Dataset Information

Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis.

ABSTRACT: OBJECTIVES:It has been suggested that the lysosomal recycling process called macro-autophagy plays a role in osteoarthritis development. We thus decided to genetically ablate the autophagy-indispensable Atg5 gene specifically in chondrocytes and analyse the development of osteoarthritis upon aging and in a post-traumatic model. METHODS:Mice lacking the Atg5 gene in their chondrocytes (Atg5cKO) were generated by crossing Atg5-floxed mice with transgenic mice that expressed cre recombinase driven by the collagen type 2 promoter. Animals were analysed at the age of 2, 6 and 12?months for age-related osteoarthritis or underwent mini-open partial medial meniscectomy at 2?months of age and were analysed 1 or 2?months after surgery. We evaluated osteoarthritis using the Osteoarthritis Research Society International (OARSI) scoring on safranin-O-stained samples. Cell death was evaluated by terminal deoxy-nucleotidyl-transferase-mediated deoxy-UTP nick end labelling (TUNEL) and by immunostaining of cleaved caspases. RESULTS:We observed the development of osteoarthritis in Atg5cKO mice with aging including fibrillation and loss of proteoglycans, which was particularly severe in males. The ablation of Atg5 was associated with an increased cell death as assessed by TUNEL, cleaved caspase 3 and cleaved caspase 9. Surprisingly, no difference in the development of post-traumatic osteoarthritis was observed between Atg5cKO and control mice. CONCLUSIONS:Autophagy protects from age-related osteoarthritis by facilitating chondrocyte survival.

SUBMITTER: Bouderlique T

PROVIDER: S-EPMC4789686 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis.

Bouderlique Thibault T Vuppalapati Karuna K KK Newton Phillip T PT Li Lei L Barenius Björn B Chagin Andrei S AS

Annals of the rheumatic diseases 20151005 3

<h4>Objectives</h4>It has been suggested that the lysosomal recycling process called macro-autophagy plays a role in osteoarthritis development. We thus decided to genetically ablate the autophagy-indispensable Atg5 gene specifically in chondrocytes and analyse the development of osteoarthritis upon aging and in a post-traumatic model.<h4>Methods</h4>Mice lacking the Atg5 gene in their chondrocytes (Atg5cKO) were generated by crossing Atg5-floxed mice with transgenic mice that expressed cre reco ...[more]

PMID: 26438374

Similar Datasets

Project description:ObjectiveTo determine the role of JNK signaling in the development of osteoarthritis (OA) induced by joint injury or aging in mice.MethodsIn the joint injury model, 12-week-old wild-type control, JNK1-/- , JNK2-/- , and JNK1fl/fl JNK2-/- aggecan-CreERT 2 double-knockout mice were subjected to destabilization of the medial meniscus (DMM) (n = 15 mice per group) or sham surgery (n = 9-10 mice per group), and OA was evaluated 8 weeks later. In the aging experiment, wild-type control, JNK1-/- , and JNK2-/- mice (n = 15 per group) were evaluated at 18 months of age. Mouse knee joints were evaluated by scoring articular cartilage structure, toluidine blue staining, osteophytes, and synovial hyperplasia, by histomorphometric analysis, and by immunostaining for the senescence marker p16INK 4a . Production of matrix metalloproteinase 13 (MMP-13) in cartilage explants in response to fibronectin fragments was measured by enzyme-linked immunosorbent assay.ResultsThere were no differences after DMM surgery between the wild-type and the JNK-knockout mouse groups in articular cartilage structure, toluidine blue, or osteophyte scores or in MMP-13 production in explants. All 3 knockout mouse groups had increased subchondral bone thickness and area of cartilage necrosis compared to wild-type mice. Aged JNK-knockout mice had significantly worse articular cartilage structure scores compared to the aged wild-type control mice (mean ± SD 52 ± 24 in JNK1-/- mice and 60 ± 25 in JNK2-/- mice versus 32 ± 18 in controls; P = 0.02 and P = 0.004, respectively). JNK1-/- mice also had higher osteophyte scores. Deletion of JNK resulted in increased expression of p16INK 4a in the synovium and cartilage in older mice.ConclusionJNK1 and JNK2 are not required for the development of OA in the mouse DMM model. Deletion of JNK1 or JNK2 is associated with more severe age-related OA and increased cell senescence, suggesting that JNK may act as a negative regulator of senescence in the joint.

Dataset Information

Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis.

Publications

Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets