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Phlpp1 regulates endochondral ossification via the chondrocyte phospho-proteome

ABSTRACT: Appendicular growth and bone mass acquisition are controlled by a variety of growth factors, hormones, and mechanical forces in a dynamic process called endochondral ossification. Chondrocytes in the growth plate must proliferate and undergo hypertrophy to drive growth plate expansion and lay the template for bone. Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 and 2 (Phlpp1 and Phlpp2) are protein phosphatases that regulate intracellular signaling cascades through posttranslational modification of AKT, PKC, and S6K, among others. Phlpp1 controls chondrocyte proliferation and survival and germline deletion of Phlpp1 suppresses bone lengthening. Here, we demonstrate that Phlpp2 does not regulate endochondral ossification. Phlpp2-/- mice are phenotypically indistinguishable from their wildtype (WT) littermates, with similar bone length, bone mass, and growth plate dynamics. By contrast, Phlpp1/2-/- mice are phenotypically indistinguishable from Phlpp1-/- mice. Deletion of Phlpp1 or Phlpp2 had moderate effects on the chondrocyte transcriptome and proteome compared to WT control cells. By contrast, Phlpp1-/- and Phlpp1/2-/- chondrocytes had significantly altered phospho-proteomes compared to WT and Phlpp2-/- chondrocytes. Data integration via multiomics analysis revealed that RAF-MEK-ERK signaling was altered in cells lacking Phlpp1. In conclusion, these data demonstrate that Phlpp1, but not Phlpp2, regulates endochondral ossification via the chondrocyte phospho-proteome.

ORGANISM(S): Mus musculus

PROVIDER: GSE265773 | GEO | 2024/09/30

REPOSITORIES: GEO

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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.

2024-10-22 | PXD055563 | Pride

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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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Phlpp1 regulates endochondral ossification via the chondrocyte phospho-proteome

Project description:Phlpp1 regulates endochondral ossification via the chondrocyte phospho-proteome

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Sorting of Growth Plate Chondrocytes Allows the Isolation and Characterization of Cells of a Defined Differentiation Status

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Mus musculus

Project description:Transcriptional profiling of growth plate chondrocyte differentiation yields insight into endochondral ossification

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Determine the effects of Hdac3 deletion on H3K27ac profiles in murine chondrocytes

Project description:Histone deacetylase inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, these drugs inhibit multiple Hdacs and have detrimental effects on the pre- and post-natal skeleton. To better understand how Hdac inhibitors affect the skeleton, we focused on understanding the role of one of their targets, Hdac3, in endochondral bone formation by deleting it in immature murine chondrocyte micro masses with Adeno-Cre. Hdac3-deficient chondrocytes expressed higher levels of pro-inflammatory and matrix degrading genes (e.g., Il-6, Mmp3, Mmp13, Saa3) and lower levels of genes related to the extracellular matrix production, bone development and ossification (e.g., Acan, Col2a1, Ihh, Col10a1). Histone acetylation was increased in and around genes with elevated expression. This SuperSeries is composed of the SubSeries listed below. High Throughput RNA sequencing and Chromatin immunopreciptation sequencing experiments were performed in chondrocyte cultures. Differential analysis was conducted on ChIP-seq and RNA-seq data to identify H3K27Ac profiles for up and down-regulated genes in Hdac3-deficient murine chondrocytes. mm10 was used as reference genome. Refer to individual Series

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