INF-γ encoding plasmid administration triggers bone loss and disrupts bone marrow microenvironment

Area of Science:

• Bone Biology
• Immunology
• Skeletal Homeostasis

Background:

• Interferon-gamma (IFN-γ) is a cytokine in the bone microenvironment with a known role in bone remodeling.
• Previous studies on recombinant IFN-γ effects on bone loss have yielded contradictory results.
• The specific role of IFN-γ encoding plasmid (pIFN-γ) in skeletal homeostasis remains unclear.

Purpose of the Study:

• To investigate the effects of pIFN-γ on bone microarchitecture and bone mineral density (BMD) in an ovariectomy-induced osteopenia mouse model.
• To assess the impact of pIFN-γ on bone marrow cellularity and mesenchymal stem cell (MSC) differentiation.
• To determine if increased IFN-γ synthesis alone can induce inflammatory and catabolic bone responses.

Main Methods:

• Ovariectomy and sham surgeries in mice.
• Intra-bone marrow injection of pIFN-γ.
• Analysis of bone mineral density (BMD) and bone microarchitecture.
• Histological examination of bone and bone marrow.
• Assessment of MSC commitment to osteoblast differentiation via osterix-positive (Osx+) cell counts.
• Evaluation of pro-inflammatory cytokine release and CXCL12 cell distribution.

Main Results:

• Ovariectomy significantly decreased BMD.
• pIFN-γ injection led to pathological bone and bone marrow phenotypes in both ovariectomized and sham-operated mice.
• Disrupted bone microarchitecture, increased pro-inflammatory cytokines, and impaired MSC osteogenic commitment were observed.
• Reduction and redistribution of CXCL12 cells correlated with bone marrow alterations.

Conclusions:

• Increased IFN-γ synthesis in the bone marrow is sufficient to induce inflammatory and catabolic responses, even without predisposing pathological conditions.
• pIFN-γ administration negatively impacts skeletal homeostasis by disrupting bone microarchitecture and impairing osteoblast differentiation.
• The findings raise safety concerns regarding the use of pIFN-γ as a vaccine adjuvant due to its potential to induce bone pathology.