{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T04:31:53Z","timestamp":1794544313365,"version":"4.9.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Discov."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Extracellular matrix glycoprotein Reelin is associated with tumor metastasis and prognosis in various malignancies. However, its effects on multiple myeloma (MM) are not fully understood. Here, we investigated the regulatory effects of Reelin on MM and its underlying pathogenic mechanisms. Lentivirus plasmid containing short hairpin RNA targeting Reelin (LV3-Reln) was transfected into SP2\/0 cells to knockdown Reelin expression. Flow cytometry assay analyzed cell cycle and apoptosis while Transwell assay evaluated invasiveness. BALB\/c mice were inoculated with LV3-Reln-transfected SP2\/0 cells to establish MM model. Primary myeloma cells and osteoblasts\/osteoclast were isolated from tumor tissue and limb long bones respectively. ELISA examined serum biomarkers and immunohistochemistry detected immunoglobulin light chain expression. Morphological changes and osteoclast\/osteoblast differentiation were observed by histological staining. mRNA and proteins expression were determined by qPCR and WB. In vitro studies showed that Reelin depletion regulated osteolysis and osteogenesis balance, cell cycle, invasiveness, and apoptosis in SP2\/0 cells. In LV3-Reln mice, tumor growth and invasiveness were suppressed, meanwhile, reduced osteoclast activation and enhanced osteoblast activity were observed. Reelin knockdown alleviated extramedullary morbidity and inhibited spleen immune cell apoptosis by down-regulating CDK5, IL-10, and Cyto-C expression. Furthermore, reduced Reelin expression restrained osteoclast differentiation while promoted osteogenesis in the bone of LV3-Reln mice. This was further supported by down-regulation of osteolytic specific mRNAs and proteins (Trap, Mmp9, Ctsk, Clcn7) and up-regulation of osteogenic specific ones (COL-1, Runx2, \u03b2-Catenin). Reelin exerted important impacts on myeloma development through rebalancing osteolysis and osteogenesis, thus might be a potential therapeutic target for MM.<\/jats:p>","DOI":"10.1038\/s41420-021-00608-8","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T10:46:44Z","timestamp":1629888404000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Reelin depletion alleviates multiple myeloma bone disease by promoting osteogenesis and inhibiting osteolysis"],"prefix":"10.1038","volume":"7","author":[{"given":"Aixia","family":"Dou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"608_CR1","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1056\/NEJMra1011442","volume":"364","author":"A Palumbo","year":"2011","unstructured":"Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046\u201360.","journal-title":"N Engl J Med"},{"key":"608_CR2","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1007\/s12185-011-0949-x","volume":"94","author":"M Abe","year":"2011","unstructured":"Abe M. Targeting the interplay between myeloma cells and the bone marrow microenvironment in myeloma. Int J Hematol. 2011;94:334\u201343.","journal-title":"Int J Hematol"},{"key":"608_CR3","doi-asserted-by":"publisher","first-page":"26826","DOI":"10.18632\/oncotarget.5025","volume":"6","author":"M Colombo","year":"2015","unstructured":"Colombo M, Galletti S, Garavelli S, Platonova N, Paoli A, Basile A, et al. Notch signaling deregulation in multiple myeloma: a rational molecular target. Oncotarget. 2015;6:26826\u201340.","journal-title":"Oncotarget"},{"key":"608_CR4","doi-asserted-by":"publisher","first-page":"33","DOI":"10.4137\/CGM.S16817","volume":"7","author":"A Hameed","year":"2014","unstructured":"Hameed A, Brady JJ, Dowling P, Clynes M, O\u2019Gorman P. Bone disease in multiple myeloma: pathophysiology and management. Cancer Growth Metastasis. 2014;7:33\u201342.","journal-title":"Cancer Growth Metastasis"},{"key":"608_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-017-0037-4","volume":"8","author":"E Terpos","year":"2018","unstructured":"Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA. Pathogenesis of bone disease in multiple myeloma: from bench to bedside. Blood Cancer J. 2018;8:7.","journal-title":"Blood Cancer J."},{"key":"608_CR6","first-page":"305","volume":"159","author":"Y Sato","year":"2016","unstructured":"Sato Y, Kobayashi D, Kohno T, Kidani Y, Prox J, Becker-Pauly C, et al. Determination of cleavage site of Reelin between its sixth and seventh repeat and contribution of meprin metalloproteases to the cleavage. J. Biochem. 2016;159:305\u201312.","journal-title":"J. Biochem"},{"key":"608_CR7","first-page":"122","volume":"10","author":"GH Lee","year":"2016","unstructured":"Lee GH, D\u2019Arcangelo G. New insights into reelin-mediated signaling pathways. Front Cell Neurosci. 2016;10:122.","journal-title":"Front Cell Neurosci."},{"key":"608_CR8","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.biocel.2019.04.009","volume":"112","author":"NC Armstrong","year":"2019","unstructured":"Armstrong NC, Anderson RC, McDermott KW. Reelin: diverse roles in central nervous system development, health and disease. Int J. Biochem Cell Biol. 2019;112:72\u20135.","journal-title":"Int J. 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Sci Rep. 2017;7:45305.","journal-title":"Sci Rep"},{"key":"608_CR21","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.7150\/jca.18808","volume":"8","author":"L Lin","year":"2017","unstructured":"Lin L, Zhang X, Cao L, An Q, Hao J, Zhang Y, et al. Reelin promotes adhesion of multiple myeloma cells to bone marrow stromal cells via integrin beta1 signaling. J Cancer. 2017;8:2212\u201322.","journal-title":"J Cancer"},{"key":"608_CR22","doi-asserted-by":"publisher","first-page":"9844","DOI":"10.18632\/oncotarget.7151","volume":"7","author":"L Lin","year":"2016","unstructured":"Lin L, Yan F, Zhao D, Lv M, Liang X, Dai H, et al. Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin beta1 signaling and STAT3. 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Int J Mol Sci. 2019;20:1998\u20132009.","journal-title":"Int J Mol Sci"}],"container-title":["Cell Death Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41420-021-00608-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-021-00608-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-021-00608-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T09:51:26Z","timestamp":1669974686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41420-021-00608-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,25]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["608"],"URL":"https:\/\/doi.org\/10.1038\/s41420-021-00608-8","relation":{},"ISSN":["2058-7716"],"issn-type":[{"value":"2058-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,25]]},"assertion":[{"value":"6 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All authors have completed the ICMJE uniform disclosure form. The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were approved by the Animal Care and Use Committee of The Second Hospital, Cheeloo College of Medicine, Shandong University, and humane care was provided according to the criteria stated in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"219"}}