A protein in cartilage drives joint aging

Osteoarthritis (wear of joint cartilage) affects a large proportion of the older population, but the precise molecular causes are not fully understood. The study, published in eLife, analyzed the gene activity profile of cartilage cells (chondrocytes) from young and old healthy donors. The protein GATA4 was found to be significantly higher in older cartilage cells, in both humans and mice.

To test the role of GATA4, the researchers elevated this protein in young cartilage cells. Those cells subsequently produced less cartilage matrix and more pro-inflammatory signaling molecules (cytokines). Conversely, when GATA4 was reduced in old cartilage cells, using a small RNA molecule (siRNA) or a small chemical inhibitor (NSC140905), cartilage production partly recovered and levels of matrix-degrading enzymes decreased.

Evidence in a mouse model of osteoarthritis

To test whether GATA4 also plays a role in living tissue, the researchers injected mice with a gene carrier that overexpressed GATA4 in the joint. Mice with elevated GATA4 developed more severe osteoarthritis, greater joint inflammation, and higher pain levels than control animals. This strengthens the case that GATA4 is not merely a byproduct of aging but actively contributes to joint deterioration.

A new target for joint aging

GATA4 was already known as a protein activated in senescent cells, where it forms part of a specific inflammatory program. That this protein also drives cartilage aging is a new finding. Whether inhibiting GATA4 is safe and practical in humans remains to be investigated. Results from cell culture and mouse experiments are promising but require further validation.

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