Rapgef3 modulates macrophage reprogramming and exacerbates synovitis and osteoarthritis under excessive mechanical...

Area of Science:

• Biomedical Engineering
• Immunology
• Orthopedics

Background:

• Mechanical loading is a key factor in osteoarthritis (OA) progression.
• The role of synovial changes, particularly macrophage inflammation, under excessive mechanical stress in OA pathogenesis remains incompletely understood.

Purpose of the Study:

• To investigate the specific pathological changes in the synovium under excessive mechanical loading.
• To elucidate the role of Rapgef3 in mediating macrophage inflammation and subsequent cartilage damage in OA.

Main Methods:

• RNA sequencing of RAW246.7 cells subjected to cyclic tensile strain.
• Verification of Rapgef3 expression in human OA synovium and DMM-OA mouse models.
• In vitro studies using primary chondrocytes and macrophage culture supernatants.
• Analysis of the p65-nuclear factor κB (NF-κB) signaling pathway.
• Intra-articular Rapgef3 knockout in DMM-OA mice.

Main Results:

• Excessive mechanical loading induced pro-inflammatory responses in synovial macrophages, a hallmark of OA.
• High Rapgef3 expression was observed in macrophages under mechanical strain and in OA patient/mouse synovium.
• Rapgef3-stimulated macrophage supernatant induced an OA phenotype in chondrocytes.
• Mechanical loading activated the p65-NF-κB pathway via Rapgef3, promoting macrophage inflammation and cartilage injury.
• Rapgef3 knockout ameliorated synovitis and cartilage degeneration.

Conclusions:

• Rapgef3 plays a critical role in mediating excessive mechanical loading-induced synovial inflammation and cartilage damage in OA.
• The Rapgef3-macrophage-NF-κB axis represents a potential therapeutic target for OA treatment.