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Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway

Background and Objectives: Damage to normal bone tissue following therapeutic irradiation (IR) represents a significant concern, as IR-induced bone microenvironment disruption can cause bone loss and create a more favorable environment for tumor metastases. The aim of the present study was to explor...

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Autores principales: Wang, Yuyang, Ren, Li, Xu, Linshan, Wang, Jianping, Zhai, Jianglong, Zhu, Guoying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10386124/
https://www.ncbi.nlm.nih.gov/pubmed/37512126
http://dx.doi.org/10.3390/medicina59071316
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author Wang, Yuyang
Ren, Li
Xu, Linshan
Wang, Jianping
Zhai, Jianglong
Zhu, Guoying
author_facet Wang, Yuyang
Ren, Li
Xu, Linshan
Wang, Jianping
Zhai, Jianglong
Zhu, Guoying
author_sort Wang, Yuyang
collection PubMed
description Background and Objectives: Damage to normal bone tissue following therapeutic irradiation (IR) represents a significant concern, as IR-induced bone microenvironment disruption can cause bone loss and create a more favorable environment for tumor metastases. The aim of the present study was to explore the cellular regulatory mechanism of IR-induced bone microenvironment disruption to effectively prevent radiotherapy-associated adverse effects in the future. Materials and Methods: In this study, a mouse model of local IR was established via local irradiation of the left hind limb of BALB/c mice with 12 Gy X-rays, and an in vitro osteocyte (OCY) model was established by exposing osteocyte-like MLO-Y4 cells to 2, 4, and 8 Gy irradiation to analyze multicellular biological injuries and cellular senescence. Small interfering RNA (siRNA) transfection at the cellular level and a selective antagonist intervention C-176 at the animal level were used to explore the potential role of the stimulator of interferon genes (STING) on IR-induced bone microenvironment disruption. Results: The results showed that 12 Gy local IR induces multicellular dysfunction, manifested as ascension of OCYs exfoliation, activation of osteoclastogenesis, degeneration of osteogenesis and fate conversion of adipogenesis, as well as cellular senescence and altered senescence-associated secretory phenotype (SASP) secretion. Furthermore, the expression of STING was significantly elevated, both in the primary OCYs harvested from locally irradiated mice and in vitro irradiated MLO-Y4 cells, accompanied by the markedly upregulated levels of phosphorylated TANK-binding kinase 1 (P-TBK1), RANKL and sclerostin (SOST). STING-siRNA transfection in vitro restored IR-induced upregulated protein expression of P-TBK1 and RANKL, as well as the mRNA expression levels of inflammatory cytokines, such as IL-1α, IL-6 and NF-κB, accompanied by the alleviation of excessive osteoclastogenesis. Finally, administration of the STING inhibitor C-176 mitigated IR-induced activation of osteoclastogenesis and restraint of osteogenesis, ameliorating the IR-induced biological damage of OCYs, consistent with the inhibition of P-TBK1, RANKL and SOST. Conclusions: The STING-P-TBK1 signaling pathway plays a crucial role in the regulation of the secretion of inflammatory cytokines and osteoclastogenesis potential in IR-induced bone microenvironment disruption. The selective STING antagonist can be used to intervene to block the STING pathway and, thereby, repair IR-induced multicellular biological damage and mitigate the imbalance between osteoclastogenesis and osteoblastgenesis.
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spelling pubmed-103861242023-07-30 Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway Wang, Yuyang Ren, Li Xu, Linshan Wang, Jianping Zhai, Jianglong Zhu, Guoying Medicina (Kaunas) Article Background and Objectives: Damage to normal bone tissue following therapeutic irradiation (IR) represents a significant concern, as IR-induced bone microenvironment disruption can cause bone loss and create a more favorable environment for tumor metastases. The aim of the present study was to explore the cellular regulatory mechanism of IR-induced bone microenvironment disruption to effectively prevent radiotherapy-associated adverse effects in the future. Materials and Methods: In this study, a mouse model of local IR was established via local irradiation of the left hind limb of BALB/c mice with 12 Gy X-rays, and an in vitro osteocyte (OCY) model was established by exposing osteocyte-like MLO-Y4 cells to 2, 4, and 8 Gy irradiation to analyze multicellular biological injuries and cellular senescence. Small interfering RNA (siRNA) transfection at the cellular level and a selective antagonist intervention C-176 at the animal level were used to explore the potential role of the stimulator of interferon genes (STING) on IR-induced bone microenvironment disruption. Results: The results showed that 12 Gy local IR induces multicellular dysfunction, manifested as ascension of OCYs exfoliation, activation of osteoclastogenesis, degeneration of osteogenesis and fate conversion of adipogenesis, as well as cellular senescence and altered senescence-associated secretory phenotype (SASP) secretion. Furthermore, the expression of STING was significantly elevated, both in the primary OCYs harvested from locally irradiated mice and in vitro irradiated MLO-Y4 cells, accompanied by the markedly upregulated levels of phosphorylated TANK-binding kinase 1 (P-TBK1), RANKL and sclerostin (SOST). STING-siRNA transfection in vitro restored IR-induced upregulated protein expression of P-TBK1 and RANKL, as well as the mRNA expression levels of inflammatory cytokines, such as IL-1α, IL-6 and NF-κB, accompanied by the alleviation of excessive osteoclastogenesis. Finally, administration of the STING inhibitor C-176 mitigated IR-induced activation of osteoclastogenesis and restraint of osteogenesis, ameliorating the IR-induced biological damage of OCYs, consistent with the inhibition of P-TBK1, RANKL and SOST. Conclusions: The STING-P-TBK1 signaling pathway plays a crucial role in the regulation of the secretion of inflammatory cytokines and osteoclastogenesis potential in IR-induced bone microenvironment disruption. The selective STING antagonist can be used to intervene to block the STING pathway and, thereby, repair IR-induced multicellular biological damage and mitigate the imbalance between osteoclastogenesis and osteoblastgenesis. MDPI 2023-07-16 /pmc/articles/PMC10386124/ /pubmed/37512126 http://dx.doi.org/10.3390/medicina59071316 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Yuyang
Ren, Li
Xu, Linshan
Wang, Jianping
Zhai, Jianglong
Zhu, Guoying
Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway
title Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway
title_full Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway
title_fullStr Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway
title_full_unstemmed Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway
title_short Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway
title_sort radiation induces bone microenvironment disruption by activating the sting-tbk1 pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10386124/
https://www.ncbi.nlm.nih.gov/pubmed/37512126
http://dx.doi.org/10.3390/medicina59071316
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