Advances in endoplasmic reticulum stress-mediated bone remodeling imbalance in periodontitis

doi:10.3877/cma.j.issn.1674-1366.2024.04.001

Abstract

Abstract:

Periodontitis is a chronic infectious disease characterized by the destruction of periodontal tissue. The host's immune response is an important cause of attachment loss and alveolar bone resorption. When protein synthesis is overloaded, it is easy to produce unfolded or misfolded proteins which accumulate in the endoplasmic reticulum lumen and cause endoplasmic reticulum stress (ERS). Although the cells can induce an unfolded protein response (UPR) to mitigate ERS through related pathways, ERS inevitably persists in the pathological environment of periodontitis, and the interacting UPR can mediate pro-inflammatory transcriptional procedures and induce apoptosis, leading to the imbalance of bone remodeling and alveolar bone loss. This article reviewed the studies on ERS mediated bone remodeling imbalance in periodontitis and its potential therapeutic targets in order to further understand the role and significance of ERS in bone metabolism and treatment of periodontitis.

Key words: Periodontitis, Endoplasmic reticulum stress, Unfolded protein response, Apoptosis, Alveolar bone loss

Hongkun Sun, Hong Ai, Zheng Chen. Advances in endoplasmic reticulum stress-mediated bone remodeling imbalance in periodontitis[J]. Chinese Journal of Stomatological Research(Electronic Edition), 2024, 18(04): 211-218.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhkqyxyjzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-1366.2024.04.001

