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IRE1α protects against osteoarthritis by regulating progranulin-dependent XBP1 splicing and collagen homeostasis

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초록

Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA.

Abstract

Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA.

참고문헌 (51)

  1. Barnett, R., "Osteoarthritis", Lancet, 391, pp.1985~ (2018)
  2. Lee, H. P., "Mechanical confinement regulates cartilage matrix formation by chondrocytes", Nat. Mater, 16, pp.1243~1251 (2017)
  3. Jiang, Y., "Origin and function of cartilage stem", progenitor cells in osteoarthritis, 2015, pp.11, 206~212
  4. Krishnan, Y, "Cartilage diseases", Matrix Biol, 71–72, pp.51~69 (2018)
  5. Mobasheri, A., "The role of metabolism in the pathogenesis of osteoarthritis", Nat. Rev. Rheumatol, 13, pp.302~311 (2017)
  6. Melrose, J., "The cartilage extracellular matrix as a transient developmental scaffold for growth plate maturation", Matrix Biol, 52–54, pp.363~383 (2016)
  7. Boot-Handford, R. P., "The unfolded protein response and its relevance to connective tissue diseases", Cell Tissue Res, 339, pp.197~211 (2010)
  8. Patterson, S. E., "Mechanisms and models of endoplasmic reticulum stress in chondrodysplasia", Dev. Dyn, 243, pp.875~893 (2014)
  9. Hetz, C., "Mechanisms, regulation and functions of the unfolded protein response", Nat. Rev. Mol. Cell Biol, 21, pp.421~438 (2020)
  10. Tohmonda, T., "IRE1α", XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis, 2015, pp.125, 3269~3279
  11. Cameron, T. L., "XBP1-independent UPR pathways suppress C", EBP-β mediated chondrocyte differentiation in ER-stress related skeletal disease, 2015, pp.11, e1005505~
  12. Tohmonda, T., "The IRE1α-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix", EMBO Rep, 12, pp.451~457 (2011)
  13. Roy, A., "The IRE1", XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism, 2021, pp.10, e73215~
  14. Kim, S., "Endoplasmic reticulum stress-induced IRE1α activation mediates cross-talk of GSK-3β and XBP-1 to regulate inflammatory cytokine production", J. Immunol, 194, pp.4498~4506 (2015)
  15. Han, X., "IRE1α dissociates with BiP and inhibits ER stress-mediated apoptosis in cartilage development", Cell. Signal, 25, pp.2136~2146 (2013)
  16. Feng, N., "Treating autoimmune inflammatory diseases with an siERN1-nanoprodrug that mediates macrophage polarization and blocks toll-like receptor signaling", ACS Nano, 15, pp.15874~15891 (2021)
  17. Huang, R., "IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis", J. Cell Physiol, 237, pp.118~127 (2022)
  18. Li, X., "Effect of XBP1 deficiency in cartilage on the regulatory network of LncRNA", circRNA-miRNA-mRNA, 2022, pp.18, 315~330
  19. Sun, K., "The PI3K", AKT, Osteoarthritis Cartilage, pp.2020, 28[DOI]
  20. Duan, L., "Cytokine networking of chondrocyte dedifferentiation in vitro and its implications for cell-based cartilage therapy", Am. J. Transl. Res, 7, pp.194~208 (2015)
  21. Wei, J. L., "Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models", Arthritis Res. Ther, 19, pp.280~ (2017)
  22. Ron, D., "Signal integration in the endoplasmic reticulum unfolded protein response", Nat. Rev. Mol. Cell Biol, 8, pp.519~529 (2007)
  23. Lin, J. H., "IRE1 signaling affects cell fate during the unfolded protein response", Science, 318, pp.944~949 (2007)
  24. Cameron, T. L., "Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization", Osteoarthritis Cartilage, 23, pp.661~670 (2015)
  25. Jeon, O. H., "Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment", Nat. Med, 23, pp.775~781 (2017)
  26. Cui, Z., "Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone", Ann. Rheum. Dis, 75, pp.1714~1721 (2016)
