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: Tokio Matsuzaki, Takehiko Matsushita, Yasuhiko Tabata, Takashi Saito, Tomoyuki Matsumoto, Kanto Nagai, Ryosuke Kuroda, Masahiro Kurosaka
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 37 Pg. 9904-9911 (Dec 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 25236536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Drug Carriers
• Hydrogels
• Immunosuppressive Agents
• Micelles
• Gelatin
• Sirolimus

Topics

• Animals
• Autophagy (drug effects)
• Chondrocytes (drug effects, pathology)
• Drug Carriers (chemistry)
• Gelatin (chemistry)
• Hydrogels (chemistry)
• Immunosuppressive Agents (administration & dosage, therapeutic use)
• Injections, Intra-Articular
• Male
• Mice
• Mice, Inbred C57BL
• Micelles
• Osteoarthritis (pathology, prevention & control)
• Sirolimus (administration & dosage, therapeutic use)