Simonis, H. F.; Middha, S.; Graf, L.; Naibi, R.; Polenz, V.; Kubatzky, K. F.; Seebach, E.

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-{beta} 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-{beta} is sufficient to inhibit osteoclastogenesis in a paracrine manner. Furthermore, autocrine IFN-{beta} signaling appears to modulate the OPG-RANKL axis, although additional regulatory factors may contribute. Together, these findings identify cGAS-STING-IFN-{beta} 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.