Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Control of lipid metabolism in chondrocytes is critical for skeletal growth

ABSTRACT: Chondrodysplasia is a genetic disorder characterized by impaired cartilage development and bone growth. Dysregulation of the endoplasmic reticulum (ER) stress disrupts chondrogenesis, contributing to chondrodysplasia. Here, we demonstrate a critical role for the ER stress regulator PPP1R15B in chondrocyte development. PPP1R15B is a protein phosphatase that constitutively represses eIF2α phosphorylation to attenuate global protein translation in response to stress. Remarkably, deletion of Ppp1r15b in Prx1⁺ skeletal progenitors (Ppp1r15bPrx1) impairs chondrogenesis, resulting in a disorganized growth plate, reduced trabecular bone, and shortened long bones in mice. Similarly, inducible deletion of Ppp1r15b in Col2⁺ chondroprogenitors (Ppp1r15bCol2) leads to abnormal cartilage development and bone growth. Remarkably, no skeletal phenotype is observed in mice lacking Ppp1r15b in committed Osx⁺ osteoprogenitors (Ppp1r15bOsx) and Dmp1⁺ mature osteoblasts and osteocytes (Ppp1r15bDmp1), indicating that its role is limited to regulation of chondrogenesis, not osteogenic differentiation. Mechanistically, PPP1R15B deletion increases eIF2α phosphorylation, which in turn enhances lipogenic gene expression by suppressing Leptin. This effect was reversed in Ppp1r15bPrx1 mice by reconstitution with wildtype PPP1R15B, but not with a mutant form incapable of eIF2α dephosphorylation. Exogenous expression of Leptin also reversed skeletal abnormalities in these mice. Collectively, these findings reveal a previously unrecognized role for PPP1R15B in cartilage development through its regulation of lipid metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE305415 | GEO | 2026/05/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ANGPTL4 binds to leptin receptor to regulate ectopic bone formation and fat metabolism

Project description:Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR (db/db) and leptin (ob/ob) are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4, a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO cite, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Surprisingly, exogenous ANGPTL4 treatment not only promoted HO, but facilitated the transformation from white to brown adipose tissue in mice. These findings identify ANGPTL4 as a novel ligand for LepR to stimulate HO and regulate fat metabolism.

2024-07-03 | PXD043087 | Pride

Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases

Project description:In childhood skeletal growth is driven by transient expansion of cartilage in the growth plate. Common belief is that energy production in this hypoxic tissue mainly relies on anaerobic glycolysis and not on mitochondrial respiratory chain (RC) activity. However, children with mitochondrial diseases causing RC dysfunction often present with short stature, which indicates that RC activity may be essential for cartilage-mediated skeletal growth. To elucidate the role of the mitochondrial RC in cartilage growth and pathology, we generated mice with impaired RC-function in cartilage. These mice develop normally until birth, but their later growth is retarded. A detailed molecular analysis revealed that metabolic signaling and extracellular matrix formation is disturbed and induces cell death at the cartilage-bone junction to cause a chondrodysplasia-like phenotype. Hence, the results demonstrate the overall importance of the metabolic switch from fetal glycolysis to postnatal RC activation in growth plate cartilage and explain why RC dysfunction can cause short stature in children with mitochondrial disease

2019-04-24 | GSE130191 | GEO

Deep phenotyping of an ATDC5 in-vitro cartilage model system

Project description:Cartilage is characterized by a highly specialized extracellular matrix (ECM) secreted by chondrocytes and limited self-regenerative capacity. In vivo investigations of chondrogenesis are limited by difficult and traumatic access, especially in humans. While it is known for decades that disturbances of chondrocyte differentiation and changed cartilage ECM composition cause severe phenotypes skeletal phenotypes in vertebrates, a detailed molecular understanding of chondrogenesis and cartilage ECM formation is still missing, especially in the context of human genetic skeletal diseases.

2026-06-05 | GSE324360 | GEO

Transcriptomic changes in C3H10T1/2 cells exposed to lipid deprivation

Project description:The avascular nature of cartilage makes it a unique tissue in the human body, but whether and how the absence of blood vessels regulates chondrogenesis remains unknown. Obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells, a process we observed to be driven by a decreased availability of extracellular lipids. To understand how lipid deprivation activates the chondrogenic programme, we profiled mRNA expression of C3H10T1/2 skeletal progenitors exposed to lipid deprivation for 1, 3 or 6 hours.

