IRE1α pathway: A potential bone metabolism mediator

Abstract

Osteoblasts and osteoclasts collaborate in bone metabolism, facilitating bone development, maintaining normal bone density and strength, and aiding in the repair of pathological damage. Endoplasmic reticulum stress (ERS) can disrupt the intracellular equilibrium between osteoclast and osteoblast, resulting in dysfunctional bone metabolism. The inositol-requiring enzyme-1α (IRE1α) pathway—the most conservative unfolded protein response pathway activated by ERS—is crucial in regulating cell metabolism. This involvement encompasses functions such as inflammation, autophagy, and apoptosis. Many studies have highlighted the potential roles of the IRE1α pathway in osteoblasts, chondrocytes, and osteoclasts and its implication in certain bone-related diseases. These findings suggest that it may serve as a mediator for bone metabolism. However, relevant reviews on the role of the IRE1α pathway in bone metabolism remain unavailable. Therefore, this review aims to explore recent research that elucidated the intricate roles of the IRE1α pathway in bone metabolism, specifically in osteogenesis, chondrogenesis, osteoclastogenesis, and osteo-immunology. The findings may provide novel insights into regulating bone metabolism and treating bone-related diseases.

References

[1] ComazzettoS, ShenB, MorrisonSJ. Niches that regulate stem cells and hematopoiesis in adult bone marrow. Dev Cell. 2021;56(13):1848-1860.

[2] van GastelN, Carmeliet G. Metabolic regulation of skeletal cell fate and function in physiology and disease. Nat Metab. 2021;3(1):11-20.

[3] GarneroP, Cremers S. Bone turnover markers. In: Bilezikian JP, Martin TJ, Clemens TL, Rosen CJ, eds. Principles of Bone Biology Chapter 78. 4th ed. Academic Press; 2020:1801-1832.

[4] ZhangY, LuoG, YuX. Cellular communication in bone homeostasis and the related anti-osteoporotic drug development. Curr Med Chem. 2020;27(7):1151-1169.

[5] WangJ, LiX, WangS, Cui J, RenX, SuJ. Bone-targeted exosomes: strategies and applications. Adv Healthc Mater. 2023;12(18):e2203361.

[6] WalshMC, KimN, KadonoY, et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol. 2006;24:33-63.

[7] BaronR, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19(2):179-192.

[8] ZhouH, ZhangL, ChenY, Zhu CH, ChenFM, LiA. Research progress on the hedgehog signalling pathway in regulating bone formation and homeostasis. Cell Prolif. 2022;55(1):e13162.

[9] BallhauseTM, JiangS, BaranowskyA, et al. Relevance of notch signaling for bone metabolism and regeneration. Int J Mol Sci. 2021;22(3):1325.

[10] WuM, ChenG, LiYP. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009.

[11] JeyabalanJ, ShahM, ViolletB, Chenu C. AMP-activated protein kinase pathway and bone metabolism. J Endocrinol. 2012;212(3):277-290.

[12] HuangM, QingY, ShiQ, CaoY, SongK. miR-342-3p elevates osteogenic differentiation of umbilical cord mesenchymal stem cells via inhibiting Sufu in vitro. Biochem Biophys Res Commun. 2017;491(3):571-577.

[13] SongK, QingY, GuoQ, et al. PDGFRA in vascular adventitial MSCs promotes neointima formation in arteriovenous fistula in chronic kidney disease. JCI Insight. 2020;5(21):ce137298.

[14] SongK, RaoNJ, ChenML, Huang ZJ, CaoYG. Enhanced bone regeneration with sequential delivery of basic fibroblast growth factor and sonic hedgehog. Injury. 2011;42(8):796-802.

[15] QingY, HuangM, CaoY, DuT, SongK. Effects of miRNA-342-3p in modulating hedgehog signaling pathway of human umbilical cord mesenchymal stem cells by down-regulating Sufu. Oral Dis. 2019;25(4):1147-1157.

[16] KhoslaS, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. 2017;5(11):898-907.

[17] BaiL, SongP, SuJ. Bioactive elements manipulate bone regeneration. Biomater Transl. 2023;4(4):248-269. doi:10.12336/biomatertransl.2023.04.005

[18] TaoZ, YuanZ, ZhouD, et al. Fabrication of magnesium-doped porous polylactic acid microsphere for bone regeneration. Biomater Transl. 2023;4(4):280-290. doi:10.12336/biomatertransl.2023.04.007

[19] HuY, ZhangH, WangS, et al. Bone/cartilage organoid on-chip: construction strategy and application. Bioact Mater. 2023;25:29-41.

[20] WangF, GuZ, YinZ, ZhangW, BaiL, SuJ. Cell unit-inspired natural nano-based biomaterials as versatile building blocks for bone/cartilage regeneration. J Nanobiotechnol. 2023;21(1):293.

