Glutathione enzyme GPX4 is lower in damaged cartilage, and losing it worsens osteoarthritis
This 2022 study of human cartilage, cartilage cells and an animal model found that glutathione peroxidase 4 (GPX4) was lower in damaged cartilage than in undamaged cartilage from the same 55 people with osteoarthritis. Lowering GPX4 made cartilage cells more sensitive to oxidative stress and made osteoarthritis worse in animals.
What they did
The researchers looked for signs of ferroptosis, a form of cell death that depends on iron and involves oxidised fats, in damaged and undamaged human cartilage. They measured GPX4 in paired samples from 55 people with osteoarthritis.
They treated osteoarthritis in cells and in animals with two ferroptosis blockers, ferrostatin-1 and deferoxamine, used gene sequencing to trace the pathways GPX4 controls, and used a virus carrying a gene-silencing sequence to lower GPX4 in the joints of living animals.
What they found
Several kinds of analysis linked ferroptosis closely with osteoarthritis. GPX4 was significantly lower in osteoarthritic cartilage than in undamaged cartilage from the same 55 patients. Both ferroptosis blockers protected against osteoarthritis, and this did not depend on necroptosis, a different form of cell death.
Lowering GPX4 made cartilage cells more sensitive to oxidative stress and increased the breakdown of the cartilage matrix through the MAPK and NF-kB signalling pathways. Lowering GPX4 in living animals worsened osteoarthritis.
What it can't tell us
Finding less GPX4 in damaged cartilage shows an association; the cause-and-effect tests were done in cells and animals, not people. The abstract does not name the animal species, the number of animals or the drug doses. It does not measure glutathione itself or test any treatment in people.
Why it matters
GPX4's full name, glutathione peroxidase 4, records that it is one of the enzymes that work with glutathione. This study places it at the crossing point of two ways cartilage is lost: cell death by ferroptosis and breakdown of the matrix around the cells. It is the main reason ferroptosis has become part of the cartilage glutathione story.
The paper
- Miao Y, Chen Y, Xue F et al. Contribution of ferroptosis and GPX4's dual functions to osteoarthritis progression. EBioMedicine 2022.
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