Myeloid-specific interferon regulatory factor 5 promotes bone formation via orchestration of osteoclast...

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 KO (Irf5^ΔM/ΔM) mice exhibit a significant osteopenic phenotype. Unexpectedly, osteoclast activity remained unaltered, while osteoblastic bone formation was significantly reduced. Interestingly, while conditioned media from WT preosteoclasts and osteoclasts increased the osteogenic potential of osteoblastic cells, this stimulatory activity was largely abrogated in conditioned media recovered from Irf5^ΔM/ΔM preosteoclasts and osteoclasts. Further, the osteogenic potential of bone marrow stromal cells was markedly inhibited when co-cultured with Irf5^ΔM/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.