Cyclic Dinucleotides Inhibit Osteoclast Differentiation Through STING ‐Mediated Interferon‐β Signaling

In this study, we investigated the effect of CDNs on the differentiation and function of osteoclasts and osteoblasts. When bone marrow‐derived macrophages (BMMs) were differentiated into osteoclasts with macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) in the presence of CDNs, the differentiation was inhibited by CDNs in a dose‐d ependent manner. In contrast, CDNs did not influence the differentiation of committed osteoclasts or osteoblast precursors. STING signaling pathway appeared to be critical for CDNs‐mediated inhibition of osteoclast differentiation since CDNs induced the phosphorylation of TBK1 and IRF3, a represen tative feature of STING activation, and osteoclast differentiation was restored in STING knockdown BMMs with siRNA. Moreover, CDNs increased the mRNA expression of STING‐meditated IFN‐β, which is a negative regulator of osteoclastogenesis. In addition, CDNs also induced the phosphorylation of S TAT1, which mediates IFN‐α/β receptor (IFNAR) signal transduction. The inhibitory effects of CDNs on osteoclast differentiation were not observed in the presence of antibody blocking IFNAR or in macrophages derived from IFNAR1‐/‐ mice. Experiments using a mouse calvarial implantation model showed that RANKL ‐induced bone resorption was inhibited by CDNs. Taken together, these results suggest that CDNs inhibit osteoclast differentiation and bone resorption through induction of IFN‐β via the STIN...
Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Original Article Source Type: research