: Sonya S
authors.initials: SS
authors.lastname: Glasson
authors.forename: Roger
authors.initials: R
authors.lastname: Askew
authors.forename: Barbara
authors.initials: B
authors.lastname: Sheppard
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Carito
authors.forename: Tracey
authors.initials: T
authors.lastname: Blanchet
authors.forename: Hak-Ling
authors.initials: HL
authors.lastname: Ma
authors.forename: Carl R
authors.initials: CR
authors.lastname: Flannery
authors.forename: Kim
authors.initials: K
authors.lastname: Kanki
authors.forename: Eunice
authors.initials: E
authors.lastname: Wang
authors.forename: Diane
authors.initials: D
authors.lastname: Peluso
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yang
authors.forename: Manas K
authors.initials: MK
authors.lastname: Majumdar
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Morris
mesh_terms: D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D053674:Aggrecans; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000201:enzymology / Q000209:etiology*; D011348:Procollagen N-Endopeptidase; D011509:Proteoglycans / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C508320:Acan protein, mouse; D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D011509:Proteoglycans; D014212:Tretinoin; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse