title: Effects of pharmacological inhibition of cathepsin K on fracture repair in mice.
abstract: Cathepsin K inhibitors (CatK-I) have been developed and established to restore bone mass in both animal models of bone loss and postmenopausal osteoporotic patients. We investigated the effects of a CatK-I L-006235 on bone repair and compared to alendronate (ALN) for its known effects on fracture healing in preclinical models. Femoral fractures were performed on wild type mice that were given vehicle (CON), CatK-I or ALN from day 0 post-fracture until euthanasia. Radiologic and micro-CT analyses demonstrated that CatK-I enhanced mineralization within the calluses at day 21 post-fracture, but to a lesser degree than ALN. Histological analyses showed residual unmineralized and mineralized cartilage in the calluses of CatK-I and ALN treated groups at day 21 post-fracture compared to that in CON. CatK-I enhanced the number of tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts in the fracture calluses compared to ALN and CON treated groups. However, relative levels of serum C-terminal telopeptides of type I collagen (CTX) normalized to the number of TRAP+ osteoclasts within the calluses were significantly decreased in both CatK-I and ALN groups compared to CON. Additionally, the percentages of osteoblast surface over mineralized calluses and levels of the bone formation marker serum N-terminal propeptide of type I procollagen (P1NP) were comparable between CatK-I versus CON groups, while these bone formation parameters were decreased by ALN. Taken together, these results indicate that unlike ALN, CatK-I inhibits osteoclastic activity without changing bone formation, and the inhibition of CatK delayed but did not abrogate callus remodeling during bone repair.
authors.affiliation: New England Musculoskeletal Institute, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Do Y
authors.initials: do Y
authors.lastname: Soung
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gentile
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.forename: Hicham
authors.initials: H
authors.lastname: Drissi
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D002146:Bony Callus; D002113:Calcification, Physiologic / Q000187:drug effects; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002452:Cell Count; D017102:Fracture Healing / Q000187:drug effects*; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D011859:Radiography
chemical_list: D011480:Protease Inhibitors; D056657:Cathepsin K