https://zhkqyxyjzz.cma-cmc.com.cn/EN/Y2024/V18/I04/211

Figures/Tables 3

References 63

[29]	Gebert M，Sobolewska A，Bartoszewska S，et al. Genome-wide mRNA profiling identifies X-box-binding protein 1（XBP1）as an IRE1 and PUMA repressor[J]. Cell Mol Life Sci，2021，78（21-22）：7061-7080. DOI：10.1007/s00018-021-03952-1.
[30]	Dhanasekaran DN，Reddy EP. JNK signaling in apoptosis[J]. Oncogene，2008，27（48）：6245-6251. DOI：10.1038/onc.2008.301.
[31]	Zhang L，Lu Z，Zhao X. Targeting Bcl-2 for cancer therapy[J]. Biochim Biophys Acta Rev Cancer，2021，1876（1）：188569. DOI：10.1016/j.bbcan.2021.188569.
[32]	Cui Z，Qin R，Feng J，et al. XBP1s gene of endoplasmic reticulum stress enhances proliferation and osteogenesis of human periodontal ligament cells[J]. Tissue Cell，2023，83：102139. DOI：10.1016/j.tice.2023.102139.
[33]	Shirakawa K，Maeda S，Gotoh T，et al. CCAAT/enhancer-binding protein homologous protein（CHOP）regulates osteoblast differentiation[J]. Mol Cell Biol，2006，26（16）：6105-6116. DOI：10.1128/MCB.02429-05.
[34]	Iyer S，Melendez-Suchi C，Han L，et al. Elevation of the unfolded protein response increases RANKL expression[J]. FASEB BioAdv，2020，2（4）：207-218. DOI：10.1096/fba.2019-00032.
[35]	Cao W，Zhang T，Feng R，et al. Hoxa5 alleviates obesity-induced chronic inflammation by reducing ER stress and promoting M2 macrophage polarization in mouse adipose tissue[J]. J Cellular Molecular Medi，2019，23（10）：7029-7042. DOI：10.1111/jcmm.14600.
[36]	Kim JH，Kim K，Kim I，et al. Endoplasmic reticulum-bound transcription factor crebh stimulates RANKL-Induced osteoclastogenesis[J]. J Immunol，2018，200（5）：1661-1670. DOI：10.4049/jimmunol.1701036.
[37]	Wang Z，Liu N，Zhou G，et al. Expression of XBP1s infibroblasts is critical for TiAl₆V₄ particle-induced RANKL expression and osteolysis[J]. J Orthop Res，2017，35（4）：752-759. DOI：10.1002/ior.23056.
[38]	Du N，Wu K，Zhang J，et al. Inonotsuoxide B regulates M1 to M2 macrophage polarization through sirtuin-1/endoplasmic reticulum stress axis[J]. Int Immunopharmacol，2021，96：107603. DOI：10.1016/j.intimp.2021.107603.
[39]	Yang F，Wang S，Liu Y，et al. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells[J]. Free Radic Biol Med，2018，124：395-407. DOI：10.1016/j.freeradbiomed.2018.06.043.
[40]	Yamazaki H，Hiramatsu N，Hayakawa K，et al. Activation of the Akt-NF-κB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response[J]. J Immunol，2009，183（2）：1480-1487. DOI：10.4049/jimmunol.0900017.
[41]	Victor P，Sarada D，Ramkumar KM. Crosstalk between endoplasmic reticulum stress and oxidative stress：Focus on protein disulfide isomerase and endoplasmic reticulum oxidase 1[J]. Eur J Pharmacol，2021，892：173749. DOI：10.1016/j.ejphar.2020.173749.
[42]	Sepulveda D，Rojas-Rivera D，Rodríguez DA，et al. Interactome screening identifies the ER luminal chaperone Hsp47 as a regulator of the unfolded protein response transducer IRE1α[J]. Molecular Cell，2018，69（2）：238-252.e7. DOI：10.1016/j.molcel.2017.12.028.
[43]	Li M，Huang S，Zhang Y，et al. Regulation of the unfolded protein response transducer IRE1α by SERPINH1 aggravates periodontitis with diabetes mellitus via prolonged ER stress[J]. Cell Signal，2022，91：110241. DOI：10.1016/j.cellsig.2022.110241.
[44]	Zheng J，Zhu X，He Y，et al. CircCDK8 regulates osteogenic differentiation and apoptosis of PDLSCs by inducing ER stress/autophagy during hypoxia[J]. Ann N Y Acad Sci，2021，1485（1）：56-70. DOI：10.1111/nyas.14483.
