2026/05/13 by Hannah F Simonis, Sanya Middha, Loris Graf +4 · 1 voice
Immunology and Microbiology · Biochemistry, Genetics and Molecular Biology · Medicine · #interferon and immune responses #Bone Metabolism and Diseases #Bone Tumor Diagnosis and Treatments
paper · doi:10.64898/2026.05.09.724040
openalex publication_date 2026/05/13 · openalex created_date 2026/05/14 · openalex updated_date 2026/07/22
SUMMARY Osteolytic bone diseases are driven by excessive osteoclast formation and bone resorption. While cGAS–STING signaling is known to regulate bone homeostasis via macrophage-intrinsic mechanisms, its role in osteoblast-mediated control of osteoclastogenesis remains poorly defined. Here, we show that cGAS–STING activation of macrophages suppresses their osteoclastogenic potential while promoting immune activation. In osteoblasts, cGAS–STING triggers IRF3-mediated IFN-β production and, notably, shifts the OPG–RANKL axis toward increased osteoprotegerin. In transwell co-culture, pre-activated osteoblasts reduce osteoclast differentiation of strain-matched macrophages. Mechanistically, osteoblast-derived IFN-β is sufficient to inhibit osteoclastogenesis in a paracrine manner. Furthermore, autocrine IFN-β signaling appears to modulate the OPG–RANKL axis, although additional regulatory factors may contribute. Together, these findings identify cGAS–STING-IFN-β signaling as a dual regulator of osteoclastogenesis, acting directly on macrophages and indirectly via osteoblast-derived anti-osteoclastogenic mediators. This highlights osteoblasts as cGAS–STING-responsive bystander cells within the bone microenvironment that can be targeted as an alternative strategy to limit pathological bone resorption. GRAPHICAL ABSTRACT