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

Autor:	Michael Larson, Neha Shah, Charlotte Edenius, Biljana Rizoska, Alison M. Bendele, Chris Jerome, Karin Tunblad, Valerie Yoder Otto, Don Maul, Urszula Grabowska, Erik Lindström
Rok vydání:	2018
Předmět:	Cartilage Articular Male 0301 basic medicine Pathology medicine.medical_specialty Anterior cruciate ligament Cathepsin K HP-1 lcsh:Medicine Osteoarthritis Cysteine Proteinase Inhibitors General Biochemistry Genetics and Molecular Biology Condyle Bone resorption 03 medical and health sciences Dogs 0302 clinical medicine medicine Animals Femur Tibia Anterior Cruciate Ligament Bone Resorption Organic Chemicals CTX-II CTX-I 030203 arthritis & rheumatology Principal Component Analysis business.industry Anterior Cruciate Ligament Injuries Research Cartilage lcsh:R Subchondral bone General Medicine medicine.disease Disease Models Animal 030104 developmental biology medicine.anatomical_structure Female Joints Rabbits business Biomarkers
Zdroj:	Journal of Translational Medicine, Vol 16, Iss 1, Pp 1-16 (2018) Journal of Translational Medicine
ISSN:	1479-5876
DOI:	10.1186/s12967-018-1425-7
Popis:	Background 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). Methods 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. Results In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p
Databáze:	OpenAIRE
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