Osteoclastogenesis Responds to <scp>STING</scp> Inhibition in a Non‐Monotonic Manner

Recent studies have indicated the paradoxical roles of stimulator of interferon genes (STING) in bone metabolism, which obscures targeting STING to treat osteoporosis. Here, by integrating ovariectomy (OVX)-induced osteoporosis models, osteoblast-specific Sting knockout mice, and staged in vitro osteoclastogenesis models, we report that STING temporally regulates osteoclast differentiation without participating in osteoblast-mediated bone homeostasis. Through the timed administration of the STING inhibitor C-176, we found a non-monotonic bone response to STING inhibition in OVX mice. Early intervention was found to significantly increase bone mass, while therapeutic efficacy progressively decreased in later stages, with intervention at the terminal stage exacerbating bone loss. Furthermore, osteoblast-specific Sting knockout mice showed no change in bone mass whether in the static state or after OVX. In vitro assays revealed that the STING downstream temporal partitioning of nuclear factor kappa-B (NF-κB) and interferon (IFN) pathways bidirectionally dictated osteoclast differentiation. Activation of the NF-κB pathway drove cell fate commitment, whereas activation of the IFN pathway inhibited multinuclear maturation. Moreover, polymerase chain reaction array and transcriptomic analyses supported the stage-specific activation of NF-κB and IFN pathways during both human and murine osteoclastogenesis. Collectively, these findings establish a critical early therapeutic window for STING inhibition and highlight a timed strategy to maximize osteoprotective efficacy while avoiding adverse outcomes in osteoporosis.