DNA demethylation of promoter region orchestrates SPI-1-induced ADAMTS-5 expression in articular cartilage of osteoarthritis mice.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 0050222 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4652 (Electronic) Linking ISSN: 00219541 NLM ISO Abbreviation: J Cell Physiol Subsets: MEDLINE

Publication: New York, NY : Wiley-Liss
Original Publication: Philadelphia, Wistar Institute of Anatomy and Biology.

Cartilage, Articular*/metabolism ; Intercellular Signaling Peptides and Proteins* ; Osteoarthritis*/pathology; Aged ; Animals ; Humans ; Male ; Mice ; Chondrocytes/metabolism ; DNA Demethylation ; HEK293 Cells ; Mice, Inbred C57BL ; Promoter Regions, Genetic/genetics

Osteoarthritis (OA) is one of the most prevalent joint diseases in aged people and characterized by articular cartilage degeneration, synovial inflammation, and abnormal bone remodeling. Recent advances in OA research have clearly shown that OA development is associated with aberrant DNA methylation status of many OA-related genes. As one of most important cartilage degrading proteases in OA, a disintegrin and metalloproteinase with thrombospondin motifs subtype 5 (ADAMTS-5) is activated to mediate cartilage degradation in human OA and experimental murine OA models. The pathological factors and signaling pathways mediating ADAMTS-5 activation during OA development are not well defined and have been a focus of intense research. ADAMTS-5 promoter is featured by CpG islands. So far there have been no reports concerning the DNA methylation status in ADAMTS-5 promoter during OA development. In this study, we sought to investigate DNA methylation status in ADAMTS-5 promoter, the role of DNA methylation in ADAMTS-5 activation in OA, and the underlying mechanisms. The potential for anti-OA intervention therapy which is based on modulating DNA methylation is also explored. Our results showed that DNA methyltransferases 1 (Dnmt1) downregulation-associated ADAMTS-5 promoter demethylation played an important role in ADAMTS-5 activation in OA, which facilitated SPI-1 binding on ADAMTS-5 promoter to activate ADAMTS-5 expression. More importantly, OA pathological phenotype of mice was alleviated in response to Dnmt1-induced DNA methylation of ADAMTS-5 promoter. Our study will benefit not only for deeper insights into the functional role and regulation mechanisms of ADAMTS-5 in OA, but also for the discovery of disease-modifying OA drugs on the basis of ADAMTS-5 via modulating DNA methylation status.
(© 2023 Wiley Periodicals LLC.)

Botter, S. M., Glasson, S. S., Hopkins, B., Clockaerts, S., Weinans, H., van Leeuwen, J. P. T. M., & van Osch, G. J. V. M. (2009). ADAMTS5−/− mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: Implications for a link between cartilage and subchondral bone changes. Osteoarthritis and Cartilage, 17(5), 636-645. https://doi.org/10.1016/j.joca.2008.09.018.
Bui, C., Barter, M. J., Scott, J. L., Xu, Y., Galler, M., Reynard, L. N., Rowan, A. D., & Young, D. A. (2012). cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis. The FASEB Journal, 26(7), 3000-3011. https://doi.org/10.1096/fj.12-206367.
Burda, P., Laslo, P., & Stopka, T. (2010). The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis. Leukemia, 24(7), 1249-1257. https://doi.org/10.1038/leu.2010.104.
Cai, D., Yin, S., Yang, J., Jiang, Q., & Cao, W. (2015). Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis. Arthritis Research & Therapy, 17, 269. https://doi.org/10.1186/s13075-015-0774-3.
Caradonna, F., Cruciata, I., Schifano, I., La Rosa, C., Naselli, F., Chiarelli, R., Perrone, A., & Gentile, C. (2018). Methylation of cytokines gene promoters in IL-1β-treated human intestinal epithelial cells. Inflammation Research, 67(4), 327-337. https://doi.org/10.1007/s00011-017-1124-5.
Chockalingam, P. S., Zeng, W., Morris, E. A., & Flannery, C. R. (2004). Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS-4 (aggrecanase 1) or ADAMTS-5 (aggrecanase 2). Arthritis & Rheumatism, 50(9), 2839-2848. https://doi.org/10.1002/art.20496.
Chu, C. R., Millis, M. B., & Olson, S. A. (2014). Osteoarthritis: From palliation to prevention: AOA critical issues. Journal of Bone and Joint Surgery, 96(15), e130. https://doi.org/10.2106/JBJS.M.01209.
Cuffaro, D., Ciccone, L., Rossello, A., Nuti, E., & Santamaria, S. (2022). Targeting aggrecanases for osteoarthritis therapy: From zinc chelation to exosite inhibition. Journal of Medicinal Chemistry, 65(20), 13505-13532. https://doi.org/10.1021/acs.jmedchem.2c01177.
Durigova, M., Soucy, P., Fushimi, K., Nagase, H., Mort, J. S., & Roughley, P. J. (2008). Characterization of an ADAMTS-5-mediated cleavage site in aggrecan in OSM-stimulated bovine cartilage. Osteoarthritis and Cartilage, 16(10), 1245-1252. https://doi.org/10.1016/j.joca.2008.02.013.
Fan, Q., Tang, T., Zhang, X., & Dai, K. (2009). The role of CCAAT/enhancer binding protein (C/EBP)-α in osteogenesis of C3H10T1/2 cells induced by BMP-2. Journal of Cellular and Molecular Medicine, 13(8B), 2489-2505. https://doi.org/10.1111/j.1582-4934.2008.00606.x.
Glasson, S. S., Askew, R., Sheppard, B., Carito, B., Blanchet, T., Ma, H. L., Flannery, C. R., Peluso, D., Kanki, K., Yang, Z., Majumdar, M. K., & Morris, E. A. (2005). Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature, 434(7033), 644-648. https://doi.org/10.1038/nature03369.
Glasson, S. S., Blanchet, T. J., & Morris, E. A. (2007). The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis and Cartilage, 15(9), 1061-1069. https://doi.org/10.1016/j.joca.2007.03.006.
Glyn-Jones, S., Palmer, A. J. R., Agricola, R., Price, A. J., Vincent, T. L., Weinans, H., & Carr, A. J. (2015). Osteoarthritis. The Lancet, 386(9991), 376-387. https://doi.org/10.1016/S0140-6736(14)60802-3.
Gu, J., Rong, J., Guan, F., Jiang, L., Zhang, T., Tao, S., Guan, G., Xu, L., & Tao, T. (2013). Association of ADAMTS5 gene polymorphisms with osteoarthritis in Chinese Han population: A community-based case-control study. Rheumatology International, 33(11), 2893-2897. https://doi.org/10.1007/s00296-012-2506-1.
Hashimoto, K., Oreffo, R. O. C., Gibson, M. B., Goldring, M. B., & Roach, H. I. (2009). DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis & Rheumatism, 60(11), 3303-3313. https://doi.org/10.1002/art.24882.
