Circular RNA CREBBP modulates cartilage degradation by activating the Smad1/5 pathway through the TGFβ2/ALK1 axis
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Osteoarthritis, characterized by articular cartilage degradation, is the leading cause of chronic disability in older adults. Studies have indicated that circular RNAs are crucial regulators of chondrocyte development and are involved in the progression of osteoarthritis. In this study, we investigated the function and mechanism of a circular RNA and its potential for osteoarthritis therapy. The expression levels of circCREBBP, screened by circular RNA sequencing during chondrogenic differentiation in adipose tissue-derived stem cells, and TGFβ2 were significantly increased in the cartilage of patients with osteoarthritis and IL-1β-induced chondrocytes. circCREBBP knockdown increased anabolism in the extracellular matrix and inhibited chondrocyte degeneration, whereas circCREBBP overexpression led to the opposite effects. Luciferase reporter assays, rescue experiments, RNA immunoprecipitation, and RNA pulldown assays confirmed that circCREBBP upregulated TGFβ2 expression by sponging miR-1208, resulting in significantly enhanced phosphorylation of Smad1/5 in chondrocytes. Moreover, intra-articular injection of adeno-associated virus-sh-circCrebbp alleviated osteoarthritis in a mouse model of destabilization of the medial meniscus. Our findings reveal a critical role for circCREBBP in the progression of osteoarthritis and provide a potential target for osteoarthritis therapy.
Abstract
Osteoarthritis, characterized by articular cartilage degradation, is the leading cause of chronic disability in older adults. Studies have indicated that circular RNAs are crucial regulators of chondrocyte development and are involved in the progression of osteoarthritis. In this study, we investigated the function and mechanism of a circular RNA and its potential for osteoarthritis therapy. The expression levels of circCREBBP, screened by circular RNA sequencing during chondrogenic differentiation in adipose tissue-derived stem cells, and TGFβ2 were significantly increased in the cartilage of patients with osteoarthritis and IL-1β-induced chondrocytes. circCREBBP knockdown increased anabolism in the extracellular matrix and inhibited chondrocyte degeneration, whereas circCREBBP overexpression led to the opposite effects. Luciferase reporter assays, rescue experiments, RNA immunoprecipitation, and RNA pulldown assays confirmed that circCREBBP upregulated TGFβ2 expression by sponging miR-1208, resulting in significantly enhanced phosphorylation of Smad1/5 in chondrocytes. Moreover, intra-articular injection of adeno-associated virus-sh-circCrebbp alleviated osteoarthritis in a mouse model of destabilization of the medial meniscus. Our findings reveal a critical role for circCREBBP in the progression of osteoarthritis and provide a potential target for osteoarthritis therapy.
참고문헌 (52)
- Hunter, D. J., "Osteoarthritis", Lancet, 393, pp.1745~1759 (2019)
- Mandl, L. A., "Osteoarthritis year in review 2018: clinical", Osteoarthr. Cartil, 27, pp.359~364 (2019)
- Wilson, H. A., "Patient relevant outcomes of unicompartmental versus total knee replacement: systematic review and meta-analysis", BMJ, 364, pp.l352~ (2019)
- Loeser, R. F., "Ageing and the pathogenesis of osteoarthritis", Nat. Rev. Rheumatol, 12, pp.412~420 (2016)
- Guilak, F., "Osteoarthritis as a disease of the cartilage pericellular matrix", Matrix Biol, 71-72, pp.40~50 (2018)
- van den Bosch, M. H. J., "Osteoarthritis year in review 2020: biology", Osteoarthr. Cartil, 29, pp.143~150 (2021)
- Mobasheri, A., "The role of metabolism in the pathogenesis of osteoarthritis", Nat. Rev. Rheumatol, 13, pp.302~311 (2017)
- Bijlsma, J. W. J., "Osteoarthritis: an update with relevance for clinical practice", Lancet, 377, pp.2115~2126 (2011)
- Shu Hu, "MicroRNA-455-3p promotes TGF-β signaling and inhibits osteoarthritis development by directly targeting PAK2", Experimental and Molecular Medicine, 51, pp.1~13 (2019), 생화학분자생물학회[DOI]
- Mao, G., "Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A", Stem Cell Res. Ther, 9, pp.247~ (2018)
- Shan, C., "Biogenesis, functions and clinical significance of circRNAs in gastric cancer", Mol. Cancer, 18, pp.136~ (2019)
- Zhang, Y., "The biogenesis of nascent circular RNAs", Cell Rep, 15, pp.611~624 (2016)
- Haque, S., "Circular RNAs(circRNAs)in health and disease", Genes, 8, pp.353~ (2017)
- Patop, I. L., "Past, present, and future of circRNAs", EMBO J, 38, pp.e100836~ (2019)
- Barrett, S. P., "Circular RNAs: analysis, expression and potential functions", Development, 143, pp.1838~1847 (2016)
- Chen, Y., "Circular RNAs : a new frontier in the study of human diseases", J. Med. Genet, 53, pp.359~365 (2016)
- Reynard, L. N., "Osteoarthritis year in review 2019 : genetics, genomics and epigenetics", Osteoarthr. Cartil, 28, pp.275~284 (2020)
