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Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes [MBD-seq]

ABSTRACT: Chondrocytes differentiated from mesenchymal stem cells play a role in determining skeletal patterns by ossification. However, it is still unclear how the maintenance DNA methylation in chondrocytes regulates differentiation and skeletal formation. In Musculoskeletal Knowledge Portal, Dnmt1 was significantly associated with “Height”. In fact, long bone of limb specific Dnmt1 deficient mice was significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Furthermore, integrated analysis of RNA-Seq and MBD-Seq revealed that in Dnmt1ΔPrx1 chondrocytes, reduced DNA methylation resulted in an increase in energy metabolism-related genes in addition to ossification-related genes. Metabolomic analysis confirmed that almost all energy metabolites were increased in Dnmt1ΔPrx1 chondrocytes. These results indicate that Dnmt1 mediated maintenance DNA methylation governs chondrocyte differentiation by regulating energy metabolism through both gene expression and metabolite supply. Taken together, this study suggested that appropriate DNA methylation status in chondrocytes can orchestrate growth plate mineralization and subsequently determine bone length.

ORGANISM(S): Mus musculus

PROVIDER: GSE270641 | GEO | 2025/09/15

REPOSITORIES: GEO

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Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes [RNA-seq]

Project description:Chondrocytes differentiated from mesenchymal stem cells play a role in determining skeletal patterns by ossification. However, it is still unclear how the maintenance DNA methylation in chondrocytes regulates differentiation and skeletal formation. In Musculoskeletal Knowledge Portal, Dnmt1 was significantly associated with “Height”. In fact, long bone of limb specific Dnmt1 deficient mice was significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Furthermore, integrated analysis of RNA-Seq and MBD-Seq revealed that in Dnmt1ΔPrx1 chondrocytes, reduced DNA methylation resulted in an increase in energy metabolism-related genes in addition to ossification-related genes. Metabolomic analysis confirmed that almost all energy metabolites were increased in Dnmt1ΔPrx1 chondrocytes. These results indicate that Dnmt1 mediated maintenance DNA methylation governs chondrocyte differentiation by regulating energy metabolism through both gene expression and metabolite supply. Taken together, this study suggested that appropriate DNA methylation status in chondrocytes can orchestrate growth plate mineralization and subsequently determine bone length.

2025-09-15 | GSE270640 | GEO

Phlpp1 alters the murine chondrocyte phospho-proteome during endochondral bone formation

Project description:Appendicular skeletal growth and bone mass acquisition are controlled by a variety of growth factors, hormones, and mechanical forces in a dynamic process called endochondral ossification. In long bones, chondrocytes in the growth plate proliferate and undergo hypertrophy to drive bone lengthening and mineralization. Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 and 2 (Phlpp1 and Phlpp2) are serine/threonine protein phosphatases that regulate cell proliferation, survival, and maturation via Akt, PKC, Raf1, S6k, and other intracellular signaling cascades. Germline deletion of Phlpp1 suppresses bone lengthening in part through parathyroid hormone receptor-dependent signaling in growth plate chondrocytes. Here, we demonstrate that Phlpp2 does not regulate endochondral ossification, and we define the molecular differences between Phlpp1 and Phlpp2 in chondrocytes. Phlpp2-/- mice are phenotypically indistinguishable from their wildtype (WT) littermates, with similar bone length, bone mass, and growth plate dynamics. Deletion of Phlpp2 had moderate effects on the chondrocyte transcriptome and proteome compared to WT cells. By contrast, Phlpp1/2-/- (double knockout) mice resembled Phlpp1-/- mice phenotypically and chondrocyte phospho-proteomes of Phlpp1-/- and Phlpp1/2-/- chondrocytes were different than WT and Phlpp2-/- chondrocyte phospho-proteomes. Data integration via multiparametric analysis identified alterations in Pdpk1 and Pak1/2 signaling pathways in chondrocytes lacking Phlpp1. In conclusion, these data demonstrate that Phlpp1, but not Phlpp2, regulates endochondral ossification through multiple and complex signaling cascades.

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Loss of Foxc1 and Foxc2 function in chondroprogenitor cells disrupts endochondral ossification.