Hashimoto, K., Otero, M., Imagawa, K., de Andrés, M. C., Coico, J. M., Roach, H. I., Oreffo, R. O. C., Marcu, K. B., & Goldring, M. B. (2013). Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1β (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. Journal of Biological Chemistry, 288(14), 10061-10072. https://doi.org/10.1074/jbc.M112.421156.
Hosokawa, H., & Rothenberg, E. V. (2021). How transcription factors drive choice of the T cell fate. Nature Reviews Immunology, 21(3), 162-176. https://doi.org/10.1038/s41577-020-00426-6.
Ilic, M. Z., East, C. J., Rogerson, F. M., Fosang, A. J., & Handley, C. J. (2007). Distinguishing aggrecan loss from aggrecan proteolysis in ADAMTS-4 and ADAMTS-5 single and double deficient mice. Journal of Biological Chemistry, 282(52), 37420-37428. https://doi.org/10.1074/jbc.M703184200.
Iliopoulos, D., Malizos, K. N., & Tsezou, A. (2007). Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: Possible molecular target for osteoarthritis therapeutic intervention. Annals of the Rheumatic Diseases, 66(12), 1616-1621. https://doi.org/10.1136/ard.2007.069377.
Imagawa, K., de Andrés, M. C., Hashimoto, K., Itoi, E., Otero, M., Roach, H. I., Goldring, M. B., & Oreffo, R. O. C. (2014). Association of reduced type IX collagen gene expression in human osteoarthritic chondrocytes with epigenetic silencing by DNA hypermethylation. Arthritis & Rheumatology, 66(11), 3040-3051. https://doi.org/10.1002/art.38774.
Kielbowski, K., Herian, M., Bakinowska, E., Banach, B., Sroczynski, T., & Pawlik, A. (2023). The role of genetics and epigenetic regulation in the pathogenesis of osteoarthritis. International Journal of Molecular Sciences, 24(14), 11655. https://doi.org/10.3390/ijms241411655.
Kim, J. H., Lee, G., Won, Y., Lee, M., Kwak, J. S., Chun, C. H., & Chun, J. S. (2015). Matrix cross-linking-mediated mechanotransduction promotes posttraumatic osteoarthritis. Proceedings of the National Academy of Sciences, 112(30), 9424-9429. https://doi.org/10.1073/pnas.1505700112.
Kim, K. I., Park, Y. S., & Im, G. I. (2013). Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage. Journal of Bone and Mineral Research, 28(5), 1050-1060. https://doi.org/10.1002/jbmr.1843.
Kim, M., Rubab, A., Chan, W. C. W., & Chan, D. (2023). Osteoarthritis year in review 2022: Genetics, genomics and epigenetics. Osteoarthritis and Cartilage, 31(7), 865-875. https://doi.org/10.1016/j.joca.2023.03.003.
Kim, Y. H., Lee, H. C., Kim, S. Y., Yeom, Y. I., Ryu, K. J., Min, B. H., Kim, D. H., Son, H. J., Rhee, P. L., Kim, J. J., Rhee, J. C., Kim, H. C., Chun, H. K., Grady, W. M., & Kim, Y. S. (2011). Epigenomic analysis of aberrantly methylated genes in colorectal cancer identifies genes commonly affected by epigenetic alterations. Annals of Surgical Oncology, 18(8), 2338-2347. https://doi.org/10.1245/s10434-011-1573-y.
Kong, X., Gong, Z., Zhang, L., Sun, X., Ou, Z., Xu, B., Huang, J., Long, D., He, X., Lin, X., Li, Q., Xu, L., & Xuan, A. (2019). JAK2/STAT3 signaling mediates IL-6-inhibited neurogenesis of neural stem cells through DNA demethylation/methylation. Brain, Behavior, and Immunity, 79, 159-173. https://doi.org/10.1016/j.bbi.2019.01.027.
Lark, M. W., Bayne, E. K., Flanagan, J., Harper, C. F., Hoerrner, L. A., Hutchinson, N. I., Singer, I. I., Donatelli, S. A., Weidner, J. R., Williams, H. R., Mumford, R. A., & Lohmander, L. S. (1997). Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. Journal of Clinical Investigation, 100(1), 93-106. https://doi.org/10.1172/JCI119526.
Lev Maor, G., Yearim, A., & Ast, G. (2015). The alternative role of DNA methylation in splicing regulation. Trends in Genetics, 31(5), 274-280. https://doi.org/10.1016/j.tig.2015.03.002.
