The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis

摘要

MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA). Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n?=?7/group) for 7?weeks. The four treatment groups were: (1) sham?+?vehicle; (2) ACLT?+?vehicle; (3) ACLT?+?MIV-711, 30?μmol/kg and (4) ACLT?+?MIV-711, 100?μmol/kg. Subchondral bone and articular cartilage structures were assessed by μCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30?μmol/kg) or vehicle (n?=?15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28?days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured. In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p?