[45]	Tan J，Zhou L，Xue P，et al. Tumor necrosis factor-α attenuates the osteogenic differentiation capacity of periodontal ligament stem cells by activating PERK signaling[J]. J Periodontol，2016，87（8）：e159-e171. DOI：10.1902/jop.2016.150718.
[46]	Zhao X，Zhang G，Wu L，et al. Inhibition of ER stress-activated JNK pathway attenuates TNF-α-induced inflammatory response in bone marrow mesenchymal stem cells[J]. Biochem Biophys Res Commun，2021，541：8-14. DOI：10.1016/j.bbrc.2020.12.101.
[47]	Chen Y，Guo Y，Li J，et al. Endoplasmic reticulum stress remodels alveolar bone formation after tooth extraction[J]. J Cell Mol Med，2020，24（21）：12411-12420. DOI：10.1111/jcmm.15753.
[48]	Yan G，Yuan Y，He M，et al. m⁶A methylation of precursor-miR-320/RUNX2 controls osteogenic potential of bone marrow-derived mesenchymal stem cells[J]. Mol Ther Nucleic Acids，2020，19：421-436. DOI：10.1016/j.omtn.2019.12.001.
[49]	Zhang Y，Gu X，Li D，et al. METTL3 regulates osteoblast differentiation and inflammatory response via smad signaling and MAPK signaling[J]. Int J Mol Sci，2019，21（1）：199. DOI：10.3390/ijms21010199.
[50]	Feng ZW，Peng B，Wang SH，et al. METTL3-mediated m6A modification of SOX4 regulates osteoblast proliferation and differentiation via YTHDF3 recognition[J]. Cell Signal，2024，115：111038. DOI：10.1016/j.cellsig.2024.111038.
[51]	Kong Y，Zhang Y，Cai Y，et al. METTL3 mediates osteoblast apoptosis by regulating endoplasmic reticulum stress during LPS-induced inflammation[J]. Cell Signal，2022，95：110335. DOI：10.1016/j.cellsig.2022.110335.
[52]	Wu T，Liu Y，Cao Y，et al. Engineering macrophage exosome disguised biodegradable nanoplatform for enhanced sonodynamic therapy of glioblastoma[J]. Adv Mater，2022，34（15）：e2110364. DOI：10.1002/adma.202110364.
[53]	Shen Z，Kuang S，Zhang Y，et al. Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism[J]. Bioact Mater，2020，5（4）：1113-1126. DOI：10.1016/j.bioactmat.2020.07.002.
[54]	Cui Y，Hong S，Xia Y，et al. Melatonin engineering M2 macrophage-derived exosomes mediate endoplasmic reticulum stress and immune reprogramming for periodontitis therapy[J]. Adv Sci（Weinh），2023，10（27）：e2302029. DOI：10.1002/advs.202302029.
[55]	Ku LC，Sheu ML，Cheng HH，et al. Melatonin protects retinal integrity through mediated immune homeostasis in the sodium iodate-induced mouse model of age-related macular degeneration[J]. Biomed Pharmacother，2023，161：114476. DOI：10.1016/j.biopha.2023.114476.
[56]	Kang M，Huang CC，Lu Y，et al. Bone regeneration is mediated by macrophage extracellular vesicles[J]. Bone，2020，141：115627. DOI：10.1016/j.bone.2020.115627.
[57]	Bouchareychas L，Duong P，Covarrubias S，et al. Macrophage exosomes resolve atherosclerosis by regulating hematopoiesis and inflammation via MicroRNA cargo[J]. Cell Rep，2020，32（2）：107881. DOI：10.1016/j.celrep.2020.107881.
[58]	Nakao Y，Fukuda T，Zhang Q，et al. Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss[J]. Acta Biomater，2021，122：306-324. DOI：10.1016/j.actbio.2020.12.046.
[59]	Li R，Li D，Wang H，et al. Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF[J]. Stem Cell Res Ther，2022，13（1）：149. DOI：10.1186/s13287-022-02823-1.
[60]	Trindade-da-Silva CA，Bettaieb A，Napimoga MH，et al. Soluble epoxide hydrolase pharmacological inhibition decreases alveolar bone loss by modulating host inflammatory response，RANK-related signaling，endoplasmic reticulum stress，and apoptosis[J]. J Pharmacol Exp Ther，2017，361（3）：408-416. DOI：10.1124/jpet.116.238113.