[21] DengS, ZhuF, DaiK, WangJ, LiuC. Harvest of functional mesenchymal stem cells derived from in vivo osteo-organoids. Biomater Transl. 2023;4(4):270-279. doi:10.12336/biomatertransl.2023.04.006

[22] MajidiniaM, Sadeghpour A, YousefiB. The roles of signaling pathways in bone repair and regeneration. J Cell Physiol. 2018;233(4):2937-2948.

[23] HattnerR, EpkerBN, FrostHM. Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling. Nature. 1965;206(983):489-490.

[24] GuoJ, RenR, SunK, HeJ, ShaoJ. PERK signaling pathway in bone metabolism: Friend or foe? Cell Prolif. 2021;54(4):e13011.

[25] HoriuchiK, Tohmonda T, MoriokaH. The unfolded protein response in skeletal development and homeostasis. Cell Mol Life Sci. 2016;73(15):2851-2869.

[26] JiangM, LiZ, ZhuG. The role of endoplasmic reticulum stress in the pathophysiology of periodontal disease. J Periodontal Res. 2022;57(5):915-932.

[27] DuangchanT, Tawonsawatruk T, AngsanuntsukhC, et al. Amelioration of osteogenesis in iPSC-derived mesenchymal stem cells from osteogenesis imperfecta patients by endoplasmic reticulum stress inhibitor. Life Sci. 2021;278:119628.

[28] IyerS, AdamsDJ. Bone and the unfolded protein response: in sickness and in health. Calcif Tissue Int. 2023;113(1):96-109.

[29] TohmondaT, Miyauchi Y, GhoshR, et al. The IRE1α-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix. EMBO Rep. 2011;12(5):451-457.

[30] GuoFJ, JiangR, LiX, ZhangP, HanX, LiuC. Regulation of chondrocyte differentiation by IRE1α depends on its enzymatic activity. Cell Signal. 2014;26(9):1998-2007.

[31] TohmondaT, YodaM, IwawakiT, et al. IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis. J Clin Invest. 2015;125(8):3269-3279.

[32] QiuQ, ZhengZ, ChangL, et al. Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J. 2013;32(18):2477-2490.

[33] KempKL, LinZ, ZhaoF, et al. The serine-threonine kinase inositol-requiring enzyme 1α (IRE1α) promotes IL-4 production in T helper cells. J Biol Chem. 2013;288(46):33272-33282.

[34] ReimoldAM, Iwakoshi NN, ManisJ, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001;412(6844):300-307.

[35] HetzC, Glimcher LH. Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell. 2009;35(5):551-561.

[36] HetzC, Martinon F, RodriguezD, GlimcherLH. The unfolded protein response: integrating stress signals through the stress sensor IRE1α. Physiol Rev. 2011;91(4):1219-1243.

[37] KimataY, KohnoK. Endoplasmic reticulum stress-sensing mechanisms in yeast and mammalian cells. Curr Opin Cell Biol. 2011;23(2):135-142.

[38] ShamuCE, WalterP. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 1996;15(12):3028-3039.

[39] SidrauskiC, WalterP. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell. 1997;90(6):1031-1039.

[40] YoshidaH, MatsuiT, YamamotoA, Okada T, MoriK. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881-891.

[41] CalfonM, ZengH, UranoF, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415(6867):92-96.

[42] LeeAH, ChuGC, IwakoshiNN, Glimcher LH. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J. 2005;24(24):4368-4380.

[43] YoshidaH, MatsuiT, HosokawaN, Kaufman RJ, NagataK, MoriK. A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell. 2003;4(2):265-271.

[44] MaurelM, ChevetE, TavernierJ, Gerlo S. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci. 2014;39(5):245-254.

[45] UranoF, WangX, BertolottiA, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287(5453):664-666.

[46] LuoR, LiaoZ, SongY, et al. Berberine ameliorates oxidative stress-induced apoptosis by modulating ER stress and autophagy in human nucleus pulposus cells. Life Sci. 2019;228:85-97.

[47] SuiX, KongN, YeL, et al. p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett. 2014;344(2):174-179.

[48] ShanB, WangX, WuY, et al. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol. 2017;18(5):519-529.

[49] LeeAH, Heidtman K, HotamisligilGS, GlimcherLH. Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc Natl Acad Sci USA. 2011;108(21):8885-8890.

[50] TufanliO, Telkoparan Akillilar P, Acosta-AlvearD, et al. Targeting IRE1 with small molecules counteracts progression of atherosclerosis. Proc Natl Acad Sci USA. 2017;114(8):E1395-E1404.

