PUM2 promoted osteoarthritis progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA...

Area of Science:

• Biochemistry
• Cell Biology
• Orthopedics

Background:

• Osteoarthritis (OA) is a widespread degenerative joint disease with limited effective treatments.
• Chondrocyte ferroptosis, a form of regulated cell death, significantly contributes to OA progression.
• The role of PUM2 in OA pathogenesis, particularly its involvement in chondrocyte ferroptosis, is currently unexplored.

Purpose of the Study:

• To investigate the role of PUM2 in OA pathogenesis and chondrocyte ferroptosis.
• To elucidate the molecular mechanisms by which PUM2 influences OA progression.
• To evaluate the therapeutic potential of targeting PUM2 in an OA mouse model.

Main Methods:

• Primary mouse chondrocytes were stimulated with IL-1β to induce OA-like injury in vitro.
• PUM2 expression was analyzed in OA cartilage tissues and IL-1β-treated chondrocytes.
• Molecular mechanisms involving PUM2, NEDD4 mRNA, PTEN, and the Nrf2/HO-1 pathway were investigated.
• An in vivo OA mouse model (destabilized medial meniscus) was established, and PUM2 was silenced using adenovirus-mediated shRNA.

Main Results:

• PUM2 expression was upregulated in OA cartilage and IL-1β-induced chondrocytes.
• Silencing PUM2 reduced IL-1β-induced chondrocyte inflammation, ECM degradation, and ferroptosis.
• PUM2 promoted chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation, leading to PTEN inhibition and subsequent activation of the Nrf2/HO-1 pathway.
• In vivo, PUM2 knockdown attenuated OA-induced cartilage damage.

Conclusions:

• PUM2 exacerbates OA progression by promoting PTEN-mediated chondrocyte ferroptosis.
• PUM2 facilitates NEDD4 mRNA degradation, which downregulates PTEN and activates ferroptosis pathways.
• Targeting PUM2 represents a promising therapeutic strategy for osteoarthritis.