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Identification of a Novel Role for Foxo3 Isoform2 in Osteoclastic Inhibition
Cheng Xu1,2, Gregory J Vitone1,2, Kazuki Inoue1,2,3
1Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021.
Abstract:
Foxo3 acts as an important central regulator that integrates signaling pathways and coordinates cellular responses to environmental changes. Recent studies show the involvement of Foxo3 in osteoclastogenesis and rheumatoid arthritis, which prompted us to further investigate the FOXO3 locus. Several databases document FOXO3 isoform2, an N-terminal truncated mutation of the full-length FOXO3 However, the biological function of FOXO3 isoform2 is unclear. In this study, we established a conditional allele of Foxo3 in mice that deletes the full-length Foxo3 except isoform2, a close ortholog of the human FOXO3 isoform2. Expression of Foxo3 isoform2 specifically in macrophage/osteoclast lineage suppresses osteoclastogenesis and leads to the osteopetrotic phenotype in mice. Mechanistically, Foxo3 isoform2 enhances the expression of type I IFN response genes to RANKL stimulation and thus inhibits osteoclastogenesis via endogenous IFN-β-mediated feedback inhibition. Our findings identify, to our knowledge, the first known biological function of Foxo3 isoform2 that acts as a novel osteoclastic inhibitor in bone remodeling.
Insights
Foxo3 isoform2 suppresses osteoclastogenesis by enhancing type I interferon response, acting as a novel inhibitor of bone remodeling and osteoclast formation. This finding clarifies its role in bone metabolism.
Area of Science:
- Molecular Biology
- Bone Biology
- Immunology
Background:
- Forkhead box O3 (Foxo3) is a key regulator of cellular responses.
- Recent research links Foxo3 to osteoclastogenesis and rheumatoid arthritis.
- The function of the N-terminal truncated FOXO3 isoform2 remains largely unknown.
Purpose of the Study:
- To investigate the biological function of FOXO3 isoform2.
- To establish a mouse model for studying Foxo3 isoform2 in vivo.
- To elucidate the mechanism by which Foxo3 isoform2 influences osteoclastogenesis.
Main Methods:
- Generation of a conditional Foxo3 allele in mice to specifically study isoform2.
- Analysis of osteoclastogenesis and bone phenotypes in genetically modified mice.
- Investigation of gene expression changes, including type I interferon response genes, upon RANKL stimulation.
Main Results:
- Expression of Foxo3 isoform2 in the macrophage/osteoclast lineage suppressed osteoclastogenesis.
- Mice with Foxo3 isoform2 expression exhibited an osteopetrotic phenotype.
- Foxo3 isoform2 enhanced type I interferon (IFN) response genes, leading to IFN-β-mediated inhibition of osteoclastogenesis.
Conclusions:
- Foxo3 isoform2 is identified as a novel inhibitor of osteoclastogenesis.
- This isoform plays a critical role in regulating bone remodeling through IFN-β-mediated feedback.
- The study provides the first known biological function for FOXO3 isoform2 in bone metabolism.
