The relationship of autophagy defects to cartilage damage during joint aging in a mouse model
Open accessAbstract
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.
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Deficient autophagy is linked with cartilage ageing and osteoarthritis.
“There is strong evidence linking deficient autophagy, essential for cellular homeostasis, with cartilage ageing and OA [21,22].”
From Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy (2019) · cites this paper as [22]
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References 43 · Cited by 204
- Authors
- Caramés, B., Olmer, M., Kiosses, W. B., & Lotz, M. K.
- Affiliations
- Universidade da Coruña (ES)
- Scripps Research Institute (US)
- Corresponding author
- Lotz, Martin K.
- Venue
- Arthritis & Rheumatology
- Publisher
- Wiley
- Published
- 2015-05-25
- Volume
- 67
- Issue
- 6
- Pages
- 1568-1576
- ISSN
- 2326-5191 (ISSN-L)
- 2326-5205
- PMC
- PMC4446178
- OpenAlex
- W1669854369
- Cited by
- 204
- References
- 43
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 20 · 2023: 16 · 2022: 30 · 2021: 16 · 2020: 23 · 2019: 19 · 2018: 20 · 2017: 19 · 2016: 16 · 2015: 6
- FWCI
- 17.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arthritis & Rheumatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (AG007996)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- autophagy, articular cartilage, joint aging, osteoarthritis, cartilage degeneration, ATG5, LC3, autophagosomes, apoptosis, poly(ADP-ribose) polymerase, cartilage cellularity, synovium, bone changes
- MeSH terms
- Autophagy-Related Protein 5, Aging, Animals, Autophagy, Cartilage, Articular, Immunohistochemistry, Mice, Transgenic, Microtubule-Associated Proteins, Osteoarthritis, Poly(ADP-ribose) Polymerases, Stifle, Microscopy, Confocal, Chondrocytes, Models, Animal, Green Fluorescent Proteins, Mice
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