{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T03:22:51Z","timestamp":1788492171596,"version":"build-2803163510"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Project funded by China Postdoctoral Science Foundation","award":["2022M723863"],"award-info":[{"award-number":["2022M723863"]}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2017YFA0106200"],"award-info":[{"award-number":["2017YFA0106200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Biol Lett"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic apical periodontitis is a prevalent oral disease characterized by bone loss, and its underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of the serine protease GZMA in osteoclasts during chronic apical periodontitis. To address this, we employed crRNA\/Cas13d to inhibit GZMA expression and examined its impact on osteoclast behavior. Our findings revealed that GZMA plays a significant role in promoting osteoclast cell proliferation while inhibiting cell apoptosis. Additionally, the inhibition of GZMA led to a notable increase in miR-25-3p expression, which, in turn, downregulated the expression of TGF-\u03b2. Consequently, the reduction in TGF-\u03b2 expression led to a decrease in PAR1 expression within the PARs pathway. These results suggest that GZMA might serve as a promising therapeutic target for the treatment of chronic apical periodontitis. Furthermore, our study highlights the potential of targeting GZMA using crRNA\/Cas13d as a valuable approach for future therapeutic interventions.<\/jats:p>","DOI":"10.1186\/s11658-023-00477-2","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T16:02:24Z","timestamp":1692979344000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["CRISPR\/Cas13d targeting GZMA in PARs pathway regulates the function of osteoclasts in chronic apical periodontitis"],"prefix":"10.1186","volume":"28","author":[{"given":"Tingting","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqiao","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"issue":"9","key":"477_CR1","doi-asserted-by":"publisher","first-page":"Cd010136","DOI":"10.1002\/14651858.CD010136.pub3","volume":"9","author":"AL Cope","year":"2018","unstructured":"Cope AL, Francis N, Wood F, Chestnutt IG. Systemic antibiotics for symptomatic apical periodontitis and acute apical abscess in adults. Cochrane Database Syst Rev. 2018;9(9):Cd010136. https:\/\/doi.org\/10.1002\/14651858.CD010136.pub3.","journal-title":"Cochrane Database Syst Rev"},{"issue":"8","key":"477_CR2","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1111\/iej.13305","volume":"53","author":"EB Sarmento","year":"2020","unstructured":"Sarmento EB, Gomes CC, Pires FR, Pinto LC, Antunes LAA, Armada L. Immunoexpression of bone resorption biomarkers in apical periodontitis in diabetics and normoglycaemics. Int Endod J. 2020;53(8):1025\u201332. https:\/\/doi.org\/10.1111\/iej.13305.","journal-title":"Int Endod J"},{"issue":"7","key":"477_CR3","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1111\/iej.12196","volume":"47","author":"MM Azuma","year":"2014","unstructured":"Azuma MM, Samuel RO, Gomes-Filho JE, Dezan-Junior E, Cintra LT. The role of IL-6 on apical periodontitis: a systematic review. Int Endod J. 2014;47(7):615\u201321. https:\/\/doi.org\/10.1111\/iej.12196.","journal-title":"Int Endod J"},{"issue":"4","key":"477_CR4","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1590\/1678-775720140140","volume":"22","author":"AC Araujo-Pires","year":"2014","unstructured":"Araujo-Pires AC, Francisconi CF, Biguetti CC, Cavalla F, Aranha AM, Letra A, et al. Simultaneous analysis of T helper subsets (Th1, Th2, Th9, Th17, Th22, Tfh, Tr1 and Tregs) markers expression in periapical lesions reveals multiple cytokine clusters accountable for lesions activity and inactivity status. J Appl Oral Sci Rev FOB. 2014;22(4):336\u201346. https:\/\/doi.org\/10.1590\/1678-775720140140.","journal-title":"J Appl Oral Sci Rev FOB"},{"issue":"4","key":"477_CR5","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1007\/s00418-018-1636-2","volume":"149","author":"T Ono","year":"2018","unstructured":"Ono T, Nakashima T. Recent advances in osteoclast biology. Histochem Cell Biol. 2018;149(4):325\u201341. https:\/\/doi.org\/10.1007\/s00418-018-1636-2.","journal-title":"Histochem Cell Biol"},{"issue":"1","key":"477_CR6","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.joen.2013.09.037","volume":"40","author":"IV Bracks","year":"2014","unstructured":"Bracks IV, Armada L, Gon\u00e7alves LS, Pires FR. Distribution of mast cells and macrophages and expression of interleukin-6 in periapical cysts. J Endod. 