[51] MaoT, ShaoM, QiuY, et al. PKA phosphorylation couples hepatic inositol-requiring enzyme 1alpha to glucagon signaling in glucose metabolism. Proc Natl Acad Sci USA. 2011;108(38):15852-15857.

[52] SoJS, HurKY, TarrioM, et al. Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 2012;16(4):487-499.

[53] CaiJ, ZhangX, ChenP, et al. The ER stress sensor inositol-requiring enzyme 1α in Kupffer cells promotes hepatic ischemia-reperfusion injury. J Biol Chem. 2022;298(1):101532.

[54] ChenY, WuZ, HuangS, et al. Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis. Nat Metab. 2022;4(9):1166-1184.

[55] HeS, FuT, YuY, et al. IRE1α regulates skeletal muscle regeneration through Myostatin mRNA decay. J Clin Invest. 2021;131(17):e143737.

[56] GuoFJ, JiangR, XiongZ, et al. IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation. Cell Death Dis. 2014;5(5):e1239.

[57] DongY, SongK, WangP, et al. Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity. Pharmacol Res. 2022;185:106513.

[58] CarrascoDR, Sukhdeo K, ProtopopovaM, et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell. 2007;11(4):349-360.

[59] RosenV. BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev. 2009;20(5–6):475-480.

[60] GuoFJ, XiongZ, HanX, et al. XBP1S, a BMP2-inducible transcription factor, accelerates endochondral bone growth by activating GEP growth factor. J Cell Mol Med. 2014;18(6):1157-1171.

[61] NakashimaK, ZhouX, KunkelG, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108(1):17-29.

[62] BenayahuD. Mesenchymal stem cell differentiation and usage for biotechnology applications: tissue engineering and food manufacturing. Biomater Transl. 2022;3(1):17-23. doi:10.12336/biomatertransl.2022.01.003

[63] MatsubaraT, KidaK, YamaguchiA, et al. BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. J Biol Chem. 2008;283(43):29119-29125.

[64] LibermanM, Johnson RC, HandyDE, LoscalzoJ, Leopold JA. Bone morphogenetic protein-2 activates NADPH oxidase to increase endoplasmic reticulum stress and human coronary artery smooth muscle cell calcification. Biochem Biophys Res Commun. 2011;413(3):436-441.

[65] YangL, DaiR, WuH, et al. Unspliced XBP1 counteracts β-catenin to inhibit vascular calcification. Circ Res. 2022;130(2):213-229.

[66] TanakaK, Yamaguchi T, KajiH, KanazawaI, Sugimoto T. Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress. Biochem Biophys Res Commun. 2013;438(3):463-467.

[67] LiuCH, RajS, ChenCH, et al. HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. J Clin Invest. 2019;129(12):5357-5373.

[68] CuiZ, QinR, FengJ, et al. XBP1s gene of endoplasmic reticulum stress enhances proliferation and osteogenesis of human periodontal ligament cells. Tissue Cell. 2023;83:102139.

[69] FengJQ, GuoFJ, JiangBC, et al. Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. FASEB J. 2010;24(6):1879-1892.

[70] ZhangZ, ZhangX, WeiX, et al. IRE1α inhibits osteogenic differentiation of mouse embryonic fibroblasts by limiting Shh signaling. Oral Dis. 2024.

[71] GiulianiN, Morandi F, TagliaferriS, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood. 2007;110(1):334-338.

[72] ZavrskiI, Krebbel H, WildemannB, et al. Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function. Biochem Biophys Res Commun. 2005;333(1):200-205.

[73] GarrettIR, ChenD, GutierrezG, et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest. 2003;111(11):1771-1782.

[74] ZhangD, De Veirman K, FanR, et al. ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation. Stem Cell Res Ther. 2020;11(1):516.

[75] Garcia-GomezA, Quwaider D, CanaveseM, et al. Preclinical activity of the oral proteasome inhibitor MLN9708 in myeloma bone disease. Clin Cancer Res. 2014;20(6):1542-1554.

[76] ZhangD, FanR, LeiL, et al. Cell cycle exit during bortezomib-induced osteogenic differentiation of mesenchymal stem cells was mediated by Xbp1s-upregulated p21(Cip1) and p27(Kip1). J Cell Mol Med. 2020;24(16):9428-9438.

[77] OrlandoS, Gallastegui E, BessonA, et al. p27Kip1 and p21Cip1 collaborate in the regulation of transcription by recruiting cyclin-Cdk complexes on the promoters of target genes. Nucleic Acids Res. 2015;43(14):6860-6873.

[78] Muñoz-AlonsoMJ, Acosta JC, RichardC, DelgadoMD, SedivyJ, LeónJ. p21Cip1 and p27Kip1 induce distinct cell cycle effects and differentiation programs in myeloid leukemia cells. J Biol Chem. 2005;280(18):18120-18129.

