The nuclear phosphoprotein ANP32A protects against oxidative degeneration of brain, bone and cartilage tissue, according to a study published in Science Translational Medicine.

To understand an already established association between risk of osteoarthritis and ANP32A polymorphisms, the researchers show that compared with patients admitted for trauma surgery, patients with hip osteoarthritis (OA) have lower gene and protein expression of ANP32A in cartilage. The protein is also expressed less in damaged areas than in healthy areas of the cartilage.

Credit: Springer Nature Limited

These findings are mirrored in both surgically-induced and age-induced mouse models of OA. Furthermore, Anp32a–/– mice are more susceptible to cartilage degeneration in a variety of OA models.

To understand the mechanism of this protective function of ANP32A, the researchers conducted genome-wide transcriptomic analyses. One of the top hits, Atm, drew their attention owing to the known anti-oxidant function of the protein kinase it encodes. They show that Atm is barely expressed in cartilage from Anp32a–/– mice and in patients with OA, especially in damaged areas of cartilage, and knockdown of ANP32A in human cartilage samples results in lower expression of ATM.

Using ChIP-qPCR and RNA polymerase II analysis the researchers found that ANP32A directly activates transcription at the ATM promoter in chondrocytes.

The therapeutic implications of these findings were probed by feeding the antioxidant N-acetyl-cysteine (NAC) to Anp32a–/– mice, resulting in cartilage protection against surgically induced OA.

Intriguingly, the pathology in Anp32a–/– mice is not restricted to cartilage as the mice also developed osteopenia plus ataxia that is associated with reduced cerebellar expression of Atm. Furthermore, the ataxic gait abnormality in these mice was reversed by NAC treatment.

…Anp32a–/– mice are more susceptible to cartilage degeneration...

“Oxidative stress has been suggested to play an important role in the progression of osteoarthritis and other degenerative or ageing-associated diseases,” explains corresponding author Rik Lories. “Our data suggest that increasing levels of ANP32A in the target tissues may be a strategy to act against these processes and treat OA and other diseases,” he concludes.