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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

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.

2021-09-08 | GSE165951 | GEO

Phlpp1 regulates endochondral ossification via the chondrocyte phospho-proteome

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

| PRJNA1104178 | ENA

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

Project description:Axial growth of long bones occurs through a coordinated process of growth plate chondrocyte proliferation and differentiation. This maturation of chondrocytes is reflected in a zonal change in gene expression and cell morphology from resting to proliferative, prehypertrophic, and hypertrophic chondrocytes of the growth plate followed by ossification. A major experimental limitation in understanding growth plate biology and pathophysiology is the lack of a robust technique to isolate cells from the different zones, particularly from small animals. Here, we report on a new strategy for separating distinct chondrocyte populations from mouse growth plates. By transcriptome profiling of microdissected zones of growth plates, we identified novel, zone-specific cell surface markers and used these for flow cytometry and immunomagnetic cell separation to quantify, enrich, and characterize chondrocytes populations with respect to their differentiation status. This approach provides a novel platform to study cartilage development and characterize mouse growth plate chondrocytes to reveal unique cellular phenotypes of the distinct subpopulations within the growth plate.

2020-02-29 | GSE144362 | GEO

C-type natriuretic peptide regulates endochondral ossification through p38 MAP kinase-dependent pathways_2

Project description:C-type natriuretic peptide (CNP) has been recently identified as an important anabolic regulator of endochondral bone growth, but the molecular mechanism mediating these effects are not completely understood. Here we demonstrate that CNP activates the p38 MAP kinase pathway in chondrocytes and that pharmacological inhibition of p38 blocks the anabolic effects of CNP in a tibia organ culture system. We further show that CNP stimulates endochondral bone growth largely through expansion of the hypertrophic zone of the growth plate, while delaying mineralization. Both effects are reversed by p38 inhibition. We performed Affymetrix microarray analyses to identify CNP target genes in the organ culture system. These studies confirmed that hypertrophic chondrocytes are the main targets of CNP signaling in the growth plate, potentially because cGMP-dependent kinases I and II, important transducers of CNP signaling and are expressed at much higher levels in these cells than in other areas of the tibia. One of the genes most strongly induced by CNP was the Ptgs2 gene, encoding Cox2. Real-time PCR confirmed that Cox2 expression was induced by CNP in hypertrophic chondrocytes, but surprisingly in a p38-independent manner. Moreover, Cox2 inhibition – in contrast to p38 inhibition - did not block the anabolic effects of CNP. In summary, our data identify novel target genes of CNP and demonstrate that the p38 pathway is a novel, essential mediator of CNP effects on endochondral ossification, with potential implications for numerous skeletal diseases. Keywords: Growth plate zone comparison and treatment response analysis

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Determine the effects of Hdac3 deletion on H3K27ac profiles in murine chondrocytes[RNA-Seq]

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. 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 profile for up and down regulated genes in Hdac3-deficient murine chondrocytes.

2016-08-10 | E-GEOD-75549 | biostudies-arrayexpress

Determine the effects of Hdac3 deletion on H3K27ac profiles in murine chondrocytes[ChIP-Seq]

2016-08-10 | E-GEOD-75547 | biostudies-arrayexpress

Human iPSC can be differentiated in vitro to articular cartilage or to osteogenic organoids via the endochondral ossification transdifferentiation pathway

Project description:The ability to generate chondrocytes and osteoblasts from induced pluripotent stem cells (iPSCs) will provide insights into skeletal development and genetic skeletal disorders and generate cells for regenerative medicine applications. Here we describe a method that directs iPSC-derived sclerotome to chondroprogenitors in 3D pellet culture then to articular chondrocytes or, alternatively, along the growth plate cartilage pathway to become hypertrophic chondrocytes that can transdifferentiate to osteoblasts. Osteogenic organoids deposit and mineralize a collagen I extracellular matrix (ECM), mirroring in vivo endochondral bone formation. We have identified gene expression signatures at key developmental stages including chondrocyte maturation, hypertrophy and transdifferentiation to osteoblasts, and show that this system can be used to model genetic cartilage and bone disorders.

2023-05-02 | GSE219215 | GEO

Mus musculus

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

| PRJNA99437 | ENA

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

2016-08-10 | E-GEOD-75552 | biostudies-arrayexpress

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