[79] GuoJ, WangF, HuY, et al. Exosome-based bone-targeting drug delivery alleviates impaired osteoblastic bone formation and bone loss in inflammatory bowel diseases. Cell Rep Med. 2023;4(1):100881.

[80] ZhangK, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454(7203):455-462.

[81] HetzC. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89-102.

[82] ChenS, WangY, YangY, et al. Psoralen inhibited apoptosis of osteoporotic osteoblasts by modulating IRE1-ASK1-JNK pathway. Biomed Res Int. 2017;2017:3524307.

[83] GhoshR, WangL, WangES, et al. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014;158(3):534-548.

[84] LernerAG, UptonJP, PraveenPV, et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 2012;16(2):250-264.

[85] ParkSJ, KimKJ, KimWU, Oh IH, ChoCS. Involvement of endoplasmic reticulum stress in homocysteine-induced apoptosis of osteoblastic cells. J Bone Miner Metab. 2012;30(4):474-484.

[86] LiuL, ZhangY, GuH, ZhangK, MaL. Fluorosis induces endoplasmic reticulum stress and apoptosis in osteoblasts in vivo. Biol Trace Elem Res. 2015;164(1):64-71.

[87] KongY, ZhangY, CaiY, LiD, YiB, XuQ. METTL3 mediates osteoblast apoptosis by regulating endoplasmic reticulum stress during LPS-induced inflammation. Cell Signal. 2022;95:110335.

[88] GuoY, HaoD, HuH. High doses of dexamethasone induce endoplasmic reticulum stress-mediated apoptosis by promoting calcium ion influx-dependent CHOP expression in osteoblasts. Mol Biol Rep. 2021;48(12):7841-7851.

[89] TanJ, ZhouY, LuoJ, et al. High glucose inhibits the osteogenic differentiation of periodontal ligament stem cells in periodontitis by activating endoplasmic reticulum stress. Ann Transl Med. 2022;10(4):204.

[90] SuzukiR, Fujiwara Y, SaitoM, et al. Intracellular accumulation of advanced glycation end products induces osteoblast apoptosis via endoplasmic reticulum stress. J Bone Miner Res. 2020;35(10):1992-2003.

[91] LevasseurR. Bone tissue and hyperhomocysteinemia. Joint Bone Spine. 2009;76(3):234-240.

[92] ZhangC, Kawauchi J, AdachiMT, et al. Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine. Biochem Biophys Res Commun. 2001;289(3):718-724.

[93] ChenYR, MeyerCF, TanTH. Persistent activation of c-Jun N-terminal kinase 1 (JNK1) in gamma radiation-induced apoptosis. J Biol Chem. 1996;271(2):631-634.

[94] SonDJ, HaSJ, SongHS, et al. Melittin inhibits vascular smooth muscle cell proliferation through induction of apoptosis via suppression of nuclear factor-kappaB and Akt activation and enhancement of apoptotic protein expression. J Pharmacol Exp Ther. 2006;317(2):627-634.

[95] LariviereWR, Melzack R. The bee venom test: a new tonic-pain test. Pain. 1996;66(2–3):271-277.

[96] FanQ, HuY, PangH, Sun J, WangZ, LiJ. Melittin protein inhibits the proliferation of MG63 cells by activating inositol-requiring protein-1α and X-box binding protein 1-mediated apoptosis. Mol Med Rep. 2014;9(4):1365-1370.

[97] MengHZ, ZhangWL, LiuF, YangMW. Advanced glycation end products affect osteoblast proliferation and function by modulating autophagy via the receptor of advanced glycation end products/Raf protein/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (RAGE/Raf/MEK/ERK) pathway. J Biol Chem. 2015;290(47):28189-28199.

[98] CaiZ, LiF, GongW, et al. Endoplasmic reticulum stress participates in aortic valve calcification in hypercholesterolemic animals. Arterioscler Thromb Vasc Biol. 2013;33(10):2345-2354.

[99] QinK, TangH, RenY, et al. Melatonin promotes sirtuin 1 expression and inhibits IRE1α-XBP1S-CHOP to reduce endoplasmic reticulum stress-mediated apoptosis in chondrocytes. Front Pharmacol. 2022;13:940629.

[100] ZhuZ, GaoS, ChenC, et al. The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway. Exp Mol Med. 2022;54(11):1927-1939.

[101] TakadaK, HiroseJ, SenbaK, et al. Enhanced apoptotic and reduced protective response in chondrocytes following endoplasmic reticulum stress in osteoarthritic cartilage. Int J Exp Pathol. 2011;92(4):232-242.

[102] HanX, ZhouJ, ZhangP, et al. IRE1α dissociates with BiP and inhibits ER stress-mediated apoptosis in cartilage development. Cell Signal. 2013;25(11):2136-2146.

