title: Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis.
abstract: OBJECTIVE
  To investigate the disease modifying effects of cathepsin K (CatK) inhibitor L-006235 compared to alendronate (ALN) in two preclinical models of osteoarthritis (OA).
  
  
  METHODS
  Skeletally mature rabbits underwent sham or anterior cruciate ligament transection (ACLT)-surgery and were treated with L-006235 (L-235, 10 mg/kg or 50 mg/kg, p.o., daily) or ALN (0.6 mg/kg, s.c., weekly) for 8-weeks. ACLT joint instability was also induced in CatK(-/-) versus wild type (wt) mice and treated for 16-weeks. Changes in cartilage degeneration, subchondral bone volume and osteophyte area were determined by histology and μ-CT. Collagen type I helical peptide (HP-I), a bone resorption marker and collagen type II C-telopeptide (CTX-II), a cartilage degradation marker were measured.
  
  
  RESULTS
  L-235 (50 mg/kg) and ALN treatment resulted in significant chondroprotective effects, reducing CTX-II by 60% and the histological Mankin score for cartilage damage by 46% in the ACLT-rabbits. Both doses of L-235 were more potent than ALN in protecting against focal subchondral bone loss, and reducing HP-I by 70% compared to vehicle. L-235 (50 mg/kg) and ALN significantly reduced osteophyte formation in histomorphometric analysis by 55%. The Mankin score in ACLT-CatK(-/-) mice was ~2.5-fold lower than the ACLT-wt mice and was not different from sham-CatK(-/-). Osteophyte development was not different among the groups.
  
  
  CONCLUSIONS
  Inhibition of CatK provides significant benefits in ACLT-model of OA, including: 1) protection of subchondral bone integrity, 2) protection against cartilage degradation and 3) reduced osteophytosis. Preclinical evidence supports the role of CatK as a potential therapeutic target for the treatment of OA.
authors.affiliation: Bone Biology Group, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hayami
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhuo
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Wesolowski
authors.forename: Maureen
authors.initials: M
authors.lastname: Pickarski
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D000070598:Anterior Cruciate Ligament Injuries; D001549:Benzamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002358:Cartilage, Articular / Q000473:pathology; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D024042:Collagen Type I / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011817:Rabbits; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D001549:Benzamides; D015415:Biomarkers; D050071:Bone Density Conservation Agents; C507712:CRA 013783; D024042:Collagen Type I; D015853:Cysteine Proteinase Inhibitors; D010446:Peptide Fragments; D010455:Peptides; D013844:Thiazoles; C052929:collagen type I trimeric cross-linked peptide; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D019386:Alendronate