[1]	Könönen E，Gursoy M，Gursoy UK. Periodontitis：A multifaceted disease of tooth-supporting tissues[J]. J Clin Med，2019，8（8）：1135. DOI：10.3390/jcm8081135.
[2]	Zou H，Zhou N，Huang Y，et al. Phenotypes，roles，and modulation of regulatory lymphocytes in periodontitis and its associated systemic diseases[J]. J Leukoc Biol，2022，111（2）：451-467. DOI：10.1002/JLB.3VMR0321-027RRR.
[3]	Herrera D，Berglundh T，Schwarz F，et al. Prevention and treatment of peri-implant diseases—The EFP S3 level clinical practice guideline[J]. J Clinic Periodontology，2023，50（Suppl 26）：4-76. DOI：10.1111/jcpe.13823.
[4]	Sculean A，Nikolidakis D，Nikou G，et al. Biomaterials for promoting periodontal regeneration in human intrabony defects：A systematic review[J]. Periodontology 2000，2015，68（1）：182-216. DOI：10.1111/prd.12086.
[5]	Shin YJ，Vavra U，Strasser R. Proper protein folding in the endoplasmic reticulum is required for attachment of a glycosylphosphatidylinositol anchor in plants[J]. Plant Physiol，2021，186（4）：1878-1892. DOI：10.1093/plphys/kiab181.
[6]	Wiseman RL，Mesgarzadeh JS，Hendershot LM. Reshaping endoplasmic reticulum quality control through the unfolded protein response[J]. Molecular Cell，2022，82（8）：1477-1491. DOI：10.1016/j.molcel.2022.03.025.
[7]	Chen X，Shi C，He M，et al. Endoplasmic reticulum stress：Molecular mechanism and therapeutic targets[J]. Signal Transduct Target Ther，2023，8（1）：352. DOI：10.1038/s41392-023-01570-w.
[8]	Chen X，Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment[J]. Nat Rev Cancer，2021，21（2）：71-88. DOI：10.1038/s41568-020-00312-2.
[9]	Briggs MD，Dennis EP，Dietmar HF，et al. New developments in chondrocyte ER-stress and related diseases[J]. F1000Res，2020，9：F1000 Faculty Rev-290. DOI：10.12688/f1000research.22275.1.
[10]	Song X，Li J，Jiao M，et al. Effect of endoplasmic reticulum stress-induced apoptosis in the role of periodontitis on vascular calcification in a rat model[J]. J Mol Histol，2021，52（5）：1097-1104. DOI：10.1007/s10735-021-10015-z.
[11]	Liu Q，Guo S，Huang Y，et al. Inhibition of TRPA1 ameliorates periodontitis by reducing periodontal ligament cell oxidative stress and apoptosis via PERK/eIF2α/ATF-4/CHOP signal pathway[J]. Oxid Med Cell Longev，2022：4107915. DOI：10.1155/2022/4107915.
[12]	Li H，Deng Y，Tan M，et al. Low-intensity pulsed ultrasound upregulates osteogenesis under inflammatory conditions in periodontal ligament stem cells through unfolded protein response[J]. Stem Cell Res Ther，2020，11（1）：215. DOI：10.1186/s13287-020-01732-5.
[13]	Ron D，Walter P. Signal integration in the endoplasmic reticulum unfolded protein response[J]. Nat Rev Mol Cell Biol，2007，8（7）：519-529. DOI：10.1038/nrm2199.
[14]	Yamada H，Nakajima T，Domon H，et al. Endoplasmic reticulum stress response and bone loss in experimental periodontitis in mice[J]. J Periodontal Res，2015，50（4）：500-508. DOI：10.1111/jre.12232.
[15]	Hu H，Tian M，Ding C，et al. The C/EBP homologous protein （CHOP）transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection[J]. Front Immunol，2019，9：3083. DOI：10.3389/fimmu.2018.03083.
[16]	Calfon M，Zeng H，Urano F，et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA[J]. Nature，2002，415（6867）：92-96. DOI：10.1038/415092a.
[17]	Estébanez B，de Paz JA，Cuevas MJ，et al. Endoplasmic reticulum unfolded protein response，aging and exercise：An update[J]. Front Physiol，2018，9：1744. DOI：10.3389/fphys.2018.01744.