2019-12-09 | E-MTAB-7564 | biostudies-arrayexpress

A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration [bulk RNA-seq]

Project description:Directed differentiation of stem cells toward chondrogenesis in vitro and in situ to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1mCherry and COL10A1eGFP double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration in situ. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.

2024-09-30 | GSE249229 | GEO

A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration [scRNA-seq]

2024-09-30 | GSE271814 | GEO

MSCs OA SILAC Mass spectrometry imaging

Project description:In osteoarthritis (OA), impairment of cartilage regeneration can be related to a defective chondrogenic differentiation of mesenchymal stromal cells (MSCs). Therefore, understanding the proteomic- and metabolomic-associated molecular events during the chondrogenesis of MSCs could provide alternative targets for therapeutic intervention. Here, a SILAC-based proteomic analysis identified 43 proteins related with metabolic pathways whose abundance was significantly altered during the chondrogenesis of OA human bone marrow MSCs (hBMSCs). Then, the level and distribution of metabolites was analyzed in these cells and healthy controls by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), leading to the recognition of characteristic metabolomic profiles at the early stages of differentiation. Finally, integrative pathway analysis showed that UDP-glucuronic acid synthesis and amino sugar metabolism were downregulated in OA hBMSCs during chondrogenesis compared to healthy cells. Alterations in these metabolic pathways may disturb the production of hyaluronic acid (HA) and other relevant cartilage extracellular matrix (ECM) components. This work provides a novel integrative insight into the molecular alterations of osteoarthritic MSCs and potential therapeutic targets for OA drug development through the enhancement of chondrogenesis.

2020-01-27 | PXD012879 | Pride

TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration in osteoarthritis

Project description:Objective: Skeletal stem cells are known to be regulated by their local self-regulating niche, that is comprised mainly of their progeny and secreted paracrine factors. What cell intrinsic factors govern the maintenance and function of the SSC remains elusive. Methods: Using the previously characterized Tet1-/- mice we investigated the differences in skeletal stem cell lineage tree. Further we examined the ability of these cells to differentiate into osteogenic and chondrogenic lineages, both with and without injury. Transcriptomic differences and inflammatory cytokines were investigated for differences in cartilage development pathways. Results: Loss of Tet1 skews the SSC lineage tree by expanding the SSC pool at the expense of its progeny as well as by enhancing the chondrogenic differentiation of SSC and the multilineage bone cartilage stromal progenitors (BCSP). Tet1 inhibition leads to enhanced chondrogenesis in mouse BCSP upon injury, in human SSC and chondroprogenitors (CP) isolated from osteoarthritic (OA) human cartilage and in late stages of OA in a mouse model. Transcriptomic analyses of SSC and BCSP lacking Tet1 revealed dysregulated pathways including alterations in Tgfb signaling, melatonin degradation and cartilage development associated genes. Conclusion: Tet1 was identified as critical regulator of SSC fate. Loss of Tet1 selectively enhances chondrogenic ability of skeletal stem cells. Supplementation of melatonin can dampen inflammation and lead to better cartilage health.

2023-08-15 | GSE232666 | GEO

Influence of DNA-methylation at multiple stages of limb chondrogenesis

Project description:Limb development is a well-established model for understanding cell fate decisions, and the formation of skeletal elements is coordinated through a sequence of events that control chondrogenesis spatiotemporally. It has been established that epigenetic control participates in cartilage maturation. Our research has shown for the first time that the inhibition of DNA methylation in interdigital tissue with 5-azacytidine results in the formation of an ectopic digit. This discovery suggested that DNA methylation dynamics could regulate the fate of cells between chondrogenesis and cell death during autopod development. We sequenced WGBS libraries from in-vivo interdigital tissue treated with 5-azacytidine or DMSO to identify genome-wide methylation changes during the early stages of 5-azacytidine-induced chondrogenesis.

2024-04-29 | GSE266119 | GEO

Identification and specification of the mouse skeletal stem cell.

Project description:How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.

2020-01-03 | GSE142873 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data