[103] GuoFJ, XiongZ, LuX, YeM, HanX, JiangR. ATF6 upregulates XBP1S and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage. Cell Signal. 2014;26(2):332-342.

[104] GuoFJ, LiuY, ZhouJ, et al. XBP1S protects cells from ER stress-induced apoptosis through Erk1/2 signaling pathway involving CHOP. Histochem Cell Biol. 2012;138(3):447-460.

[105] WuL, LiuH, LiL, et al. 5,7,3’4’-Tetramethoxyflavone protects chondrocytes from ER stress-induced apoptosis through regulation of the IRE1α pathway. Connect Tissue Res. 2018;59(2):157-166.

[106] LiZ, HuangZ, ZhangH, et al. IRE1-mTOR-PERK Axis coordinates autophagy and ER stress-apoptosis induced by P2X7-mediated Ca(2+) influx in osteoarthritis. Front Cell Dev Biol. 2021;9:695041.

[107] YangH, WenY, ZhangM, et al. MTORC1 coordinates the autophagy and apoptosis signaling in articular chondrocytes in osteoarthritic temporomandibular joint. Autophagy. 2020;16(2):271-288.

[108] CameronTL, Gresshoff IL, BellKM, et al. Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization. Osteoarthr Cartil. 2015;23(4):661-670.

[109] FanM, GengN, LiX, et al. IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization. Genes Dis. 2024;11(1):464-478.

[110] GoldringMB. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012;4(4):269-285.

[111] ZhongJ, MaT, HuangC, et al. Flavonoids from Litsea coreana decreases TNF-α secretion from peritoneal macrophages in adjuvant-induced arthritis rats via UPR pathway. Am J Chin Med. 2014;42(4):905-919.

[112] TianY, FengX, ZhouZ, et al. Ginsenoside compound K ameliorates osteoarthritis by inhibiting the chondrocyte endoplasmic reticulum stress-mediated IRE1α-TXNIP-NLRP3 Axis and Pyroptosis. J Agric Food Chem. 2023;71(3):1499-1509.

[113] KungLHW, MullanL, SoulJ, et al. Cartilage endoplasmic reticulum stress may influence the onset but not the progression of experimental osteoarthritis. Arthritis Res Ther. 2019;21(1):206.

[114] CameronTL, BellKM, TatarczuchL, et al. Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy. PLoS One. 2011;6(9):e24600.

[115] PirógKA, DennisEP, HartleyCL, et al. XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease. PLoS Genet. 2019;15(7):e1008215.

[116] CameronTL, BellKM, GresshoffIL, et al. XBP1-independent UPR pathways suppress C/EBP-β mediated chondrocyte differentiation in ER-stress related skeletal disease. PLoS Genet. 2015;11(9):e1005505.

[117] KimSM, HanY, YuSM, KimSJ. Gallotannin attenuates 2-deoxy-D-glucose-induced dedifferentiation and endoplasmic reticulum stress through inhibition of inositol-requiring enzyme 1 downstream p38 kinase pathway in chondrocytes. Mol Med Rep. 2019;20(6):5249-5256.

[118] ZhangT, Yamagata K, IwataS, et al. Epstein-Barr virus-induced gene 3 commits human mesenchymal stem cells to differentiate into chondrocytes via endoplasmic reticulum stress sensor. PLoS One. 2022;17(12):e0279584.

[119] TeitelbaumSL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504-1508.

[120] BoyleWJ, Simonet WS, LaceyDL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337-342.

[121] HuangW, GongY, YanL. ER stress, the unfolded protein response and osteoclastogenesis: a review. Biomolecules. 2023;13(7):1050.

[122] LeeEG, SungMS, YooHG, Chae HJ, KimHR, YooWH. Increased RANKL-mediated osteoclastogenesis by interleukin-1β and endoplasmic reticulum stress. Joint Bone Spine. 2014;81(6):520-526.

[123] LeeWS, JeongJH, LeeEG, et al. Tacrolimus regulates endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation: in vitro and collagen-induced arthritis mouse model. Cell Biol Int. 2018;42(4):393-402.

[124] WangK, NiuJ, KimH, Kolattukudy PE. Osteoclast precursor differentiation by MCPIP via oxidative stress, endoplasmic reticulum stress, and autophagy. J Mol Cell Biol. 2011;3(6):360-368.

[125] YipKH, ZhengMH, SteerJH, et al. Thapsigargin modulates osteoclastogenesis through the regulation of RANKL-induced signaling pathways and reactive oxygen species production. J Bone Miner Res. 2005;20(8):1462-1471.

[126] Negishi-KogaT, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev. 2009;231(1):241-256.

[127] Acosta-AlvearD, ZhouY, BlaisA, et al. XBP1 controls diverse cell type-and condition-specific transcriptional regulatory networks. Mol Cell. 2007;27(1):53-66.

