Single cell analysis of Idh mutant growth plates identifies cell populations responsible for longitudinal bone growth and enchondroma formation.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
31 Oct 2024
31 Oct 2024
Historique:
received:
20
05
2024
accepted:
15
10
2024
medline:
1
11
2024
pubmed:
1
11
2024
entrez:
1
11
2024
Statut:
epublish
Résumé
Enchondromas are a common tumor in bone that can occur as multiple lesions in enchondromatosis, which is associated with deformity of the affected bone. These lesions harbor somatic mutations in IDH and driving expression of a mutant Idh1 in Col2 expressing cells in mice causes an enchondromatosis phenotype. Here we compared growth plates from E18.5 mice expressing a mutant Idh1 with control littermates using single cell RNA sequencing. Data from Col2 expressing cells were analysed using UMAP and RNA pseudo-time analyses. A unique cluster of cells was identified in the mutant growth plates that expressed genes known to be upregulated in enchondromas. There was also a cluster of cells that was underrepresented in the mutant growth plates that expressed genes known to be important in longitudinal bone growth. Immunofluorescence showed that the genes from the unique cluster identified in the mutant growth plates were expressed in multiple growth plate anatomic zones, and pseudo-time analysis also suggested these cells could arise from multiple growth plate chondrocyte subpopulations. This data supports the notion that a subpopulation of chondrocytes become enchondromas at the expense of contributing to longitudinal growth.
Identifiants
pubmed: 39482341
doi: 10.1038/s41598-024-76539-y
pii: 10.1038/s41598-024-76539-y
doi:
Substances chimiques
Isocitrate Dehydrogenase
EC 1.1.1.41
Collagen Type II
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26208Subventions
Organisme : NIH HHS
ID : R01 AR066765
Pays : United States
Organisme : NIH HHS
ID : R01 AR066765
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Hong, E. D. et al. Prevalence of shoulder enchondromas on routine MR imaging. Clin. Imaging. 35 (5), 378–384 (2011).
pubmed: 21872128
doi: 10.1016/j.clinimag.2010.10.012
Walden, M. J., Murphey, M. D. & Vidal, J. A. Incidental enchondromas of the knee. AJR Am. J. Roentgenol. 190 (6), 1611–1615 (2008).
pubmed: 18492914
doi: 10.2214/AJR.07.2796
Amary, M. F. et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224 (3), 334–343 (2011).
pubmed: 21598255
doi: 10.1002/path.2913
Pansuriya, T. C. et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat. Genet. 43 (12), 1256–1261 (2011).
pubmed: 22057234
pmcid: 3427908
doi: 10.1038/ng.1004
Hirata, M. et al. Mutant IDH is sufficient to initiate enchondromatosis in mice. Proc. Natl. Acad. Sci. U S A. 112 (9), 2829–2834 (2015).
pubmed: 25730874
pmcid: 4352794
doi: 10.1073/pnas.1424400112
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 465 (7300), 966 (2010).
pubmed: 20559394
pmcid: 3766976
doi: 10.1038/nature09132
Marcucci, G. et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J. Clin. Oncol. 28 (14), 2348–2355 (2010).
pubmed: 20368543
pmcid: 2881719
doi: 10.1200/JCO.2009.27.3730
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N Engl. J. Med. 360 (8), 765–773 (2009).
pubmed: 19228619
pmcid: 2820383
doi: 10.1056/NEJMoa0808710
Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 324 (5924), 261–265 (2009).
pubmed: 19359588
pmcid: 3251015
doi: 10.1126/science.1170944
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18 (6), 553–567 (2010).
pubmed: 21130701
pmcid: 4105845
doi: 10.1016/j.ccr.2010.11.015
Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 483 (7390), 479–483 (2012).
pubmed: 22343889
pmcid: 3351699
doi: 10.1038/nature10866
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19 (1), 17–30 (2011).
pubmed: 21251613
pmcid: 3229304
doi: 10.1016/j.ccr.2010.12.014
Lu, C. et al. Induction of sarcomas by mutant IDH2. Genes Dev. 27 (18), 1986–1998 (2013).
pubmed: 24065766
pmcid: 3792475
doi: 10.1101/gad.226753.113
Zhang, H. et al. Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma. JCI Insight, 5 (11). (2019).
