IFN-γ Targeting the JAK2/STAT3-METTL3 Pathway Ameliorates Mandibular Osteogenic Differentiation in Postmenopausal...

Area of Science:

• Immunology
• Bone Biology
• Cellular Metabolism

Background:

• Postmenopausal osteoporosis (POP) is characterized by significant bone loss, particularly in the jawbone.
• Estrogen deficiency in POP impairs osteogenic differentiation of jawbone marrow stromal cells (JBMSCs).
• Interferon-gamma (IFN-γ) is investigated for its potential role in mitigating POP.

Purpose of the Study:

• To determine if IFN-γ alleviates POP by regulating METTL3 through the JAK2/STAT3 pathway.
• To investigate IFN-γ's effect on osteogenic differentiation of JBMSCs.
• To explore the therapeutic potential of the JAK2/STAT3-METTL3 axis in POP.

Main Methods:

• Ovariectomized (OVX) rat model treated with IFN-γ.
• Assessment of jawbone mass using micro-CT and HE staining.
• In vitro studies on JBMSCs evaluating osteogenic differentiation, METTL3 expression, and JAK2/STAT3 pathway activity using qRT-PCR, Western blot, and specific inhibitors/overexpression constructs.

Main Results:

• IFN-γ treatment reduced alveolar bone loss in OVX rats, increasing osteocytes and decreasing osteoclasts.
• IFN-γ upregulated osteogenic genes (Runx2, OPN, OPG) and mineralization in JBMSCs.
• IFN-γ activated the JAK2/STAT3 pathway, leading to increased METTL3 expression, which was crucial for osteogenesis; METTL3 overexpression counteracted OVX-induced bone loss.

Conclusions:

• IFN-γ alleviates POP by activating the JAK2/STAT3 pathway, which drives METTL3 transcription and enhances osteogenic differentiation.
• METTL3 plays a critical role in IFN-γ-mediated bone protection and forms a positive feedback loop with JAK2/STAT3.
• The JAK2/STAT3-METTL3 axis represents a promising therapeutic target for managing postmenopausal osteoporosis.