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Myeloid-specific interferon regulatory factor 5 promotes bone formation via orchestration of osteoclast lineage-osteoblast coupling
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DOI：10.1016/j.jbc.2026.113279.png)
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Abstract
En 中文
Bone remodeling is orchestrated by the balanced activity of bone-resorbing osteoclasts and bone-forming osteoblasts. Interferon regulatory factor 5 (IRF5), a member of the IRF family of transcription factors, serves as a critical regulator of macrophage immune-related activity. However, macrophages also serve as the precursor cell of osteoclasts where the role of IRF5 in osteoclast-mediated bone remodeling in vivo remains undefined. Here, we find that IRF5 exhibits nuclear localization specifically in preosteoclasts during macrophage-osteoclast transition in vitro. In turn, myeloid cell-specific Irf5 conditional knockout (Irf5ΔM/ΔM) mice exhibit a significant osteopenic phenotype. Unexpectedly, osteoclast activity remained unaltered, while osteoblastic bone formation was significantly reduced. Interestingly, while conditioned media from wild-type preosteoclasts and osteoclasts increased the osteogenic potential of osteoblastic cells, this stimulatory activity was largely abrogated in conditioned media recovered from Irf5ΔM/ΔM preosteoclasts and osteoclasts. Further, the osteogenic potential of bone marrow stromal cells was markedly inhibited when co-cultured with Irf5ΔM/ΔM osteoclasts. Complementing these findings, genome wide analysis revealed that the Irf5-deficient osteoclast lineage displayed major changes in transcriptional programs related to extracellular matrix organization, bone development, and Notch signaling. Taken together, our study identifies IRF5 as a previously unrecognized transcriptional regulator of osteoblast-stimulating factors within the osteoclast lineage, thereby offering new insights on osteoimmune regulation of bone remodeling.
Keywords:
IRF5
Osteoclast
Bone remodeling
Bone coupling
Cell crosstalk
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3.9
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28.3W
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Cited Papers