2014;40(1):63\u20138. https:\/\/doi.org\/10.1016\/j.joen.2013.09.037.","journal-title":"J Endod"},{"issue":"2","key":"477_CR7","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.joen.2013.10.036","volume":"40","author":"IJ M\u00e1rton","year":"2014","unstructured":"M\u00e1rton IJ, Kiss C. Overlapping protective and destructive regulatory pathways in apical periodontitis. J Endod. 2014;40(2):155\u201363. https:\/\/doi.org\/10.1016\/j.joen.2013.10.036.","journal-title":"J Endod"},{"key":"477_CR8","doi-asserted-by":"publisher","first-page":"931","DOI":"10.3389\/fimmu.2020.00931","volume":"11","author":"KR van Daalen","year":"2020","unstructured":"van Daalen KR, Reijneveld JF, Bovenschen N. Modulation of inflammation by extracellular granzyme A. Front Immunol. 2020;11:931. https:\/\/doi.org\/10.3389\/fimmu.2020.00931.","journal-title":"Front Immunol"},{"issue":"2","key":"477_CR9","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/j.celrep.2014.06.012","volume":"8","author":"MA Arias","year":"2014","unstructured":"Arias MA, Jim\u00e9nez de Bag\u00fces MP, Aguil\u00f3 N, Menao S, Herv\u00e1s-Stubbs S, de Martino A, et al. Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis. Cell Rep. 2014;8(2):420\u20139. https:\/\/doi.org\/10.1016\/j.celrep.2014.06.012.","journal-title":"Cell Rep"},{"issue":"29","key":"477_CR10","doi-asserted-by":"publisher","first-page":"13028","DOI":"10.1073\/pnas.1000546107","volume":"107","author":"K S\u00f6derstr\u00f6m","year":"2010","unstructured":"S\u00f6derstr\u00f6m K, Stein E, Colmenero P, Purath U, M\u00fcller-Ladner U, de Matos CT, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci USA. 2010;107(29):13028\u201333. https:\/\/doi.org\/10.1073\/pnas.1000546107.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"477_CR11","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1002\/art.39857","volume":"69","author":"L Santiago","year":"2017","unstructured":"Santiago L, Menaa C, Arias M, Martin P, Jaime-S\u00e1nchez P, Metkar S, et al. Granzyme A Contributes to inflammatory arthritis in mice through stimulation of osteoclastogenesis. Arthritis Rheumatol (Hoboken N J). 2017;69(2):320\u201334. https:\/\/doi.org\/10.1002\/art.39857.","journal-title":"Arthritis Rheumatol (Hoboken N J)"},{"issue":"3","key":"477_CR12","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.cell.2018.02.033","volume":"173","author":"S Konermann","year":"2018","unstructured":"Konermann S, Lotfy P, Brideau NJ, Oki J, Shokhirev MN, Hsu PD. Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell. 2018;173(3):665\u2013676e614. https:\/\/doi.org\/10.1016\/j.cell.2018.02.033.","journal-title":"Cell"},{"issue":"3","key":"477_CR13","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/s41422-020-0290-0","volume":"30","author":"TM Nguyen","year":"2020","unstructured":"Nguyen TM, Zhang Y, Pandolfi PP. Virus against virus: a potential treatment for 2019-nCov (SARS-CoV-2) and other RNA viruses. Cell Res. 2020;30(3):189\u201390. https:\/\/doi.org\/10.1038\/s41422-020-0290-0.","journal-title":"Cell Res"},{"issue":"5","key":"477_CR14","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s41592-021-01124-4","volume":"18","author":"C Xu","year":"2021","unstructured":"Xu C, Zhou Y, Xiao Q, He B, Geng G, Wang Z, et al. Programmable RNA editing with compact CRISPR-Cas13 systems from uncultivated microbes. Nat Methods. 2021;18(5):499\u2013506. https:\/\/doi.org\/10.1038\/s41592-021-01124-4.","journal-title":"Nat Methods"},{"key":"477_CR15","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1385\/1-59259-366-6:153","volume":"80","author":"P Collin-Osdoby","year":"2003","unstructured":"Collin-Osdoby P, Yu X, Zheng H, Osdoby P. RANKL-mediated osteoclast formation from murine RAW 264.7 cells. Methods Mol Med. 2003;80:153\u201366. https:\/\/doi.org\/10.1385\/1-59259-366-6:153.","journal-title":"Methods Mol Med"},{"issue":"7","key":"477_CR16","doi-asserted-by":"publisher","first-page":"e0270584","DOI":"10.1371\/journal.pone.0270584","volume":"17","author":"D Kaiserman","year":"2022","unstructured":"Kaiserman D, Zhao P, Rowe CL, Leong A, Barlow N, Joeckel LT, et al. Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2. PLoS ONE. 2022;17(7):e0270584. https:\/\/doi.org\/10.1371\/journal.pone.0270584.","journal-title":"PLoS ONE"},{"issue":"8","key":"477_CR17","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1002\/ijc.30862","volume":"141","author":"T Wang","year":"2017","unstructured":"Wang T, Jiao J, Zhang H, Zhou W, Li Z, Han S, et al. TGF-\u03b2 induced PAR-1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone. Int J Cancer. 2017;141(8):1630\u201342. https:\/\/doi.org\/10.1002\/ijc.30862.","journal-title":"Int J Cancer"},{"issue":"1","key":"477_CR18","doi-asserted-by":"publisher","first-page":"8541","DOI":"10.1038\/s41598-019-44865-1","volume":"9","author":"B Genz","year":"2019","unstructured":"Genz B, Coleman MA, Irvine KM, Kutasovic JR, Miranda M, Gratte FD, et al. Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-\u03b2-induced collagen expression in hepatic stellate cells. Sci Rep. 2019;9(1):8541. https:\/\/doi.org\/10.1038\/s41598-019-44865-1.","journal-title":"Sci Rep"},{"issue":"2","key":"477_CR19","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.gpb.2017.09.004","volume":"16","author":"K Wu","year":"2018","unstructured":"Wu K, He J, Pu W, Peng Y. The role of exportin-5 in microRNA biogenesis and cancer. Genom Proteom Bioinform. 2018;16(2):120\u20136. https:\/\/doi.org\/10.1016\/j.gpb.2017.09.004.","journal-title":"Genom Proteom Bioinform"},{"issue":"sup2","key":"477_CR20","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1080\/15476286.2021.1984096","volume":"18","author":"X Zhang","year":"2021","unstructured":"Zhang X, Liu F, Yang F, Meng Z, Zeng Y. Selectivity of exportin 5 binding to human precursor microRNAs. RNA Biol. 2021;18(sup2):730\u20137. https:\/\/doi.org\/10.1080\/15476286.2021.1984096.","journal-title":"RNA Biol"},{"issue":"1","key":"477_CR21","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/j.0105-2896.2010.00902.x","volume":"235","author":"J Lieberman","year":"2010","unstructured":"Lieberman J. Granzyme A activates another way to die. Immunol Rev. 2010;235(1):93\u2013104. https:\/\/doi.org\/10.1111\/j.0105-2896.2010.00902.x.","journal-title":"Immunol Rev"},{"issue":"8","key":"477_CR22","doi-asserted-by":"publisher","first-page":"3781","DOI":"10.7150\/thno.49288","volume":"11","author":"M Garz\u00f3n-Titua\u00f1a","year":"2021","unstructured":"Garz\u00f3n-Titua\u00f1a M, Sierra-Monz\u00f3n JL, Comas L, Santiago L, Khaliulina-Ushakova T, Uranga-Murillo I, et al. Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis. Theranostics. 2021;11(8):3781\u201395. https:\/\/doi.org\/10.7150\/thno.49288.","journal-title":"Theranostics"},{"issue":"2","key":"477_CR23","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1053\/j.gastro.2015.10.041","volume":"150","author":"GW Tew","year":"2016","unstructured":"Tew GW, Hackney JA, Gibbons D, Lamb CA, Luca D, Egen JG, et al. Association between response to etrolizumab and expression of integrin \u03b1E and Granzyme A in colon biopsies of patients with ulcerative colitis. Gastroenterology. 2016;150(2):477\u2013487e479. https:\/\/doi.org\/10.1053\/j.gastro.2015.10.041.","journal-title":"Gastroenterology"},{"issue":"3","key":"477_CR24","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.4049\/jimmunol.1000430","volume":"185","author":"DA Anthony","year":"2010","unstructured":"Anthony DA, Andrews DM, Chow M, Watt SV, House C, Akira S, et al. A role for granzyme M in TLR4-driven inflammation and endotoxicosis. J Immunol (Baltimore Md : 1950). 2010;185(3):1794\u2013803. https:\/\/doi.org\/10.4049\/jimmunol.1000430.","journal-title":"J Immunol (Baltimore Md : 1950)"},{"key":"477_CR25","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jaut.2016.06.003","volume":"73","author":"Y Hamel","year":"2016","unstructured":"Hamel Y, Mauvais FX, Pham HP, Kratzer R, Marchi C, Barilleau \u00c9, et al. A unique CD8(+) T lymphocyte signature in pediatric type 1 diabetes. J Autoimmun. 