title: Intra-articular administration of gelatin hydrogels incorporating rapamycin-micelles reduces the development of experimental osteoarthritis in a murine model.
abstract: Autophagy is a cellular homeostasis mechanism that may have a protective role against osteoarthritis (OA). The present study investigated the therapeutic effect of local administration of rapamycin, a potent activator of autophagy, against OA. To achieve controlled intra-articular administration of rapamycin, gelatin hydrogels incorporating rapamycin-micelles were created and the release profile was evaluated in vitro. The therapeutic effects of gelatin hydrogels incorporating rapamycin-micelles were then tested in a murine OA model. Mice were divided into four groups: Group 1, gelatin hydrogels alone; Group 2, single injection of 1 μg rapamycin; and Groups 3 and 4, gelatin hydrogels incorporating 100 ng or 1 μg rapamycin-micelles, respectively. Immunohistochemical analysis revealed that autophagic marker-positive chondrocytes were increased in the rapamycin-treated mice at 10 weeks after surgery. The histologic score was better in Groups 3 and 4 than in Groups 1 and 2, and Group 2 had a better score than Group 1. Delayed OA progression was maintained even at 16 weeks after surgery in Group 4. Microarray and real-time polymerase chain reaction analysis indicated that OA mediator genes were downregulated in the rapamycin-treated mice. Our novel system for intra-articular administration of rapamycin could be a novel therapeutic approach for treating patients with OA.
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Tokio
authors.initials: T
authors.lastname: Matsuzaki
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan. Electronic address: matsushi@med.kobe-u.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Kanto
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D005780:Gelatin / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007270:Injections, Intra-Articular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D010003:Osteoarthritis / Q000473:pathology / Q000517:prevention & control*; D020123:Sirolimus / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: D004337:Drug Carriers; D020100:Hydrogels; D007166:Immunosuppressive Agents; D008823:Micelles; D005780:Gelatin; D020123:Sirolimus
keywords: Animal model; Arthritis; Biodegradation; Cartilage; Matrix metalloproteinase