[128] RaimondiL, De Luca A, FontanaS, et al. Multiple myeloma-derived extracellular vesicles induce osteoclastogenesis through the activation of the XBP1/IRE1α axis. Cancers. 2020;12(8):2167.

[129] IwawakiT, AkaiR, YamanakaS, Kohno K. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci USA. 2009;106(39):16657-16662.

[130] KurodaY, Hisatsune C, NakamuraT, MatsuoK, Mikoshiba K. Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis. Proc Natl Acad Sci USA. 2008;105(25):8643-8648.

[131] RuizA, MatuteC, AlberdiE. Endoplasmic reticulum Ca(2+) release through ryanodine and IP(3) receptors contributes to neuronal excitotoxicity. Cell Calcium. 2009;46(4):273-281.

[132] KolanusW. Guanine nucleotide exchange factors of the cytohesin family and their roles in signal transduction. Immunol Rev. 2007;218:102-113.

[133] GrčevićD, Kovačić N, LeeS-K. The role of sex steroids in the effects of immune system on bone. In: Lorenzo J, Horowitz MC, Choi Y, Takayanagi H, Schett G, eds. Osteoimmunology Chapter 12. 2nd ed. Academic Press; 2016:215-239.

[134] OnoT, Hayashi M, SasakiF, NakashimaT. RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen. 2020;40:2.

[135] DattaNS, Abou-Samra AB. PTH and PTHrP signaling in osteoblasts. Cell Signal. 2009;21(8):1245-1254.

[136] JüppnerH, Abou-Samra AB, FreemanM, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991;254(5034):1024-1026.

[137] HecktT, KellerJ, PetersS, et al. Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts. Bone. 2016;92:85-93.

[138] TohmondaT, YodaM, MizuochiH, et al. The IRE1α-XBP1 pathway positively regulates parathyroid hormone (PTH)/PTH-related peptide receptor expression and is involved in pth-induced osteoclastogenesis. J Biol Chem. 2013;288(3):1691-1695.

[139] KorenyT, Tunyogi-Csapó M, GálI, VermesC, JacobsJJ, GlantTT. The role of fibroblasts and fibroblast-derived factors in periprosthetic osteolysis. Arthritis Rheum. 2006;54(10):3221-3232.

[140] WangZ, LiuN, ShiT, et al. ER stress mediates TiAl6V4 particle-induced peri-implant osteolysis by promoting RANKL expression in fibroblasts. PLoS One. 2015;10(9):e0137774.

[141] WangZ, LiuN, ZhouG, et al. Expression of XBP1s in fibroblasts is critical for TiAl(6) V(4) particle-induced RANKL expression and osteolysis. J Orthop Res. 2017;35(4):752-759.

[142] WangR, WangZ, MaY, et al. Particle-induced osteolysis mediated by endoplasmic reticulum stress in prosthesis loosening. Biomaterials. 2013;34(11):2611-2623.

[143] XuG, LiuK, AndersonJ, et al. Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation. Blood. 2012;119(18):4205-4214.

[144] WynnTA, ChawlaA, PollardJW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445-455.

[145] TheofilopoulosAN, Baccala R, BeutlerB, KonoDH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307-336.

[146] TakayanagiH, KimS, MatsuoK, et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature. 2002;416(6882):744-749.

[147] SmithJA, TurnerMJ, DeLayML, Klenk EI, SowdersDP, ColbertRA. Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1. Eur J Immunol. 2008;38(5):1194-1203.

[148] ZengL, LiuYP, ShaH, ChenH, QiL, SmithJA. XBP-1 couples endoplasmic reticulum stress to augmented IFN-beta induction via a cis-acting enhancer in macrophages. J Immunol. 2010;185(4):2324-2330.

[149] ZhouCM, LuoLM, LinP, et al. Annexin A2 regulates unfolded protein response via IRE1-XBP1 axis in macrophages during P. aeruginosa infection. J Leukoc Biol. 2021;110(2):375-384.

[150] MartinonF, ChenX, LeeAH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11(5):411-418.

[151] EnglishBC, SavageHP, MahanSP, et al. The IRE1α-XBP1 signaling Axis promotes glycolytic reprogramming in response to inflammatory stimuli. MBio. 2023;14(1):e0306822.

[152] GuimarãesES, Gomes MTR, SanchesRCO, MatteucciKC, Marinho FV, OliveiraSC. The endoplasmic reticulum stress sensor IRE1α modulates macrophage metabolic function during Brucella abortus infection. Front Immunol. 2022;13:1063221.

[153] GuoM, ZhuangH, SuY, et al. SIRT3 alleviates imiquimod-induced psoriatic dermatitis through deacetylation of XBP1s and modulation of TLR7/8 inducing IL-23 production in macrophages. Front Immunol. 2023;14:1128543.

