Lysosomal dysfunction in osteoarthritis and aged cartilage triggers apoptosis in chondrocytes through BAX mediated release of cytochrome c.

Title

Lysosomal dysfunction in osteoarthritis and aged cartilage triggers apoptosis in chondrocytes through BAX mediated release of cytochrome c.

Creator

Ansari M Y;Ball HC;Wase SJ;Novak K;Haqqi TM

Publisher

Osteoarthritis and Cartilage

Date

2020
2020-11-05

Description

OBJECTIVE: Lysosomes are the major catabolic organelle of the cell and regulate the macromolecular and organelle turnover and programmed cell death. Here, we investigated the lysosome dysfunction in cartilage and its role in chondrocytes apoptosis and the associated mechanism. DESIGN: Lysosomal acidification in OA and aged cartilage was determined by LysoSensor staining. Lysosomal function in chondrocytes was blocked by siRNA mediated depletion of LAMP2 or with lysosome inhibitors. Chondrocyte apoptosis was determined by LDH release, Caspase-3/7 activation, TUNEL and PI uptake assays. Loss of mitochondrial membrane potential (MMP/ΔΨM) and mitochondrial superoxide level was determined by JC-1 and MitoSOX staining, respectively. Colocalization of mitochondria with BAX and Cytochrome c was determined by immunostaining. DMM was performed to induce OA in mice. RESULTS: Lysosomal acidification was found to be significantly decreased in aged mouse and human and mouse OA cartilage which also showed increased chondrocyte apoptosis. Inhibition of lysosomal function resulted in increased oxidative stress, accumulation of dysfunctional mitochondria and apoptosis in chondrocytes in monolayer and in cartilage explant cultures. Depletion of LAMP2 expression or treatment of chondrocytes with lysosomal function inhibitors increased the expression and mitochondrial translocation of BAX leading to Cytochrome c release. Lysosomal dysfunction-induced apoptosis in chondrocytes was not blocked by antioxidants MitoTempo or DPI but was abrogated by inhibiting BAX. CONCLUSION: Lysosomal dysfunction induce apoptosis in chondrocytes through BAX-mediated mitochondrial damage and release of Cytochrome c. Our data points to lysosomal function restoration and/or BAX inhibition in chondrocytes as a therapeutic approach for OA.

Subject

Osteoarthritis; Mitochondrial dysfunction; Apoptosis; Ageing; BAX; Lysosomal dysfunction

Format

journalArticle

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

ISSN

1522-9653 1063-4584

NEOMED College

NEOMED College of Medicine

NEOMED Department

Department of Anatomy & Neurobiology
NEOMED Student Publications

Update Year & Number

October 2020 List

Citation

Ansari M Y;Ball HC;Wase SJ;Novak K;Haqqi TM, “Lysosomal dysfunction in osteoarthritis and aged cartilage triggers apoptosis in chondrocytes through BAX mediated release of cytochrome c.,” NEOMED Bibliography Database, accessed October 25, 2021, https://neomed.omeka.net/items/show/11325.

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