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DNA hydroxymethylases Tet1 and Tet2 regulate bone aging and BMSC metabolism through the IGF-1/ mTOR signalling axis

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dc.contributor.authorSmith, N.
dc.contributor.authorCakouros, D.
dc.contributor.authorRyan, F.J.
dc.contributor.authorLynn, D.J.
dc.contributor.authorPaton, S.
dc.contributor.authorArthur, A.
dc.contributor.authorGronthos, S.
dc.date.issued2025
dc.descriptionAdvance access publication 6 May 2025
dc.description.abstractThe Ten-Eleven Translocases (Tet) family of DNA hydroxymethylases have recently been implicated in bone development, with Tet1 and Tet2 mediating Bone Marrow Stromal Cell (BMSC) growth and osteogenic differentiation. The present study investigated the effects of Tet1 and Tet2 deregulation on bone development and age-related bone loss, with respect to BMSC function. Histomorphometric and micro-CT analysis of skeletal parameters found significant reductions to trabecular structure and volume as well as reduced osteoblast numbers within the bone of Prx-1:Cre driven Tet1 and Tet2 double knockout (TetDKO) mice at skeletal maturity. Moreover, these effects were exacerbated with age, particularly in male mice. In vitro studies found a significant reduction in TetDKO BMSC osteogenic potential and a shift towards adipogenesis, as well as changes to DNA repair, proliferation and senescence properties. RNA sequencing of BMSC derived from TetDKO male mice uncovered several differentially expressed genes, and an array of significantly enriched gene set pathways. Notably Pappa2, involved in regulation of IGF-1 signalling, was significantly differentially regulated, leading to reduction in IGF-1 bioavailability and signalling in BMSC and differentiated osteoblasts. Furthermore, changes in mTOR activity in TetDKO animals indicated altered metabolic activity, differentiation and proliferation capabilities of TetDKO BMSC. These findings indicate that Tet1 and 2 regulate the IGF-1 regulatory element, Pappa2, where deregulation of Tet1 and Tet2 in BMSC can disrupt this pathway leading to enhanced bone loss and premature aging. Targeting of these novel regulatory pathways may offer new therapeutic approaches for treatment of age-related bone loss.
dc.description.statementofresponsibilityNicholas Smith, Dimitrios Cakouros, Feargal J Ryan, David J Lynn, Sharon Paton, Agnieszka Arthur, Stan Gronthos
dc.identifier.citationStem Cells, 2025; 43(8):sxaf026-1-sxaf026-17
dc.identifier.doi10.1093/stmcls/sxaf026
dc.identifier.issn1066-5099
dc.identifier.issn1549-4918
dc.identifier.orcidCakouros, D. [0000-0001-6136-0761]
dc.identifier.orcidPaton, S. [0000-0001-7031-3510]
dc.identifier.orcidArthur, A. [0000-0002-0539-8797]
dc.identifier.orcidGronthos, S. [0000-0002-6225-3084]
dc.identifier.urihttps://hdl.handle.net/2440/146792
dc.language.isoen
dc.publisherOxford University Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1141361
dc.rights© The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
dc.source.urihttps://doi.org/10.1093/stmcls/sxaf026
dc.subject5hmc
dc.subject5mc
dc.subjectAging
dc.subjectBMSC
dc.subjectBone
dc.subjectBone marrow stromal cell
dc.subjectDNA hydroxymethylation
dc.subjectEpigenetics
dc.subjectMesenchymal Stem Cell
dc.subjectSkeletal
dc.subjectTet1
dc.subjectTet2
dc.titleDNA hydroxymethylases Tet1 and Tet2 regulate bone aging and BMSC metabolism through the IGF-1/ mTOR signalling axis
dc.typeJournal article
pubs.publication-statusPublished

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