{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:29:43Z","timestamp":1780511383693,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, FOR2722)","award":["407176282"],"award-info":[{"award-number":["407176282"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, FOR2722)","award":["384170921"],"award-info":[{"award-number":["384170921"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, FOR2722)","award":["2022A1515011121"],"award-info":[{"award-number":["2022A1515011121"]}]},{"name":"Guangdong Province Basic and Applied Basic Research Fund Project","award":["407176282"],"award-info":[{"award-number":["407176282"]}]},{"name":"Guangdong Province Basic and Applied Basic Research Fund Project","award":["384170921"],"award-info":[{"award-number":["384170921"]}]},{"name":"Guangdong Province Basic and Applied Basic Research Fund Project","award":["2022A1515011121"],"award-info":[{"award-number":["2022A1515011121"]}]},{"name":"Guangzhou Elite Project","award":["407176282"],"award-info":[{"award-number":["407176282"]}]},{"name":"Guangzhou Elite Project","award":["384170921"],"award-info":[{"award-number":["384170921"]}]},{"name":"Guangzhou Elite Project","award":["2022A1515011121"],"award-info":[{"award-number":["2022A1515011121"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensation by actin-bundling proteins ACTN1, ACTN4, and FSCN1 was investigated in zebrafish following morpholino-mediated pls3 knockdown. Primary dermal fibroblasts from six patients with a PLS3 variant were also used to examine expression of these proteins during osteogenic differentiation. In addition, Pls3 knockdown in the murine MLO-Y4 cell line was employed to provide insights in global gene expression. Our results showed that ACTN1 and ACTN4 can rescue the skeletal deformities in zebrafish after pls3 knockdown, but this was inadequate for FSCN1. Patients\u2019 fibroblasts showed the same osteogenic transdifferentiation ability as healthy donors. RNA-seq results showed differential expression in Wnt1, Nos1ap, and Myh3 after Pls3 knockdown in MLO-Y4 cells, which were also associated with the Wnt and Th17 cell differentiation pathways. Moreover, WNT2 was significantly increased in patient osteoblast-like cells compared to healthy donors. Altogether, our findings in different bone cell types indicate that the mechanism of PLS3-related pathology extends beyond actin-bundling proteins, implicating broader pathways of bone metabolism.<\/jats:p>","DOI":"10.3390\/cells13171507","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T04:15:01Z","timestamp":1725855301000},"page":"1507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Functional Insights in PLS3-Mediated Osteogenic Regulation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9864-225X","authenticated-orcid":false,"given":"Wenchao","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Clinical Chemistry, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Neugebauer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2974-6224","authenticated-orcid":false,"given":"Janak L.","family":"Pathak","sequence":"additional","affiliation":[{"name":"Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4091-7115","authenticated-orcid":false,"given":"Gerard","family":"Pals","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9186-3423","authenticated-orcid":false,"given":"M. Carola","family":"Zillikens","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 CE Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5399-676X","authenticated-orcid":false,"given":"Elisabeth M. W.","family":"Eekhoff","sequence":"additional","affiliation":[{"name":"Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands"},{"name":"Department Internal Medicine, Endocrinology and Metabolism, Amsterdam UMC Location Vrije Universiteit Amsterdam, Rare Bone Disease Center, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Bravenboer","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingbin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3709-8166","authenticated-orcid":false,"given":"Matthias","family":"Hammerschmidt","sequence":"additional","affiliation":[{"name":"Developmental Biology Unit, Institute of Zoology, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-5191","authenticated-orcid":false,"given":"Brunhilde","family":"Wirth","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7890-4411","authenticated-orcid":false,"given":"Dimitra","family":"Micha","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1056\/NEJMoa1308223","article-title":"PLS3 mutations in X-linked osteoporosis with fractures","volume":"369","author":"Zillikens","year":"2013","journal-title":"N. 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