Li, J., Liao, Y., Huang, J., Sun, Y., Chen, H., Chen, C., Li, S., & Yang, Z. (2018). Epigenetic silencing of ADAMTS5 is associated with increased invasiveness and poor survival in patients with colorectal cancer. Journal of Cancer Research and Clinical Oncology, 144(2), 215-227. https://doi.org/10.1007/s00432-017-2545-9.
Ludwig, A. K., Zhang, P., & Cardoso, M. C. (2016). Modifiers and readers of DNA modifications and their impact on genome structure, expression, and stability in disease. Frontiers in Genetics, 7, 115. https://doi.org/10.3389/fgene.2016.00115.
Luo, J., An, X., Yao, Y., Erb, C., Ferguson, A., Kolls, J. K., Fan, S., & Chen, K. (2019). Epigenetic regulation of IL-17-induced chemokines in lung epithelial cells. Mediators of Inflammation, 2019, 9050965. https://doi.org/10.1155/2019/9050965.
Malfait, A. M., Ritchie, J., Gil, A. S., Austin, J. S., Hartke, J., Qin, W., Tortorella, M. D., & Mogil, J. S. (2010). ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization. Osteoarthritis and Cartilage, 18(4), 572-580. https://doi.org/10.1016/j.joca.2009.11.013.
Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D'Souza, C., Fouse, S. D., Johnson, B. E., Hong, C., Nielsen, C., Zhao, Y., Turecki, G., Delaney, A., Varhol, R., Thiessen, N., Shchors, K., Heine, V. M., Rowitch, D. H., Xing, X., Fiore, C., … Costello, J. F. (2010). Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature, 466(7303), 253-257. https://doi.org/10.1038/nature09165.
Peng, Y., Sun, X., & Liang, Y. (2020). Role of DNA methylation on human CTSG in dermatomyositic myoideum. Cell Biology International, 44(12), 2409-2415. https://doi.org/10.1002/cbin.11447.
Pritzker, K. P. H., Gay, S., Jimenez, S. A., Ostergaard, K., Pelletier, J. P., Revell, P. A., Salter, D., & van den Berg, W. B. (2006). Osteoarthritis cartilage histopathology: Grading and staging. Osteoarthritis and Cartilage, 14(1), 13-29. https://doi.org/10.1016/j.joca.2005.07.014.
Razin, A., & Cedar, H. (1977). Distribution of 5-methylcytosine in chromatin. Proceedings of the National Academy of Sciences, 74(7), 2725-2728. https://doi.org/10.1073/pnas.74.7.2725.
Roach, H. I., Yamada, N., Cheung, K. S. C., Tilley, S., Clarke, N. M. P., Oreffo, R. O. C., Kokubun, S., & Bronner, F. (2005). Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis & Rheumatism, 52(10), 3110-3124. https://doi.org/10.1002/art.21300.
Santamaria, S. (2020). ADAMTS-5: A difficult teenager turning 20. International Journal of Experimental Pathology, 101(1-2), 4-20. https://doi.org/10.1111/iep.12344.
Scott, J. L., Gabrielides, C., Davidson, R. K., Swingler, T. E., Clark, I. M., Wallis, G. A., Boot-Handford, R. P., Kirkwood, T. B. L., Talyor, R. W., & Young, D. A. (2010). Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Annals of the Rheumatic Diseases, 69(8), 1502-1510. https://doi.org/10.1136/ard.2009.119966.
Sesselmann, S., Söder, S., Voigt, R., Haag, J., Grogan, S. P., & Aigner, T. (2009). DNA methylation is not responsible for p21WAF1/CIP1 down-regulation in osteoarthritic chondrocytes. Osteoarthritis and Cartilage, 17(4), 507-512. https://doi.org/10.1016/j.joca.2008.09.006.
Solomon, L. A., Podder, S., He, J., Jackson-Chornenki, N. L., Gibson, K., Ziliotto, R. G., Rhee, J., & DeKoter, R. P. (2017). Coordination of myeloid differentiation with reduced cell cycle progression by PU.1 induction of microRNAs targeting cell cycle regulators and lipid anabolism. Molecular and Cellular Biology, 37(10), e00013-17. https://doi.org/10.1128/MCB.00013-17.
Song, R. H., D. Tortorella, M., Malfait, A. M., Alston, J. T., Yang, Z., Arner, E. C., & Griggs, D. W. (2007). Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis & Rheumatism, 56(2), 575-585. https://doi.org/10.1002/art.22334.