[154] IovinoM, Colonval M, WilkinC, et al. Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid. Front Immunol. 2023;14:1204126.

[155] KimS, JoeY, KimHJ, et al. Endoplasmic reticulum stress-induced IRE1α activation mediates cross-talk of GSK-3β and XBP-1 to regulate inflammatory cytokine production. J Immunol. 2015;194(9):4498-4506.

[156] LubambaBA, JonesLC, O’NealWK, BoucherRC, Ribeiro CM. X-box-binding protein 1 and innate immune responses of human cystic fibrosis alveolar macrophages. Am J Respir Crit Care Med. 2015;192(12):1449-1461.

[157] Lara-ReynaS, Scambler T, HolbrookJ, et al. Metabolic reprograming of cystic fibrosis macrophages via the IRE1α arm of the unfolded protein response results in exacerbated inflammation. Front Immunol. 2019;10:1789.

[158] ZhaoY, JiangY, ChenL, et al. Inhibition of the endoplasmic reticulum (ER) stress-associated IRE-1/XBP-1 pathway alleviates acute lung injury via modulation of macrophage activation. J Thorac Dis. 2020;12(3):284-295.

[159] DongL, TanCW, FengPJ, et al. Activation of TREM-1 induces endoplasmic reticulum stress through IRE-1α/XBP-1s pathway in murine macrophages. Mol Immunol. 2021;135:294-303.

[160] HorwoodNJ, Kartsogiannis V, QuinnJM, RomasE, MartinTJ, GillespieMT. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun. 1999;265(1):144-150.

[161] KongYY, FeigeU, SarosiI, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304-309.

[162] RifasL, Arackal S, WeitzmannMN. Inflammatory T cells rapidly induce differentiation of human bone marrow stromal cells into mature osteoblasts. J Cell Biochem. 2003;88(4):650-659.

[163] NamD, MauE, WangY, et al. T-lymphocytes enable osteoblast maturation via IL-17F during the early phase of fracture repair. PLoS One. 2012;7(6):e40044.

[164] LeeY. The role of interleukin-17 in bone metabolism and inflammatory skeletal diseases. BMB Rep. 2013;46(10):479-483.

[165] KotakeS, Udagawa N, TakahashiN, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103(9):1345-1352.

[166] BrunsingR, OmoriSA, WeberF, et al. B-and T-cell development both involve activity of the unfolded protein response pathway. J Biol Chem. 2008;283(26):17954-17961.

[167] KamimuraD, BevanMJ. Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection. J Immunol. 2008;181(8):5433-5441.

[168] MaX, BiE, LuY, et al. Cholesterol induces CD8(+) T cell exhaustion in the tumor microenvironment. Cell Metab. 2019;30(1):143-156.e5.

[169] ZhangY, ChenG, LiuZ, et al. Genetic vaccines to potentiate the effective CD103+ dendritic cell-mediated cross-priming of antitumor immunity. J Immunol. 2015;194(12):5937-5947.

[170] PoeC, Youngblood C, HodgeK, KempK. Treatment of established TH2 cells with 4µ8c, an inhibitor of IRE1α blocks IL-5 but not IL-4 secretion. BMC Immunol. 2019;20(1):3.

[171] XuY, Melo-Cardenas J, ZhangY, et al. The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine-induced ER stress response. JCI Insight. 2019;4(5):e121887.

[172] BaiG, WangH, CuiN. mTOR pathway mediates endoplasmic reticulum stress-induced CD4(+) T cell apoptosis in septic mice. Apoptosis. 2022;27(9–10):740-750.

[173] ZengX, XiaoX, HuS, et al. XBP1 is required in Th2 polarization induction in airway allergy. Theranostics. 2022;12(12):5337-5349.

[174] YangG, ZengXH, GengXR, et al. The transcription factor XBP1 in dendritic cells promotes the T(H)2 cell response in airway allergy. Sci Signal. 2023;16(791):eabm9454.

[175] IwaszkoM, Biały S, Bogunia-KubikK. Significance of interleukin (IL)-4 and IL-13 in inflammatory arthritis. Cells. 2021;10(11):3000.

[176] LiY, Terauchi M, VikulinaT, Roser-PageS, Weitzmann MN. B cell production of both OPG and RANKL is significantly increased in aged mice. Open Bone J. 2014;6:8-17.

[177] WalshMC, ChoiY. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front Immunol. 2014;5:511.

[178] LiY, Toraldo G, LiA, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839-3848.

[179] LiuH, ZengL, YangY, Guo C, WangH. Bcl-3: a double-edged sword in immune cells and inflammation. Front Immunol. 2022;13:847699.

