Interferon regulatory factor 5 regulates bone remodeling via orchestration of osteoclast lineage-osteoblast coupling

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 increase the osteogenic potential of osteoblastic cells, this stimulatory activity was largely abrogated in conditioned media recovered from Irf5ΔM/ΔM preosteoclasts and osteoclasts. Genome wide analysis further revealed that the Irf5-deficient osteoclast lineage displays major changes in transcriptional programs related to extracellular matrix organization, bone development, and Notch signaling. Taken together, we have identified IRF5 as a novel osteoimmune transcription factor that coordinates bone remodeling by regulating osteoclast lineage-mediated bone coupling, thus providing novel insights into developing effective preventive and/or therapeutic strategies against metabolic bone diseases.