- Yang, Y. R., "Circular RNA CREBBP suppresses hepatic fibrosis via targeting the hsa-miR-1291", LEFTY2 axis, 2021, pp.12, 741151~
- Qiao, J., "Microarray analysis of circRNAs expression profile in gliomas reveals that circ_0037655 could promote glioma progression by regulating miR-214", PI3K signaling, 2020, pp.245, 117363~
- Zhang, L., "Circ-CREBBP promotes cell tumorigenesis and glutamine catabolism in glioma by regulating miR-375", glutaminase axis, 2022, pp.1775, 147730~
- Wu, P., "Identification of crucial circRNAs in skeletal muscle during chicken embryonic development", BMC Genomics, 23, pp.330~ (2022)
- Massague, J., "TGFbeta signalling in context", Nat. Rev. Mol. Cell Biol, 13, pp.616~630 (2012)
- Tzavlaki, K., "TGF-beta signaling", Biomolecules, 10, pp.487~ (2020)
- Hata, A., "TGF-beta signaling from receptors to Smads", Cold Spring Harb. Perspect. Biol, 8, pp.a022061~ (2016)
- Wrighton, K. H., "Phospho-control of TGF-beta superfamily signaling", Cell Res, 19, pp.8~20 (2009)
- Dituri, F., "The Interactivity between TGFbeta and BMP signaling in organogenesis, fibrosis, and cancer", Cells, 8, pp.1130~ (2019)
- Liu, I. M., "TGFbeta-stimulated Smad1", 5 phosphorylation requires the ALK5 L45loop and mediates the pro-migratory TGFbeta switch, 2009, pp.28, 88~98
- Tan Timur, U., "Increased TGF-beta and BMP levels and improved chondrocyte-specific marker expression in vitro under cartilage-specific physiological osmolarity", Int. J. Mol. Sci, 20, pp.795~ (2019)
- Li, H., "Inhibition of miR-490-5p promotes human adipose-derived stem cells chondrogenesis and protects chondrocytes via the PITPNM1", PI3K, Front. Cell Dev. Biol, pp.2020, 8[DOI]
- Mao, G., "Long non-coding RNA HOTTIP promotes CCL3 expression and induces cartilage degradation by sponging miR-455-3p", Front. Cell Dev. Biol, 7, pp.161~ (2019)
- Mao, G., "Exosome-transported circRNA_0001236 enhances chondrogenesis and suppress cartilage degradation via the miR-3677-3p", Sox9 axis, 2021, pp.12, 389~
- Livak, K. J., "Analysis of relative gene expression data using realtime quantitative PCR and the 2(-Delta Delta C(T))method", Methods, 25, pp.402~408 (2001)
- Xu, Y., "Long non-coding RNAs LOC100126784 and POM121L9P derived from bone marrow mesenchymal stem cells enhance osteogenic differentiation via the miR-503-5p", SORBS1 axis, 2021, pp.9, 723759~
- Bradley, C. A., "Opening up a pathway for disease modification in osteoarthritis", Nat. Rev. Drug Discov, 18, pp.497~ (2019)
- Mao, X., "Biological roles and therapeutic potential of circular RNAs in osteoarthritis", Mol. Ther. Nucleic Acids, 24, pp.856~867 (2021)
- Shen, S., "CircSERPINE2 protects against osteoarthritis by targeting miR-1271and ETS-related gene", Ann. Rheum. Dis, 78, pp.826~836 (2019)
- Zhou, X., "Down-regulated ciRS-7", up-regulated miR-7 axis aggravated cartilage degradation and autophagy defection by PI3K, mTOR activation mediated by IL-17A in osteoarthritis, pp.Aging, 2020[DOI]
- Wu, Y., "Circular RNA circPDE4D protects against osteoarthritis by binding to miR-103a-3p and regulating FGF18", Mol. Ther, 29, pp.308~323 (2021)
- Yao, T., "Circ0083429 regulates osteoarthritis progression via the Mir-346", SMAD3 axis, 2020, pp.8, 579945~
- Mao, G., "MicroRNA-92a-3p regulates the expression of cartilage-specific genes by directly targeting histone deacetylase 2 in chondrogenesis and degradation", Osteoarthr. Cartil, 25, pp.521~532 (2017)
- Meng, F., "Chondrogenic differentiation of ATDC5 and hMSCs could be induced by a novel scaffold-tricalcium phosphate-collagen-hyaluronan without any exogenous growth factors in vitro", J. Biomed. Mater. Res. A, 102, pp.2725~2735 (2014)
- Meng, F., "MicroRNA-193b-3p regulates chondrogenesis and chondrocyte metabolism by targeting HDAC3", Theranostics, 8, pp.2862~2883 (2018)
- Jiang, Y., "CREBBP inactivation promotes the development of HDAC3-dependent lymphomas", Cancer Discov, 7, pp.38~53 (2017)
- Kristensen, L. S., "The biogenesis, biology and characterization of circular RNAs", Nat. Rev. Genet, 20, pp.675~691 (2019)
- Kubiczkova, L., "TGF-beta—an excellent servant but a bad master", J. Transl. Med, 10, pp.183~ (2012)
- Furumatsu, T., "Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein", p300recruitment, 2005, pp.280, 8343~8350
- van der Kraan, P. M., "A role for agerelated changes in TGFbeta signaling in aberrant chondrocyte differentiation and osteoarthritis", Arthritis Res. Ther, 12, pp.201~ (2010)
- Finnson, K. W., "Endoglin differentially regulates TGF-beta-induced Smad2", 3and Smad1, Osteoarthr. Cartil, pp.2010, 18[DOI]
- Goumans, M. J., "Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors", EMBO J, 21, pp.1743~1753 (2002)
- van der Kraan, P. M., "Agedependent alteration of TGF-beta signalling in osteoarthritis", Cell Tissue Res, 347, pp.257~265 (2012)
- Gun-Il Im, "Perspective on Intra-articular Injection Cell Therapy for Osteoarthritis Treatment", 조직공학과 재생의학, 16(4), pp.357~363 (2019), 한국조직공학과 재생의학회[DOI]
- Jones, I. A., "Intraarticular treatment options for knee osteoarthritis", Nat. Rev. Rheumatol, 15, pp.77~90 (2019)