MEGF8-mediated GDF8 phosphorylation drives TGF-β hyperactivation in osteoarthritis cartilage degeneration: Mechanism...

Area of Science:

• Biomedical research
• Molecular biology
• Drug discovery

Background:

• Osteoarthritis (OA) progression is linked to aberrant transforming growth factor-beta (TGF-β) signaling, but regulatory mechanisms and treatments are lacking.
• Understanding the specific molecular players driving OA pathogenesis is crucial for developing targeted therapies.

Purpose of the Study:

• To identify key genes and molecular mechanisms involved in OA progression.
• To investigate the role of Multiple Epidermal Growth Factor-like Domains 8 (MEGF8) in OA.
• To discover FDA-approved drugs that can target the identified OA pathway for potential repurposing.

Main Methods:

• Integrated Gene Expression Omnibus datasets (GSE169077/GSE178557) to identify core OA-related genes.
• Utilized siRNA/lentiviral knockdown to validate MEGF8's role in OA.
• Employed co-immunoprecipitation, molecular docking, and dynamics simulations to identify MEGF8-interacting proteins and potential drug candidates.
• Conducted in vitro and in vivo experiments to verify drug efficacy.

Main Results:

• MEGF8 is highly expressed in OA cartilage, promoting matrix metalloproteinase (MMP)-13 upregulation and collagen II degradation.
• MEGF8 forms a complex with growth differentiation factor 8 (GDF8) and activin receptor type 2B (ACVR2B), activating Smad2/3 signaling and inducing MMP expression.
• Virtual screening identified Conivaptan, Noxafil, and Lomitapide as compounds that target the MEGF8 complex, significantly inhibiting OA progression.

Conclusions:

• The MEGF8-GDF8-ACVR2B complex acts as a critical switch for TGF-β hyperactivation in OA.
• Targeting this complex with repurposed small molecules offers a novel disease-modifying therapeutic strategy for osteoarthritis.