{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:06:17Z","timestamp":1792785977825,"version":"4.5.0"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01-AG072705-1"],"award-info":[{"award-number":["R01-AG072705-1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Daniel B. Burke Endowed Chair for Diabetes Research"},{"name":"Henry Ruppenthal Family Endowed Professorship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Genome wide association study (GWAS)-implicated bone mineral density (BMD) signals have been shown to localize in cis-regulatory regions of distal effector genes using 3D genomic methods. Detailed characterization of such genes can reveal novel causal genes for BMD determination. Here, we elected to characterize the \u201cDNM3\u201d locus on chr1q24, where the long non-coding RNA DNM3OS and the embedded microRNA MIR199A2 (miR-199a-5p) are implicated as effector genes contacted by the region harboring variation in linkage disequilibrium with BMD-associated sentinel single nucleotide polymorphism, rs12041600. During osteoblast differentiation of human mesenchymal stem\/progenitor cells (hMSC), miR-199a-5p expression was temporally decreased and correlated with the induction of osteoblastic transcription factors RUNX2 and Osterix. Functional relevance of miR-199a-5p downregulation in osteoblastogenesis was investigated by introducing miR-199a-5p mimic into hMSC. Cells overexpressing miR-199a-5p depicted a cobblestone-like morphological change and failed to produce BMP2-dependent extracellular matrix mineralization. Mechanistically, a miR-199a-5p mimic modified hMSC propagated normal SMAD1\/5\/9 signaling and expressed osteoblastic transcription factors RUNX2 and Osterix but depicted pronounced upregulation of SOX9 and enhanced expression of essential chondrogenic genes ACAN, COMP, and COL10A1. Mineralization defects, morphological changes, and enhanced chondrogenic gene expression associated with miR-199a-5p mimic over-expression were restored with miR-199a-5p inhibitor suggesting specificity of miR-199a-5p in chondrogenic fate specification. The expression of both the DNM3OS and miR-199a-5p temporally increased and correlated with hMSC chondrogenic differentiation. Although miR-199a-5p overexpression failed to further enhance chondrogenesis, blocking miR-199a-5p activity significantly reduced chondrogenic pellet size, extracellular matrix deposition, and chondrogenic gene expression. Taken together, our results indicate that oscillating miR-199a-5p levels dictate hMSC osteoblast or chondrocyte terminal fate. Our study highlights a functional role of miR-199a-5p as a BMD effector gene at the DNM3 BMD GWAS locus, where patients with cis-regulatory genetic variation which increases miR-199a-5p expression could lead to reduced osteoblast activity.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziae051","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T18:51:10Z","timestamp":1712170270000},"source":"Crossref","is-referenced-by-count":10,"title":["Osteoporosis GWAS-implicated\n                    <i>DNM3<\/i>\n                    locus contextually regulates osteoblastic and chondrogenic fate of mesenchymal stem\/progenitor cells through oscillating miR-199a-5p levels"],"prefix":"10.1093","volume":"8","author":[{"given":"Gurcharan","family":"Kaur","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A","family":"Pippin","sequence":"additional","affiliation":[{"name":"Center for Spatial and Functional Genomics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solomon","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Redmond","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"},{"name":"Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Chesi","sequence":"additional","affiliation":[{"name":"Center for Spatial and Functional Genomics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , United States"},{"name":"Division of Human Genetics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , United States"},{"name":"Department of Pathology and Laboratory Medicine , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"},{"name":"University of Pennsylvania , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D","family":"Wells","sequence":"additional","affiliation":[{"name":"Center for Spatial and Functional Genomics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , United States"},{"name":"Department of Pathology and Laboratory Medicine , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"},{"name":"University of Pennsylvania , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan","family":"Maerz","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Struan F A","family":"Grant","sequence":"additional","affiliation":[{"name":"Center for Spatial and Functional Genomics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , United States"},{"name":"Division of Human Genetics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , United States"},{"name":"Division of Diabetes and Endocrinology, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , United States"},{"name":"Department of Pediatrics , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"},{"name":"University of Pennsylvania , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"},{"name":"Institute of Diabetes , Obesity and Metabolism, Perelman School of Medicine, , Philadelphia, PA 19104 , United States"},{"name":"University of Pennsylvania , Obesity and Metabolism, Perelman School of Medicine, , Philadelphia, PA 19104 , United States"},{"name":"Department of Genetics , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"},{"name":"University of Pennsylvania , Perelman School of Medicine, , Philadelphia, PA 19104 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhima M","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"},{"name":"Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt D","family":"Hankenson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"},{"name":"Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-4267","authenticated-orcid":false,"given":"Yadav","family":"Wagley","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"issue":"1","key":"2024042902364066900_ref1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5152\/eurjrheum.2016.048","article-title":"An overview and management of 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