2016;73:54\u201363. https:\/\/doi.org\/10.1016\/j.jaut.2016.06.003.","journal-title":"J Autoimmun"},{"issue":"12","key":"477_CR26","doi-asserted-by":"publisher","first-page":"3041","DOI":"10.2337\/db17-0517","volume":"66","author":"ZUA Mollah","year":"2017","unstructured":"Mollah ZUA, Quah HS, Graham KL, Jhala G, Krishnamurthy B, Dharma JFM, et al. Granzyme A deficiency breaks immune tolerance and promotes autoimmune diabetes through a type I interferon-dependent pathway. Diabetes. 2017;66(12):3041\u201350. https:\/\/doi.org\/10.2337\/db17-0517.","journal-title":"Diabetes"},{"key":"477_CR27","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.bone.2014.11.004","volume":"72","author":"K Tudpor","year":"2015","unstructured":"Tudpor K, van der Eerden BC, Jongwattanapisan P, Roelofs JJ, van Leeuwen JP, Bindels RJ, et al. Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL\/OPG ratio. Bone. 2015;72:14\u201322. https:\/\/doi.org\/10.1016\/j.bone.2014.11.004.","journal-title":"Bone"},{"key":"477_CR28","doi-asserted-by":"publisher","first-page":"908859","DOI":"10.3389\/fcimb.2022.908859","volume":"12","author":"X Luo","year":"2022","unstructured":"Luo X, Wan Q, Cheng L, Xu R. Mechanisms of bone remodeling and therapeutic strategies in chronic apical periodontitis. Front Cell Infect Microbiol. 2022;12:908859. https:\/\/doi.org\/10.3389\/fcimb.2022.908859.","journal-title":"Front Cell Infect Microbiol"},{"key":"477_CR29","doi-asserted-by":"publisher","first-page":"866800","DOI":"10.3389\/fcell.2022.866800","volume":"10","author":"R Gupta","year":"2022","unstructured":"Gupta R, Ghosh A, Chakravarti R, Singh R, Ravichandiran V, Swarnakar S, et al. Cas13d: a new molecular scissor for transcriptome engineering. Front Cell Dev Biol. 2022;10:866800. https:\/\/doi.org\/10.3389\/fcell.2022.866800.","journal-title":"Front Cell Dev biol"},{"issue":"1","key":"477_CR30","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s13059-021-02263-9","volume":"22","author":"Y Zhang","year":"2021","unstructured":"Zhang Y, Nguyen TM, Zhang XO, Wang L, Phan T, Clohessy JG, et al. Optimized RNA-targeting CRISPR\/Cas13d technology outperforms shRNA in identifying functional circRNAs. Genome Biol. 2021;22(1):41. https:\/\/doi.org\/10.1186\/s13059-021-02263-9.","journal-title":"Genome Biol"},{"issue":"2","key":"477_CR31","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1093\/nar\/gkab1256","volume":"50","author":"A Kilikevicius","year":"2022","unstructured":"Kilikevicius A, Meister G, Corey DR. Reexamining assumptions about miRNA-guided gene silencing. Nucleic Acids Res. 2022;50(2):617\u201334. https:\/\/doi.org\/10.1093\/nar\/gkab1256.","journal-title":"Nucleic Acids Res"},{"key":"477_CR32","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s11658-019-0171-z","volume":"24","author":"M Liu","year":"2019","unstructured":"Liu M, Han X, Liu H, Chen D, Li Y, Hu W. The effects of CRISPR-Cas9 knockout of the TGF- \u03b21 gene on antler cartilage cells in vitro. Cell Mol Biol Lett. 2019;24:44. https:\/\/doi.org\/10.1186\/s11658-019-0171-z.","journal-title":"Cell Mol Biol Lett"},{"issue":"1","key":"477_CR33","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s11658-023-00454-9","volume":"28","author":"J Li","year":"2023","unstructured":"Li J, Liang Q, Zhou H, Zhou M, Huang H. Profiling the impact of the promoters on CRISPR-Cas12a system in human cells. Cell Mol Biol Lett. 2023;28(1):41. https:\/\/doi.org\/10.1186\/s11658-023-00454-9.","journal-title":"Cell Mol Biol Lett"}],"container-title":["Cellular &amp; Molecular Biology Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s11658-023-00477-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s11658-023-00477-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s11658-023-00477-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,19]],"date-time":"2023-11-19T16:02:57Z","timestamp":1700409777000},"score":1,"resource":{"primary":{"URL":"https:\/\/cmbl.biomedcentral.com\/articles\/10.1186\/s11658-023-00477-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,25]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["477"],"URL":"https:\/\/doi.org\/10.1186\/s11658-023-00477-2","relation":{},"ISSN":["1689-1392"],"issn-type":[{"value":"1689-1392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,25]]},"assertion":[{"value":"5 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"None.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"None.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"70"}}