# The glycolytic enzyme PFKFB3 alleviates DNA damage and chondrocyte senescence in osteoarthritis

## TL;DR

The enzyme PFKFB3 helps protect cartilage cells from aging and DNA damage in osteoarthritis, suggesting it could be a new treatment target.

## Contribution

This study identifies PFKFB3 as a novel regulator of chondrocyte senescence and DNA damage in osteoarthritis.

## Key findings

- PFKFB3 expression is reduced in osteoarthritic cartilage and senescent chondrocytes.
- PFKFB3 overexpression improves DNA repair and reduces OA severity.
- PFKFB3 loss activates NF-κB signaling and promotes inflammation and senescence.

## Abstract

Chondrocyte senescence is a key driver of osteoarthritis (OA) progression. This study examined the role of the glycolytic enzyme PFKFB3 in regulating chondrocyte senescence during OA. Using a destabilization of the medial meniscus (DMM) mouse model, we found that PFKFB3 expression was reduced in human and mouse OA cartilage and in hydrogen peroxide–treated chondrocytes. PFKFB3 knockdown or overexpression in primary chondrocytes was achieved through RNA interference or lentiviral delivery, followed by RNA sequencing and molecular analyses. PFKFB3 loss impaired DNA damage repair, activated NF-κB signaling, elevated pro-inflammatory cytokines, and promoted chondrocyte senescence, whereas PFKFB3 overexpression enhanced DNA repair and alleviated OA severity. Pharmacologic inhibition of NF-κB reduced inflammatory and senescent phenotypes in PFKFB3-deficient chondrocytes. These findings indicate that PFKFB3 regulates chondrocyte senescence via NF-κB signaling and DNA damage responses, suggesting PFKFB3 as a potential therapeutic target for OA.