Zhang, H. et al. Distinct roles of glutamine metabolism in Benign and malignant cartilage tumors with IDH mutations. J. Bone Min. Res. 37 (5), 983–996 (2022).
doi: 10.1002/jbmr.4532
DiFrisco, J., Love, A. C. & Wagner, G. P. Character identity mechanisms: a conceptual model for comparative-mechanistic biology. Biol. Philos. 35 (4), 44 (2020).
doi: 10.1007/s10539-020-09762-2
Kobayashi, T. et al. Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP. J. Clin. Invest. 115 (7), 1734–1742 (2005).
pubmed: 15951842
pmcid: 1143590
doi: 10.1172/JCI24397
Lefebvre, V. & Smits, P. Transcriptional control of chondrocyte fate and differentiation. Birth Defects Res. C Embryo Today. 75 (3), 200–212 (2005).
pubmed: 16187326
doi: 10.1002/bdrc.20048
Tagariello, A. et al. Ucma—a novel secreted factor represents a highly specific marker for distal chondrocytes. Matrix Biol. 27 (1), 3–11 (2008).
pubmed: 17707622
doi: 10.1016/j.matbio.2007.07.004
Eitzinger, N. et al. Ucma is not necessary for normal development of the mouse skeleton. Bone. 50 (3), 670–680 (2012).
pubmed: 22155508
doi: 10.1016/j.bone.2011.11.017
Kato, K. et al. SOXC transcription factors induce cartilage growth plate formation in mouse embryos by promoting noncanonical WNT signaling. J. Bone Min. Res. 30 (9), 1560–1571 (2015).
doi: 10.1002/jbmr.2504
Surmann-Schmitt, C. et al. Wif-1 is expressed at cartilage-mesenchyme interfaces and impedes Wnt3a-mediated inhibition of chondrogenesis. J. Cell. Sci. 122 (Pt 20), 3627–3637 (2009).
pubmed: 19755491
doi: 10.1242/jcs.048926
Li, J. et al. Systematic reconstruction of molecular cascades regulating GP development using single-cell RNA-Seq. Cell Rep. 15 (7), 1467–1480 (2016).
pubmed: 27160914
doi: 10.1016/j.celrep.2016.04.043
Zhang, C. H. et al. Creb5 establishes the competence for Prg4 expression in articular cartilage. Commun. Biol. 4 (1), 332 (2021).
pubmed: 33712729
pmcid: 7955038
doi: 10.1038/s42003-021-01857-0
Ng, J. Q. et al. Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis. Nat. Commun. 14 (1), 6909 (2023).
pubmed: 37907525
pmcid: 10618187
doi: 10.1038/s41467-023-42199-1
Liddiard, K. et al. DNA ligase 1 is an essential mediator of sister chromatid telomere fusions in G2 cell cycle phase. Nucleic Acids Res. 47 (5), 2402–2424 (2019).
pubmed: 30590694
doi: 10.1093/nar/gky1279
Koltes, J. E. et al. Transcriptional profiling of PRKG2-null growth plate identifies putative down-stream targets of PRKG2. BMC Res. Notes. 8, 177 (2015).
pubmed: 25924610
pmcid: 4419418
doi: 10.1186/s13104-015-1136-6
Akiyama, H. et al. Indian hedgehog in the late-phase differentiation in mouse chondrogenic EC cells, ATDC5: upregulation of type X collagen and osteoprotegerin ligand mRNAs. Biochem. Biophys. Res. Commun. 257 (3), 814–820 (1999).
pubmed: 10208865
doi: 10.1006/bbrc.1999.0494
Zheng, Q. et al. Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J. Cell. Biol. 162 (5), 833–842 (2003).
pubmed: 12952936
pmcid: 2172833
doi: 10.1083/jcb.200211089
Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108 (1), 17–29 (2002).
pubmed: 11792318
doi: 10.1016/S0092-8674(01)00622-5
Qin, X. et al. Runx2 is essential for the transdifferentiation of chondrocytes into osteoblasts. PLoS Genet. 16 (11), e1009169 (2020).
pubmed: 33253203
pmcid: 7728394
doi: 10.1371/journal.pgen.1009169
See, P. et al. A single-cell sequencing guide for immunologists. Front. Immunol. 9, 2425 (2018).
