RRC ID 32719
Author Caramés B, Olmer M, Kiosses WB, Lotz MK.
Title The relationship of autophagy defects to cartilage damage during joint aging in a mouse model.
Journal Arthritis Rheumatol
Abstract OBJECTIVE:Aging is a main risk factor for osteo arthritis (OA), the most prevalent musculoskeletal disorder. Defects in autophagy, an essential cellular homeostasis mechanism, have recently been observed in OA articular cartilage. The objectives of this study were to establish the constitutive level of autophagy activation in normal cartilage and to monitor the temporal relationship between changes in autophagy and aging-related degradation of cartilage in a mouse model.
METHODS:In GFP-LC3-transgenic mice, green fluorescent protein (GFP)-light chain 3 (LC3) is ubiquitously expressed, and the accumulation of GFP puncta, representing autophagosomes, was quantified by confocal microscopy as a measure of autophagy activation. Expression of the autophagy proteins autophagy-related protein 5 (ATG-5) and microtubule-associated protein 1 light chain 3 (LC3) was analyzed by immunohistochemistry. Cartilage cellularity, apoptotic cell death, and cartilage structural damage and changes in synovium and bone were examined by histology and immunohistochemistry.
RESULTS:Basal autophagy activation was detected in liver and knee articular cartilage from young (6-month-old) mice, with higher levels in cartilage than in liver in the same animals. In 28-month-old mice, there was a statistically significant reduction in the total number of autophagic vesicles per cell (P < 0.01) and in the total area of vesicles per cell (P < 0.01) in the articular cartilage as compared to that from young 6-month-old mice. With increasing age, the expression of ATG-5 and LC3 decreased, and this was followed by a reduction in cartilage cellularity and an increase in the apoptosis marker poly(ADP-ribose) polymerase p85. Cartilage structural damage progressed in an age-dependent manner subsequent to the autophagy changes.
CONCLUSION:Autophagy is constitutively activated in normal cartilage. This is compromised with aging and precedes cartilage cell death and structural damage.
Volume 67(6)
Pages 1568-76
Published 2015-6-1
DOI 10.1002/art.39073
PMID 25708836
PMC PMC4446178
MeSH Aging / physiology* Animals Autophagy / physiology* Autophagy-Related Protein 5 Cartilage, Articular / metabolism* Cartilage, Articular / physiopathology Chondrocytes / metabolism* Green Fluorescent Proteins / genetics Immunohistochemistry Mice Mice, Transgenic Microscopy, Confocal Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism* Models, Animal Osteoarthritis / metabolism* Osteoarthritis / physiopathology Poly(ADP-ribose) Polymerases / metabolism Stifle
IF 9.586
Times Cited 85
Mice RBRC00806