[18]	Cao SS，Luo KL，Shi L. Endoplasmic reticulum stress interacts with inflammation in human diseases[J]. J Cell Physiol，2016，231（2）：288-294. DOI：10.1002/jcp.25098.
[19]	Feng Y，Zhang R，Wang Y rong，et al. Inhibition of endoplasmic reticulum stress by 4-phenyl butyric acid presents therapeutic effects on periodontitis：Experimental studies in vitro and in rats[J]. Stem Cells Int，2021：1-10. DOI：10.1155/2021/6618943.
[20]	Xue P，Li B，An Y，et al. Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation[J]. Cell Death Differ，2016，23（11）：1862-1872. DOI：10.1038/cdd.2016.74.
[21]	Bhattarai KR，Chaudhary M，Kim HR，et al. Endoplasmic reticulum（ER）stress response failure in diseases[J]. Trends Cell Biol，2020，30（9）：672-675. DOI：10.1016/j.tcb.2020.05.004.
[22]	Wang K，Niu J，Kim H，et al. Osteoclast precursor differentiation by MCPIP via oxidative stress，endoplasmic reticulum stress，and autophagy[J]. J Mol Cell Biol，2011，3（6）：360-368. DOI：10.1093/jmcb/mjr021.
[23]	Lee W，Jeong J，Lee E，et al. Tacrolimus regulates endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation：In vitro and collagen-induced arthritis mouse model[J]. Cell Biol Int，2018，42（4）：393-402. DOI：10.1002/cbin.10861.
[24]	Chen J，Chen J，Cheng Y，et al. Mesenchymal stem cell-derived exosomes protect beta cells against hypoxia-induced apoptosis via miR-21 by alleviating ER stress and inhibiting p38 MAPK phosphorylation[J]. Stem Cell Res Ther，2020，11（1）：97. DOI：10.1186/s13287-020-01610-0.
[25]	张杨，王垭铮，费栋栋，等.炎性牙周膜干细胞通过调控巨噬细胞内质网应激介导白介素-1β分泌的研究[J].中华口腔医学杂志，2021，56（4）：329-334. DOI：10.3760/cma.j.cn112144-20201105-00553.
[26]	Garaicoa-Pazmino C，Fretwurst T，Squarize CH，et al. Characterization of macrophage polarization in periodontal disease[J]. J Clinic Periodontology，2019，46（8）：830-839. DOI：10.1111/jcpe.13156.
[27]	Kourtzelis I，Li X，Mitroulis I，et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation[J]. Nat Immunol，2019，20（1）：40-49. DOI：10.1038/s41590-018-0249-1.
[28]	Díaz-Bulnes P，Saiz ML，López-Larrea C，et al. Crosstalk between hypoxia and er stress response：A key regulator of macrophage polarization[J]. Front Immunol，2020，10：2951. DOI：10.3389/fimmu.2019.02951.
[61]	Kimura F，Miyazawa K，Hamamura K，et al. Suppression of alveolar bone resorption by salubrinal in a mouse model of periodontal disease[J]. Life Sciences，2021，284：119938. DOI：10.1016/j.lfs.2021.119938.
[62]	Sukprasansap M，Chanvorachote P，Tencomnao T. Cyanidin-3-glucoside activates Nrf2-antioxidant response element and protects against glutamate-induced oxidative and endoplasmic reticulum stress in HT22 hippocampal neuronal cells[J]. BMC Complement Med Ther，2020，20（1）：46. DOI：10.1186/s12906-020-2819-7.
[63]	Tu HP，Kuo CY，Fu MMJ，et al. Cyanidin-3-O-glucoside downregulates ligation-activated endoplasmic reticulum stress and alleviates induced periodontal destruction in rats[J]. Arch Oral Biol，2022，134：105313. DOI：10.1016/j.archoralbio.2021.105313.

靶点	涉及通路	上调/下调	机制
TRPA1	PERK	下调	抑制炎性PDLSC的氧化应激和凋亡^[11]
HSP47	IRE1α	下调	导致HGEC发生持续或严重的ERS^[41]
METTL3	-	下调	诱导OC凋亡^[45]
CircCDK8	-	上调	抑制PDLSC成骨分化^[47]
XBP1	IRE1α	上调	促进PDLSC成骨能力^[31]
TNF-α	JNK、PERK	上调	抑制BMSC和PDLSC的成骨分化^[48,49]

靶点	涉及通路	上调/下调	机制
TRPA1	PERK	下调	抑制炎性PDLSC的氧化应激和凋亡^[11]
HSP47	IRE1α	下调	导致HGEC发生持续或严重的ERS^[41]
METTL3	-	下调	诱导OC凋亡^[45]
CircCDK8	-	上调	抑制PDLSC成骨分化^[47]
XBP1	IRE1α	上调	促进PDLSC成骨能力^[31]
TNF-α	JNK、PERK	上调	抑制BMSC和PDLSC的成骨分化^[48,49]

Please choose a citation manager

Content to export