pubmed: 30405621
pmcid: 6205970
doi: 10.3389/fimmu.2018.02425
Suzuki, N. et al. Teneurin-4, a transmembrane protein, is a novel regulator that suppresses chondrogenic differentiation. J. Orthop. Res. 32 (7), 915–922 (2014).
pubmed: 24648313
doi: 10.1002/jor.22616
Matsumoto, M. et al. Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology. Proc. Natl. Acad. Sci. 105 (18), 6720–6724 (2008).
pubmed: 18436651
pmcid: 2373361
doi: 10.1073/pnas.0709345105
Witte, F. et al. Comprehensive expression analysis of all wnt genes and their major secreted antagonists during mouse limb development and cartilage differentiation. Gene Expr. Patterns 9 (4), 215–223 (2009).
pubmed: 19185060
doi: 10.1016/j.gep.2008.12.009
Jonca, N. et al. Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses. Eur. J. Dermatol. 21 (Suppl 2), 35–42 (2011).
pubmed: 21628128
Karna, E. et al. Proline-dependent regulation of collagen metabolism. Cell. Mol. Life Sci. 77 (10), 1911–1918 (2020).
pubmed: 31740988
doi: 10.1007/s00018-019-03363-3
Yao, B. et al. Investigating the molecular control of deer antler extract on articular cartilage. J. Orthop. Surg. Res. 16 (1), 8 (2021).
pubmed: 33407721
pmcid: 7788833
doi: 10.1186/s13018-020-02148-w
Li, Y., Yang, S. T. & Yang, S. Trp53 controls chondrogenesis and endochondral ossification by negative regulation of TAZ activity and stability via beta-TrCP-mediated ubiquitination. Cell. Death Discov. 8 (1), 317 (2022).
pubmed: 35831272
pmcid: 9279315
doi: 10.1038/s41420-022-01105-2
Surmann-Schmitt, C. et al. Ucma, a Novel secreted cartilage-specific protein with implications in osteogenesis*. J. Biol. Chem. 283 (11), 7082–7093 (2008).
pubmed: 18156182
doi: 10.1074/jbc.M702792200
Trainor, P. A. & Merrill, A. E. Ribosome biogenesis in skeletal development and the pathogenesisof skeletal disorders. Biochim. Biophys. Acta Mol. Basis Dis. 1842 (6), 769–778 (2014).
doi: 10.1016/j.bbadis.2013.11.010
Shi, Z. et al. Exploring the key genes and pathways in enchondromas using a gene expression microarray. Oncotarget. 8 (27), 43967–43977 (2017).
pubmed: 28410203
pmcid: 5546454
doi: 10.18632/oncotarget.16700
Al-Jazrawe, M. et al. CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation. Cancer Res. Commun. 3 (4), 697–708 (2023).
pubmed: 37377751
pmcid: 10128091
doi: 10.1158/2767-9764.CRC-22-0403
Long, F. et al. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development. 128 (24), 5099–5108 (2001).
pubmed: 11748145
doi: 10.1242/dev.128.24.5099
Villani, A. C. et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 356 (6335) (2017).
Macosko, E. Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161 (5), 1202–1214 (2015).
pubmed: 26000488
doi: 10.1016/j.cell.2015.05.002
Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).
pubmed: 26653891
pmcid: 4676162
doi: 10.1186/s13059-015-0844-5
Cao, J. et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature. 566 (7745), 496–502 (2019).
pubmed: 30787437
pmcid: 6434952
doi: 10.1038/s41586-019-0969-x
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 29 (1), 15–21 (2013).
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 30 (7), 923–930 (2014).
pubmed: 24227677
doi: 10.1093/bioinformatics/btt656
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15 (12), 550 (2014).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Yu, G. et al. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics. 16 (5), 284–287 (2012).
pubmed: 22455463
pmcid: 3339379
doi: 10.1089/omi.2011.0118
Ramírez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44 (W1), W160–W165 (2016).
pubmed: 27079975
pmcid: 4987876
doi: 10.1093/nar/gkw257
Patro, R. et al. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods. 14 (4), 417–419 (2017).
pubmed: 28263959
pmcid: 5600148
doi: 10.1038/nmeth.4197