Targeting STING: From antiviral immunity to treat osteoporosis

Abstract

The cGAS-STING signaling pathway can trigger innate immune responses by detecting dsDNA from outside or within the host. In addition, the cGAS-STING signaling pathway has emerged as a critical mediator of the inflammatory response and a new target for inflammatory diseases. STING activation leads to dimerization and translocation to the endoplasmic reticulum Golgi intermediate compartment or Golgi apparatus catalyzed by TBK1, triggers the production of IRF3 and NF-κB and translocates to the nucleus to induce a subsequent interferon response and pro-inflammatory factor production. Osteoporosis is a degenerative bone metabolic disease accompanied by chronic sterile inflammation. Activating the STING/IFN-β signaling pathway can reduce bone resorption by inhibiting osteoclast differentiation. Conversely, activation of STING/NF-κB leads to the formation of osteoporosis by increasing bone resorption and decreasing bone formation. In addition, activation of STING inhibits the generation of type H vessels with the capacity to osteogenesis, thereby inhibiting bone formation. Here, we outline the mechanism of action of STING and its downstream in osteoporosis and discuss the role of targeting STING in the treatment of osteoporosis, thus providing new ideas for the treatment of osteoporosis.

Keywords: IFN-β; NF-κB; STING; osteoporosis; type H vessels.

Figure 1

The role of STING in bone metabolism Bone metabolism is mainly composed of osteoblast-mediated bone formation and osteoclast-mediated bone resorption. In addition, type H vessels also can induce bone formation and thus participate in bone remodeling. Osteoblasts are differentiated from mesenchymal stem cells (MSCs), whereas osteoclasts are differentiated from bone marrow macrophages. STING can act as an upstream of NF-κB, stimulating its activation and transcription and thus exerting biological effects. NF-κB inhibits the differentiation of MSCs toward osteogenesis and inhibits osteoblast activity, thus inhibiting bone formation. In osteoclasts, NF-κB can promote osteoclast production and activity, thereby promoting bone resorption. IFN-β is also a downstream target of STING. However, unlike NF-κB, although IFN-β is induced in osteoclasts after activation by STING, it can inhibit osteoclast activation through its negative feedback, thereby inhibiting bone resorption. In addition, STING can inhibit the formation of type H vessels, inhibiting bone formation.

Figure 2

The cGAS-STING signaling pathway STING is a pattern recognition receptor (PRR) on the endoplasmic reticulum (ER) that does not bind directly to DNA. Pathogenic microorganisms and damaged host cells can release double-stranded DNA (dsDNA). The cytoplasmic DNA sensor, cyclic GMP–AMP synthase (cGAS), recognizes dsDNA and catalyzes the synthesis of cGAMP from ATP and GTP. The cGAMP binds to STING, triggering STING conformational transitions, dimerization, and translocation to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and the Golgi apparatus (Golgi). The dimerized STING recruits TBK1, which induces the production of IRF3 and NF-κB. Subsequently, IRF3 and NF-κB translocate to the nucleus to induce the production of IFN-I and pro-inflammatory factors.

Figure 3

osteoclastogenesis and the role of IFN-β in it Osteoclasts are differentiated from BMMs by stimulating receptor activators for nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Osteoblasts release RANKL and osteoprotegerin (OPG) to regulate bone homeostasis. RANK is a receptor for RANKL, expressed in osteoclasts. In osteoclasts, RANK-RANKL interaction activates downstream signaling pathways that induce the expression of osteoclast-associated genes such as c-Fos and TRAF6. In comparison, OPG binds to RANK to reduce RANK-RANKL signaling to balance bone resorption. C-Fos is essential for osteoclast differentiation. The RANK-RANKL interaction has been shown to induce IFN-β production by the c-Fos. IFN receptor (IFNAR) is a class of heterodimers on the cell membrane consisting of two subunits, IFNAR1 and IFNAR2. IFN-β binds to its receptor to activate the downstream protein kinases JAK1 and TYK2, then activating the transcription factors STAT1 and STAT2, forming a dimer that can enter the nucleus and bind to IRF9 to constitute ISGF-3, which exerts its IFN-β mediated transcriptional effects to inhibit osteoclast production. Thus, IFN-β forms negative feedback, inhibiting osteoclast differentiation. In addition, TRAF6 is essential for osteoclastogenesis and induces the production of NF-κB. In the resting state, NF-κB in the cytoplasm binds to the inhibitor protein IκB while leaving NF-κB inactive. IκB kinase (IKK) phosphorylates NF-κB to degrade IκB, and the released p65 and p50 subunits enter the nucleus for transcription of osteoclast-related genes, thus inducing bone resorption.