RRC ID 49246
Author Meckes JK, Caramés B, Olmer M, Kiosses WB, Grogan SP, Lotz MK, D'Lima DD.
Title Compromised autophagy precedes meniscus degeneration and cartilage damage in mice.
Journal Osteoarthritis Cartilage
Abstract OBJECTIVE:Autophagy is a cellular homeostasis mechanism that facilitates normal cell function and survival. Objectives of this study were to determine associations between autophagic responses with meniscus injury, joint aging, and osteoarthritis (OA), and to establish the temporal relationship with structural changes in menisci and cartilage.
METHODS:Constitutive activation of autophagy during aging was measured in GFP-LC3 transgenic reporter mice between 6 and 30 months. Meniscus injury was created by surgically destabilizing the medial meniscus (DMM) to induce posttraumatic OA in C57BL/6J mice. Levels of autophagy proteins and activation were analyzed by confocal microscopy and immunohistochemistry. Associated histopathological changes, such as cellularity, matrix staining, and structural damage, were graded in the meniscus and compared to changes in articular cartilage.
RESULTS:In C57BL/6J mice, basal autophagy was lower in the meniscus than in articular cartilage. With increasing age, expression of the autophagy proteins ATG5 and LC3 was significantly reduced by 24 months. Age-related changes included abnormal Safranin-O staining and reduced cellularity, which preceded structural damage in the meniscus and articular cartilage. In mice with DMM, autophagy was induced in the meniscus while it was suppressed in cartilage. Articular cartilage exhibited the most profound changes in autophagy and structure that preceded meniscus degeneration. Systemic administration of rapamycin to mice with DMM induced autophagy activation in cartilage and reduced degenerative changes in both meniscus and cartilage.
CONCLUSION:Autophagy is significantly affected in the meniscus during aging and injury and precedes structural damage. Maintenance of autophagic activity appears critical for meniscus and cartilage integrity.
Volume 25(11)
Pages 1880-1889
Published 2017-11-1
DOI 10.1016/j.joca.2017.07.023
PII S1063-4584(17)31132-9
PMID 28801209
PMC PMC5650923
MeSH Aging / metabolism* Animals Autophagy / drug effects Autophagy / physiology* Autophagy-Related Protein 5 / metabolism Cartilage, Articular / drug effects Cartilage, Articular / pathology* Green Fluorescent Proteins / genetics Immunosuppressive Agents / pharmacology Menisci, Tibial / pathology* Menisci, Tibial / surgery Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Confocal Microtubule-Associated Proteins / metabolism Osteoarthritis, Knee / etiology Osteoarthritis, Knee / pathology* Osteoarthritis, Knee / physiopathology Sirolimus / pharmacology Tibial Meniscus Injuries / complications
IF 4.793
Times Cited 12
Mice RBRC00806