title: Osteoarthritic change is delayed in a Ctsk-knockout mouse model of osteoarthritis.
abstract: OBJECTIVE
  Several studies have shown that cathepsin K (CTK) is overexpressed in osteoarthritic (OA) cartilage and subchondral bone. However, it has not been well established whether CTK expression is harmful or beneficial. We undertook this study to investigate the direct involvement of CTK in OA development using Ctsk-knockout (Ctsk(-/-)) mice in a joint instability-induced model of OA.
  
  
  METHODS
  We analyzed the natural course of the phenotype of 25-week-old Ctsk(-/-) mice. OA development was evaluated with a modified Mankin histologic score up to 8 weeks after surgery was performed to destabilize the knee in Ctsk(-/-) and Ctsk(+/+) mice. Histologic analysis was used to evaluate expression of CTK, matrix metalloproteinase 13 (MMP-13), ADAMTS-5, and tartrate-resistant acid phosphatase (TRAP) proteins in chondrocytes, synovial cells, and osteoclasts. Bone architecture was analyzed by histomorphometry.
  
  
  RESULTS
  Bone mineral content and bone volume were higher in Ctsk(-/-) mice at 25 weeks, whereas OA did not develop spontaneously in either Ctsk(-/-) or Ctsk(+/+) mice. In a model of destabilization-induced OA, OA progression was significantly delayed in Ctsk(-/-) mice. CTK was overexpressed in chondrocytes and synovial cells of knee joints developing OA in Ctsk(+/+) mice. MMP-13 and ADAMTS-5 were less strongly expressed in chondrocytes of Ctsk(-/-) mice, and MMP-13 was less strongly expressed in synovial cells. TRAP-positive osteoclasts were overexpressed in Ctsk(-/-) mice.
  
  
  CONCLUSIONS
  These results indicate that CTK plays crucial direct roles in the early to intermediate stage of OA development. CTK-positive chondrocytes and synovial cells may be a possible target to prevent disease progression in OA.
authors.affiliation: Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kozawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishida
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Urakawa
authors.forename: Eisuke
authors.initials: E
authors.lastname: Arai
authors.forename: Naohisa
authors.initials: N
authors.lastname: Futamura
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.forename: Lina
authors.initials: L
authors.lastname: Hu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology*; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13