  27. Yang, H., "MTORC1 coordinates the autophagy and apoptosis signaling in articular chondrocytes in osteoarthritic temporomandibular joint", Autophagy, 16, pp.271~288 (2020)
  28. Feng, K., "Quercetin attenuates oxidative stress-induced apoptosis via SIRT1", AMPK-mediated inhibition of ER stress in rat chondrocytes and prevents the progression of osteoarthritis in a rat model, 2019, pp.234, 18192~18205
  29. Rahmati, M., "ER stress : a therapeutic target in rheumatoid arthritis?", Trends Pharmacol. Sci, 39, pp.610~623 (2018)
  30. Kaser, A., "XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease", Cell, 134, pp.743~756 (2008)
  31. Duvigneau, J. C., "Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases", Cytokine, 124, pp.154577~ (2019)
  32. Li, Y. H., "The unfolded protein response genes in human osteoarthritic chondrocytes : PERK emerges as a potential therapeutic target", Arthritis Res. Ther, 18, pp.172~ (2016)
  33. Mobasheri, A., "Osteoarthritis Year in Review 2016: biomarkers (biochemical markers)", Osteoarthritis Cartilage, 25, pp.199~208 (2017)
  34. Li, X., "Type II collagen-positive progenitors are important stem cells in controlling skeletal development and vascular formation", Bone Res, 10, pp.46~ (2022)
  35. Nagao, M., "Col2-Cre and tamoxifen-inducible Col2-CreER target different cell populations in the knee joint", Osteoarthritis Cartilage, 24, pp.188~191 (2016)
  36. Pan, Y., "Progranulin regulation of autophagy contributes to its chondroprotective effect in osteoarthritis", Genes Dis, 10, pp.1582~1595 (2022)
  37. Wang, C., "Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice", J. Neuroinflammation, 16, pp.238~ (2019)
  38. Schmitz, K., "Progranulin deficiency confers resistance to autoimmune encephalomyelitis in mice", Cell. Mol. Immunol, 17, pp.1077~1091 (2020)
  39. Buraschi, S., "Progranulin", EphA2 axis : a novel oncogenic mechanism in bladder cancer, 2020, pp.93, 10~24
  40. Cui, Y., "Progranulin: a conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases", Cytokine Growth Factor Rev, 45, pp.53~64 (2019)
  41. Bai, X. H., "ADAMTS-7, a direct target of PTHrP, adversely regulates endochondral bone growth by associating with and inactivating GEP growth factor", Mol. Cell. Biol, 29, pp.4201~4219 (2009)
  42. Liu, C., "Progranulin-derived Atsttrin directly binds to TNFRSF25(DR3)and inhibits TNF-like ligand 1A(TL1A)activity", PLoS ONE, 9, pp.e92743~ (2014)
  43. Altmann, C., "Progranulin promotes peripheral nerve regeneration and reinnervation : role of notch signaling", Mol. Neurodegener, 11, pp.69~ (2016)
  44. Liu, C. J., "Progranulin : a growth factor, a novel TNFR ligand and a drug target", Pharmacol. Ther, 133, pp.124~132 (2012)
  45. Tanimoto, R., "The perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin", Matrix Biol, 64, pp.27~39 (2017)
  46. Kong, L., "Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor", FASEB J, 30, pp.2741~2754 (2016)
  47. Almeida, S., "Progranulin, a glycoprotein deficient in frontotemporal dementia, is a novel substrate of several protein disulfide isomerase family proteins", PLoS ONE, 6, pp.e26454~ (2011)
  48. Chen, Y., "Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease", J. Mol. Med, 96, pp.1359~1373 (2018)
  49. Jian, J., "Progranulin acts as a shared chaperone and regulates multiple lysosomal enzymes", Genes Dis, 4, pp.125~126 (2017)
  50. Zhao, Y. P., "Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling", Ann. Rheum. Dis, 74, pp.2244~2253 (2015)
  51. Guo, F. J., "XBP1S, a BMP2-inducible transcription factor, accelerates endochondral bone growth by activating GEP growth factor", J. Cell Mol. Med, 18, pp.1157~1171 (2014)

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