FGF9 attenuates osteoarthritis progression through the NRF2/GPX3 antioxidant axis

Listen to Lisa and Brian discuss the paper 'FGF9 attenuates osteoarthritis progression through the NRF2/GPX3 antioxidant axis' published in the June 2026 issue of Bone & Joint Research.

Click here to read the paper.

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Transcript

[00:00:00] Welcome back to another episode of AI Talks with Bone & Joint from the publishers of Bone & Joint Research. Today, we're delving into the paper 'FGF9 attenuates osteoarthritis progression through the NRF2/GPX3 antioxidant axis', published in June 2026 by YS Lo and colleagues. I am Brian, and alongside me is my co-host, Lisa.

Hello, everyone. Brian, this paper presents some fascinating research on how FGF9 might revolutionize osteoarthritis treatment. To start, can you summarize the main motivation behind this research?

Of course. Osteoarthritis is one of the most common forms of degenerative joint disease, affecting approximately 250 million people around the globe.

It's marked by chronic pain, limited mobility, and significant impacts on quality of life. Despite its prevalence, effective treatments that alter the disease itself, rather than merely [00:01:00] alleviating symptoms, are still elusive. The primary aim of this research was to investigate the role of fibroblast growth factor 9, or FGF9, in osteoarthritis, particularly its involvement in chondrocyte degeneration and the broader pathogenesis of the disease. That's a crucial area of focus, considering how debilitating osteoarthritis can be. So, what specific methods did the researchers employ to explore the effects of FGF9?

The researchers used a comprehensive approach. They started with gene expression profiling of primary chondrocytes from osteoarthritis patients and compared them to normal controls.

To assess cellular senescence and reactive oxygen species levels, they employed beta-galactosidase staining and flow cytometry. Additionally, they conducted short hairpin RNA-mediated knockdown experiments of FGF9 and treated cells with FGF9-conditioned media. Extending this [00:02:00] further, they examined the effects of FGF9-enriched exosomes in vitro and adenovirus-delivered FGF9 in a mouse model of osteoarthritis.

One of the significant findings was that FGF9 expression was markedly downregulated in chondrocytes from osteoarthritis patients. When FGF9 was knocked down in these cells, reactive oxygen species levels and cellular senescence increased due to suppression of the NRF2/GPX3 antioxidant axis.

Conversely, FGF9 seemed to promote chondrogenesis in mesenchymal stem cells. In vivo, intra-articular FGF9 gene therapy reduced osteoarthritis progression in mice. They also discovered that FGF9-enriched exosomes significantly reduced chondrocyte senescence in vitro. Those findings are indeed impressive, especially the reduction in cellular senescence. Can you explain the NRF2/GPX3 [00:03:00] antioxidant axis mentioned earlier?

The NRF2/GPX3 antioxidant axis involves a sequence of reactions where NRF2, a transcription factor, activates genes including glutathione peroxidase 3 or GPX3. GPX3 is an enzyme that helps mitigate oxidative stress by reducing harmful peroxides in the cell. In the context of osteoarthritis, FGF9 appears to maintain redox homeostasis through this pathway, reducing the accumulation of reactive oxygen species and thereby preventing cellular senescence, which is linked to cartilage degeneration.

So essentially, FGF9 helps keep oxidative stress in check, which in turn protects the chondrocytes. For gene therapy, they utilize adenovirus to deliver FGF9 into the joints of mice that had been induced with osteoarthritis through a destabilization of the medial meniscus. They observed [00:04:00] reduced osteoarthritis progression, indicated by increased cartilage thickness and lower scores in the Osteoarthritis Research Society International scoring system.

Regarding the exosomes, they extracted these from FGF9 overexpressing chondrocytes and applied them to primary chondrocytes in vitro. These FGF9-enriched exosomes notably reduce cellular senescence. That does sound very promising for potential OA treatments. Were there any limitations mentioned in the study that our listeners should be aware of?

Indeed. The authors noted that while their findings were significant, further in vivo studies are necessary to validate the safety and efficacy of FGF9-enriched exosomes before progressing towards clinical applications. They also highlighted the need to explore the specific roles of different antioxidant enzymes and the efficacy of FGF9 in various osteoarthritis models.

The key takeaways are that [00:05:00] FGF9 plays a crucial role in regulating oxidative stress and cellular senescence in chondrocytes through the NRF2/GPX3 antioxidant axis. Down-regulation of FGF9 in osteoarthritis leads to increased reactive oxygen species levels and accelerated chondrocyte senescence, contributing to cartilage degeneration.

However, FGF9 gene therapy and FGF9-enriched exosomes have shown promise in attenuating osteoarthritis progression and reducing chondrocyte senescence, highlighting the therapeutic potential of targeting this pathway. This research undoubtedly opens up exciting new possibilities for treating osteoarthritis.

If you wish to read the full paper, it's available in the June 2026 issue of Bone & Joint Research. That's all for today's episode of AI Talks with Bone & Joint. Thanks for tuning in, [00:06:00] and we'll catch you next time. Thanks, Brian. Goodbye, everyone.