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

Abstract

Cyclic dinucleotides (CDNs), such as cyclic diadenylate monophosphate and cyclic diguanylate monophosphate, are commensal bacteria‐derived second messengers in the gut that modulate bacterial survival, colonization, and biofilm formation. Recently, CDNs have been discovered to have an immunomodulatory activity by inducing the expression of type I interferon (IFN) through STING signaling pathway in macrophages. Because CDNs are possibly absorbed and delivered into the bone marrow, where bone‐resorbing osteoclasts are derived from monocyte/macrophage lineages, CDNs could affect bone metabolism by regulating osteoclast differentiation. 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‐dependent 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 representative 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 STAT1, 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 STING signaling pathway. © 2019 American Society for Bone and Mineral Research.

TANK‐binding kinase 1 mediates osteoclast differentiation by regulating NF‐κB, MAPK and Akt signaling pathways

“…This discrepancy may possibly be because of the differential amounts of exogenous TBK1 protein expression by the method employed. Furthermore, another recent study indicated that the cytosolic DNA sensor stimulator of interferon genes and its downstream TBK1–interferon regulatory factor 3 signaling cascade are activated during the inhibition of OC differentiation caused by cyclic dinucleotides 27 . These controversial observations suggest that the regulatory effects of TBK1 on bone remodeling are complicated, and may be signal and context dependent.…”

Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns

“…Interestingly, CDNs can also influence bone metabolism. CDNs inhibit RANKL-induced osteoclast differentiation from mouse bone marrow-derived macrophages through STING-dependent signaling pathway [ 18 ]. Authors demonstrated that CDNs potently trigger STING-TBK1-IRF3 cascade and induce the mRNA expression of IFN-β during osteoclast differentiation from macrophages.…”

“…The recognition of MAMPs by pattern recognition receptors (PRRs) is crucial for inducing host immune responses [ 15 ]. In addition, secretory microbial molecules including short chain fatty acid (SCFA), extracellular vesicle (EV), extracellular polysaccharide, and cyclic dinucleotide (CDN) also modulate bone cells [ 16 , 17 , 18 ]. Therefore, for a clear understanding of the regulation of bone metabolism by bacteria, it is essential to understand the effects of MAMPs and secretory microbial molecules on bone cells and their regulatory mechanism.…”

Immune Regulation of the cGAS-STING Signaling Pathway in the Tumor Microenvironment and Its Clinical Application

“…[114][115][116] There are two sources of CDNs: the cGAS pathway, which produces the atypical dinucleotide 2ʹ,3ʹ-cGAMP after the detection of cytoplasmic DNA; the other is found in the cytoplasm owing to the presence of pathogens. 112,[117][118][119] Numerous studies found that CDNs have strong antitumor effects and application prospects in the treatment of melanoma, colon cancer, and oral cancer. 39,[120][121][122] However, there are limitations in the use of CDNs as candidate drugs.…”