Project description:Endochondral ossification forms and grows the majority of the mammalian skeleton and is tightly controlled through gene regulatory networks. The forkhead box transcription factors Foxc1 and Foxc2 have been demonstrated to regulate aspects of osteoblast function in the formation of the skeleton but their roles in chondrocytes to control endochondral ossification are less clear. We demonstrate that Foxc1 expression is directly regulated by SOX9 activity, one of the earliest transcription factors to specify the chondrocyte lineages. Moreover we demonstrate that elevelated expression of Foxc1 promotes chondrocyte differentiation in mouse embryonic stem cells and loss of Foxc1 function inhibits chondrogenesis in vitro. Using chondrocyte-targeted deletion of Foxc1 and Foxc2 in mice, we reveal a role for these factors in chondrocyte differentiation in vivo. Loss of both Foxc1 and Foxc2 caused a general skeletal dysplasia predominantly affecting the vertebral column. The long bones of the limb were smaller and mineralization was reduced and organization of the growth plate was disrupted. In particular, the stacked columnar organization of the proliferative chondrocyte layer was reduced in size and cell proliferation in growth plate chondrocytes was reduced. Differential gene expression analysis indicated disrupted expression patterns in chondrogenesis and ossification genes throughout the entire process of endochondral ossification in Col2-cre;Foxc1Δ/Δ;Foxc2Δ/Δ embryos. Our results suggest that Foxc1 and Foxc2 are required for correct chondrocyte differentiation and function. Loss of both genes results in disorganization of the growth plate, reduced chondrocyte proliferation and delays in chondrocyte hypertrophy that prevents correct ossification of the endochondral skeleton.

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Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression

Project description:Transcriptional regulation can be tightly orchestrated by epigenetic regulators. Among these, ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) is reported to have diverse epigenetic functions, including regulation of DNA methylation. However, the physiological functions of Uhrf1 in skeletal tissues remain unclear. Here we show that limb mesenchymal cell-specific Uhrf1 conditional knockout mice (Uhrf1ΔLimb/ΔLimb) exhibit remarkably shortened long bones that have morphological deformities due to dysregulated chondrocyte differentiation as well as proliferation. RNA-seq performed on primary cultured chondrocytes obtained from Uhrf1ΔLimb/ΔLimb mice demonstrates abnormal acceleration of chondrocyte differentiation. In addition, integrative analyses using RNA-seq and MBD-seq reveal that Uhrf1 deficiency cause decreased genome-wide DNA methylation status and reduction in the promoters of specific genes such as Hspb1, which affects chondrocyte differentiation. These results indicate that Uhrf1 governs cell-type specific transcriptional regulation through genome-wide DNA methylation alteration and regulates consequent cell differentiation and skeletal maturation.

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Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation

Project description:Chondrocyte differentiation is regulated at a transcriptional level and by various hormonal stimuli. Since chondrocyte differentiation is important for normal skeletal growth, inadequate amounts of differentiation can lead to pathological conditions such as osteoarthritis. Transcriptional regulation can be tightly orchestrated by epigenetic regulators. Among these, ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) is reported to have diverse epigenetic functions, including regulation of DNA methylation. However, the physiological functions of Uhrf1 in skeletal tissues remain unclear. Here we show that limb mesenchymal cell-specific Uhrf1 conditional knockout mice (Uhrf1ΔLimb/ΔLimb) exhibit shortened long bones that have morphological deformities due to impaired chondrocyte differentiation and proliferation. RNA-seq performed on primary cultured chondrocytes obtained from control and Uhrf1ΔLimb/ΔLimb mice revealed that expression levels of proliferative chondrocyte marker genes were downregulated, whereas hypertrophic chondrocyte marker genes were upregulated. In addition, gene ontology analyses and Gene Set Enrichment Analysis (GSEA) suggested that limb growth retardation due to compromised chondrocyte differentiation might be caused by increased activity of the focal adhesion signaling pathway. These results indicated that Uhrf1 has a crucial role in normal skeletal maturation by coordinating transcriptional regulatory networks during chondrocyte differentiation.

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Involvement of ERK, Wnt and BMP2 signaling in human articular chondrocyte dedifferentiation in monolayer culture

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