Stanton, H., Rogerson, F. M., East, C. J., Golub, S. B., Lawlor, K. E., Meeker, C. T., Little, C. B., Last, K., Farmer, P. J., Campbell, I. K., Fourie, A. M., & Fosang, A. J. (2005). ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature, 434(7033), 648-652. https://doi.org/10.1038/nature03417.
Su, J. Q., Lai, P. Y., Hu, P. H., Hu, J. M., Chang, P. K., Chen, C. Y., Wu, J. J., Lin, Y. J., Sun, C. A., Yang, T., Hsu, C. H., Lin, H. C., & Chou, Y. C. (2022). Differential DNA methylation analysis of SUMF2, ADAMTS5, and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan. World Journal of Gastroenterology, 28(8), 825-839. https://doi.org/10.3748/wjg.v28.i8.825.
Troeberg, L., & Nagase, H. (2012). Proteases involved in cartilage matrix degradation in osteoarthritis. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1824(1), 133-145. https://doi.org/10.1016/j.bbapap.2011.06.020.
Tu, J., Chen, W., Fang, Y., Han, D., Chen, Y., Jiang, H., Tan, X., Xu, Z., Wu, X., Wang, H., Zhu, X., Hong, W., Li, Z., Zhu, C., Wang, X., & Wei, W. (2023). PU.1 promotes development of rheumatoid arthritis via repressing FLT3 in macrophages and fibroblast-like synoviocytes. Annals of the Rheumatic Diseases, 82(2), 198-211. https://doi.org/10.1136/ard-2022-222708.
Turkistany, S. A., & DeKoter, R. P. (2011). The transcription factor PU.1 is a critical regulator of cellular communication in the immune system. Archivum Immunologiae et Therapiae Experimentalis, 59(6), 431-440. https://doi.org/10.1007/s00005-011-0147-9.
Wang, M., Shen, J., Jin, H., Im, H. J., Sandy, J., & Chen, D. (2011). Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis. Annals of the New York Academy of Sciences, 1240, 61-69. https://doi.org/10.1111/j.1749-6632.2011.06258.x.
Wylie, J. D., Ho, J. C., Singh, S., McCulloch, D. R., & Apte, S. S. (2012). Adamts5 (aggrecanase-2) is widely expressed in the mouse musculoskeletal system and is induced in specific regions of knee joint explants by inflammatory cytokines. Journal of Orthopaedic Research, 30(2), 226-233. https://doi.org/10.1002/jor.21508.
Yamamoto, K., Owen, K., Parker, A. E., Scilabra, S. D., Dudhia, J., Strickland, D. K., Troeberg, L., & Nagase, H. (2014). Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4). Journal of Biological Chemistry, 289(10), 6462-6474. https://doi.org/10.1074/jbc.M113.545376.
Yamamoto, K., Troeberg, L., Scilabra, S. D., Pelosi, M., Murphy, C. L., Strickland, D. K., & Nagase, H. (2013). LRP-1-mediated endocytosis regulates extracellular activity of ADAMTS-5 in articular cartilage. The FASEB Journal, 27(2), 511-521. https://doi.org/10.1096/fj.12-216671.
Yang, C. Y., Chanalaris, A., & Troeberg, L. (2017). ADAMTS and ADAM metalloproteinases in osteoarthritis - Looking beyond the ‘usual suspects’. Osteoarthritis and Cartilage, 25(7), 1000-1009. https://doi.org/10.1016/j.joca.2017.02.791.
Yao, Z., Chen, P., Wang, S., Deng, G., Hu, Y., Lin, Q., Zhang, X., & Yu, B. (2019). Reduced PDGF-AA in subchondral bone leads to articular cartilage degeneration after strenuous running. Journal of Cellular Physiology, 234(10), 17946-17958. https://doi.org/10.1002/jcp.28427.
Zhang, M., & Wang, J. (2015). Epigenetic regulation of gene expression in osteoarthritis. Genes & Diseases, 2(1), 69-75. https://doi.org/10.1016/j.gendis.2014.12.005.
Zhu, X., Chen, F., Lu, K., Wei, A., Jiang, Q., & Cao, W. (2019). PPARγ preservation via promoter demethylation alleviates osteoarthritisin mice. Annals of the Rheumatic Diseases, 78(10), 1420-1429. https://doi.org/10.1136/annrheumdis-2018-214940.

2019GSF108205 Key Technology Research and Development Program of Shandong

Keywords: ADAMTS-5; DNA methylation; SPI-1; epigenetics; osteoarthritis

0 (Intercellular Signaling Peptides and Proteins)
129712-62-5 (lambda Spi-1)
EC 3.4.24.- (Adamts5 protein, mouse)

Date Created: 20231227 Date Completed: 20240216 Latest Revision: 20240216

20250114

10.1002/jcp.31170

38149721