STING inhibition accelerates the bone healing process while enhancing type H vessel formation

Abstract

The stimulator of interferon genes (STING), one of the critical factors of innate immunity, is indicated to be closely related to angiogenesis. This study examined STING's role in angiogenesis and the formation of type H vessels, a specific subtype of bone vessels that regulates bone healing. Different concentrations of 2′,3′-cGAMP, and H-151 or C-176 were applied to activate or inhibit STING, respectively. Human umbilical vein endothelial cells were used to examine the effect of STING on angiogenesis in vitro; cell viability, cell migration, and quantitative real-time polymerase chain reactions were performed. Also, the metatarsal experiment was applied as ex vivo proof. Bone fracture or defect mice models were used to examine the effect of STING in vivo; the bone healing process was evaluated by radiography weekly and by μCT on the 14th day after surgery. The formation of type H vessels (CD31 hi Emcn hi endothelial cells) and osteogenesis (OCN-positive cells) was assessed using the cryosection and paraffin section.STING activation inhibited angiogenesis both in vitro and ex vivo and slowed down the bone healing process in vivo. Histological analysis showed an increased callus formation, fewer type H vessels, and almost no callus mineralization in the STING activation group compared to the control group. By contrast, H-151 (a hsSTING inhibitor) promoted angiogenesis at a low dose. Moreover, inhibition of mmSTING by C-176 enhanced type H vessels' formation, implying osteogenesis promotion in bone healing (higher bone volume density and more OCN-positive cells). Our data suggested that STING inhibition accelerates the bone healing process while enhancing type H vessel formation.

Targeting STING: From antiviral immunity to treat osteoporosis

“…In addition, the prolonged inflammatory response stimulated by the STING pathway delays the bone healing process. Activation of STING inhibits angiogenesis both in vitro and in vivo and slows the bone healing process in vivo ( 12 ). Conversely, inhibition of STING accelerated bone healing by enhancing type H vessel formation during coupled osteogenesis ( 12 ).…”

“…Activation of STING inhibits angiogenesis both in vitro and in vivo and slows the bone healing process in vivo ( 12 ). Conversely, inhibition of STING accelerated bone healing by enhancing type H vessel formation during coupled osteogenesis ( 12 ). Therefore, targeting STING to enhance type H vessel formation and thus promote osteogenesis provides a new idea for the treatment of osteoporosis.…”

“…In addition, STING can act on vascular endothelial cells (ECs) to regulate the formation of type H vessels, which can control bone formation. STING activation can impair their formation and thus affect bone formation ( 12 ) ( Table 1 ). Therefore, the role of STING in osteoporosis deserves further investigation to determine how to target STING for osteoporosis treatment.…”

DNAzyme Nanoconstruct-Integrated Autonomously-Adaptive Coatings Enhance Titanium-Implant Osteointegration by Cooperative Angiogenesis and Vessel Remodeling

“…DNAzyme is an emerging gene therapeutic technology that employs catalytic active DNA sequences to degrade the cognate mRNAs in a gene-specific sequence, thus allowing the precise manipulation of targets that are previously considered nondruggable. , Indeed, several preliminary studies already demonstrated the feasibility of using synthetic DNAzymes to selectively inhibit STING expression in predetermined cell populations, supporting the potential application of DNAzyme-enabled STING inhibition in peri-implant ECs for promoting type H vessel formation. , Nevertheless, the DNA sequences are intrinsically susceptible to degradation after entering the human body, which would undermine their therapeutic potency in vivo . Moreover, the catalytic function of DNAzymes requires bivalent metal ions (Pb 2+ , Zn 2+ , etc.)…”

“…11,12 Recent studies show that type H vessel formation is usually suppressed under certain pathological conditions such as arthritis and osteoporosis due to the overactivation of stimulator of interferon genes (STING) signaling in endothelial cells (EC), which further contributes to implant osseointegration under osteoporosis conditions. 13 However, currently there are still no approved STING inhibitors in the clinic due to the crucial roles of STING in maintaining host immunity, warranting the development of alternative therapeutic strategies for the in situ inhibition of STING signaling in ECs in peri-implant vessels.…”