[180] WangF, GuoJ, WangS, et al. B-cell lymphoma-3 controls mesenchymal stem cell commitment and senescence during skeletal aging. Clin Transl Med. 2022;12(7):e955.

[181] SunW, MeednuN, RosenbergA, et al. B cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation. Nat Commun. 2018;9(1):5127.

[182] ZoualiM. The emerging roles of B cells as partners and targets in periodontitis. Autoimmunity. 2017;50(1):61-70.

[183] HuCC, DouganSK, McGeheeAM, Love JC, PloeghHL. XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells. EMBO J. 2009;28(11):1624-1636.

[184] BenhamronS, HadarR, IwawakyT, So JS, LeeAH, TiroshB. Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells. Eur J Immunol. 2014;44(3):867-876.

[185] TangCH, ChangS, PatonAW, et al. Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization. J Cell Biol. 2018;217(5):1739-1755.

[186] MobasheriA, RaymanMP, GualilloO, Sellam J, van der KraanP, FearonU. The role of metabolism in the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2017;13(5):302-311.

[187] FengN, YeY, PanY, et al. The circUbqln1, regulated by XBP1s, interplays with 14-3-3ζ to inhibit collagen synthesis and promote osteoarthritis by controlling PRODH activity and proline metabolism. J Adv Res. 2024.

[188] LiangL, ZhangF, FengN, et al. IRE1α protects against osteoarthritis by regulating progranulin-dependent XBP1 splicing and collagen homeostasis. Exp Mol Med. 2023;55(11):2376-2389.

[189] KoJS, KohJM, SoJS, JeonYK, KimHY, Chung DH. Palmitate inhibits arthritis by inducing t-bet and gata-3 mRNA degradation in iNKT cells via IRE1α-dependent decay. Sci Rep. 2017;7(1):14940.

[190] El-GabalawyH. The preclinical stages of RA: lessons from human studies and animal models. Best Pract Res Clin Rheumatol. 2009;23(1):49-58.

[191] SavicS, Ouboussad L, DickieLJ, et al. TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes. J Autoimmun. 2014;50(100):59-66.

[192] SongAF, KangL, WangYF, Wang M. MiR-34a-5p inhibits fibroblast-like synoviocytes proliferation via XBP1. Eur Rev Med Pharmacol Sci. 2020;24(22):11675-11682. doi:10.26355/eurrev_202011_23812

[193] WangL, FanY, GuiY, et al. Endoplasmic reticulum stress triggered autophagy and regulated the phenotype transformation of rheumatoid arthritis synovial fibroblasts via the IRE1/JNK pathway. Ann Transl Med. 2022;10(13):725.

[194] AmanoT, Yamasaki S, YagishitaN, et al. Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes Dev. 2003;17(19):2436-2449.

[195] GaoB, LeeSM, ChenA, et al. Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis. EMBO Rep. 2008;9(5):480-485.

[196] AhmadianyM, Alavi-Samani M, HashemiZ, MoosaviMA, Rahmati M. The increased RNase activity of IRE1α in PBMCs from patients with rheumatoid arthritis. Adv Pharm Bull. 2019;9(3):505-509.

[197] GillT, Rosenbaum JT. Putative Pathobionts in HLA-B27-associated Spondyloarthropathy. Front Immunol. 2020;11:586494.

[198] FengY, DingJ, FanCM, Zhu P. Interferon-γ contributes to HLA-B27-associated unfolded protein response in spondyloarthropathies. J Rheumatol. 2012;39(3):574-582.

[199] RanganathanV, GraceyE, BrownMA, Inman RD, HaroonN. Pathogenesis of ankylosing spondylitis—recent advances and future directions. Nat Rev Rheumatol. 2017;13(6):359-367.

[200] DingF, ShaoZW, XiongLM. Cell death in intervertebral disc degeneration. Apoptosis. 2013;18(7):777-785.

[201] SakaiD, GradS. Advancing the cellular and molecular therapy for intervertebral disc disease. Adv Drug Deliv Rev. 2015;84:159-171.

[202] WenT, XueP, YingJ, Cheng S, LiuY, RuanD. The role of unfolded protein response in human intervertebral disc degeneration: Perk and IRE1-α as two potential therapeutic targets. Oxid Med Cell Longev. 2021;2021:6492879.

[203] KangH, DongY, PengR, et al. Inhibition of IRE1 suppresses the catabolic effect of IL-1β on nucleus pulposus cell and prevents intervertebral disc degeneration in vivo. Biochem Pharmacol. 2022;197:114932.

[204] LiuH, SuJ. Organoid extracellular vesicle-based therapeutic strategies for bone therapy. Biomater Transl. 2023;4(4):199-212. doi:10.12336/biomatertransl.2023.04.002

RIGHTS & PERMISSIONS

2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.