Compromised autophagy precedes meniscus degeneration and cartilage damage in mice

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 structura...

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Published in:	Osteoarthritis and cartilage Vol. 25; no. 11; pp. 1880 - 1889
Main Authors:	Meckes, J.K., Caramés, B., Olmer, M., Kiosses, W.B., Grogan, S.P., Lotz, M.K., D'Lima, D.D.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-11-2017
Subjects:	Aging Aging - metabolism Animals Autophagy Autophagy - drug effects Autophagy - physiology Autophagy-Related Protein 5 - metabolism Cartilage Cartilage, Articular - drug effects Cartilage, Articular - pathology Green Fluorescent Proteins - genetics Immunosuppressive Agents - pharmacology Menisci, Tibial - pathology Menisci, Tibial - surgery Meniscus Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Confocal Microtubule-Associated Proteins - metabolism Osteoarthritis Osteoarthritis, Knee - etiology Osteoarthritis, Knee - pathology Osteoarthritis, Knee - physiopathology Sirolimus - pharmacology Tibial Meniscus Injuries - complications Aging Cartilage Meniscus Autophagy Osteoarthritis
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Summary:	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. 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1063-4584 1522-9653
DOI:	10.1016/j.joca.2017.07.023