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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

ABSTRACT: We investigated the Prkar1a+/- mice when bred with Prkaca+/- genetic backgrounds. Prkar1a+/-Prkaca+/- mice not only continued to develop bone lesions but also demonstrated a significant increase in both the number and the severity of the lesions, as well as a reduction in the age of first appearance of any bone abnormality. Histological analysis of bone from Prkar1a+/-Prkaca+/- mice showed that lesions had similarity to tumors from humans with CNC and some resemblance (but also differences) from humans and mice with fibrous dysplasia (FD). Prkar1a+/- and Prkar1a+/-Prkaca+/- mouse lesions always involved a particular sub-population of cells that could be identified as belonging to the osteoblastic lineage, that were initially located on the endosteal surface of the periosteum and nearby trabecular bone proximal to the growth plate of the long bones and vertebrae, and resembled bone stromal cells (BSCs). The bone lesions expressed high level of mesenchymal proteins like n-cadherin, vimentin, snail1, twist1, mmp2 and mmp9 when compared to WT bone. On top of this, bone lesions from Prkar1a+/-Prkaca+/- mice also showed an increased expression of keratin related genes, which are involved in hair follicle and epithelial differentiation, when compared to lesions from Prkar1a+/- mice. Total RNA obtained from bone lesions from Prkar1a+/- and Prkar1a+/-Prkaca+/- mice were compared to those obtained from WT and Prkaca+/- mice.

ORGANISM(S): Mus musculus

SUBMITTER: C Cheadle

PROVIDER: E-GEOD-20984 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

Project description:We investigated the Prkar1a+/- mice when bred with Prkaca+/- genetic backgrounds. Prkar1a+/-Prkaca+/- mice not only continued to develop bone lesions but also demonstrated a significant increase in both the number and the severity of the lesions, as well as a reduction in the age of first appearance of any bone abnormality. Histological analysis of bone from Prkar1a+/-Prkaca+/- mice showed that lesions had similarity to tumors from humans with CNC and some resemblance (but also differences) from humans and mice with fibrous dysplasia (FD). Prkar1a+/- and Prkar1a+/-Prkaca+/- mouse lesions always involved a particular sub-population of cells that could be identified as belonging to the osteoblastic lineage, that were initially located on the endosteal surface of the periosteum and nearby trabecular bone proximal to the growth plate of the long bones and vertebrae, and resembled bone stromal cells (BSCs). The bone lesions expressed high level of mesenchymal proteins like n-cadherin, vimentin, snail1, twist1, mmp2 and mmp9 when compared to WT bone. On top of this, bone lesions from Prkar1a+/-Prkaca+/- mice also showed an increased expression of keratin related genes, which are involved in hair follicle and epithelial differentiation, when compared to lesions from Prkar1a+/- mice.

2010-03-21 | GSE20984 | GEO

Single nuclei RNAseq of the periosteal response to bone fracture in mice

Project description:Bone regeneration is a highly efficient process allowing scarless healing after injury. The periosteum, the outer layer of bones, is a critical source of skeletal stem/progenitor cells (SSPCs), as well as immune, endothelial and neural cells during bone repair. In our study, we generated a single-nuclei atlas of the murine periosteal response to bone fracture. We generated single nuclei datasets from uninjured periosteum and from injured periosteum and hematoma/fracture callus at days 5 and 7 post-injury from wild-type mice.

2024-04-01 | GSE234451 | GEO

Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin

Project description:Bone regeneration relies on the activation of skeletal stem cells (SSCs) that still remain poorly characterized. Here, we show that periosteum contains SSCs with high bone regenerative potential compared to bone marrow stromal cells/skeletal stem cells (BMSCs) in mice. Although periosteal cells (PCs) and BMSCs are derived from a common embryonic mesenchymal lineage, post-natally PCs exhibit greater clonogenicity, growth and differentiation capacity than BMSCs. During bone repair, PCs can efficiently contribute to cartilage and bone, and integrate long-term after transplantation. Molecular profiling uncovers genes encoding Periostin and other extracellular matrix molecules associated with the enhanced response to injury of PCs. Periostin gene deletion impairs PC functions and fracture consolidation. Periostin-deficient periosteum cannot reconstitute a pool of PCs after injury demonstrating the presence of SSCs within periosteum and the requirement of Periostin in maintaining this pool. Overall our results highlight the importance of analyzing periosteum and PCs to understand bone phenotypes.

2018-10-18 | E-MTAB-6417 | biostudies-arrayexpress

Prkar1a haploinsufficiency leads to an overall increase in tumors caused by other genetic defects or chemical induction

Project description:[original title] Prkar1a haploinsufficiency in mice leads to an overall increase in tumors caused by other genetic defects or chemical induction We investigated the Prkar1a+/- mice when bred within the Rb1+/- or Trp53+/- genetic backgrounds, or treated with a 2-step skin carcinogenesis protocol. Prkar1a+/-Trp53+/- mice developed more bone sarcomas than Trp53+/- mice (p<0.05) and Prkar1a+/-Rb1+/- mice grew more and larger pituitary and thyroid tumors than Rb1+/- mice. All mice with double heterozygosity had significantly reduced life-spans compared with their single-heterozygous counterparts. Finally, Prkar1a+/- mice developed more papillomas than wild-type animals when treated with a 2-step skin carcinogenesis protocol. A whole-genome transcriptome profiling of tumors produced by all three models identified Wnt signaling as the main pathway activated by abnormal cAMP signaling in these tissues, along with (expected) cell cycle gene abnormalities, all confirmed by qRT-PCR array and immunohistochemical analyses.

2009-12-24 | GSE19576 | GEO

Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations

Project description:PRKAR1A inactivating mutations are responsible for primary pigmented nodular adrenocortical disease (PPNAD) whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome (MAS), ACTH-independent hyperplasia (AIMAH) and, rarely, cortisol-producing adenomas (CPA). The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Total RNA obtained from adrenal tumors were compared to those samples obtained from normal adrenal pools

2011-11-15 | E-GEOD-33694 | biostudies-arrayexpress

Gene expression profile of murine bone marrow endosteal populations

Project description:This SuperSeries is composed of the following subset Series: GSE17569: Gene expression profile of murine bone marrow endosteal populations (1) GSE17570: Gene expression profile of murine bone marrow endosteal populations (2) Refer to individual Series

2010-08-10 | E-GEOD-17597 | biostudies-arrayexpress

Craniofacial periosteum-derived cells as source for bone tissue engineering

Project description:The development of alternatives for autologous bone grafts is a major focus of bone tissue engineering. To produce living implants, the use of skeletal stem and progenitor cells (SSPCs) are envisioned as key ingredients. SSPCs can be obtained from bone marrow, adipogenic tissue, dental pulp and periosteum. Human periosteum-derived cells (hPDCs) exhibit a number of progenitor characteristics and have well-documented in vivo bone formation capacity. Here, we have characterized and compared hPDCs derived from tibia with new sources of hPDCs, i.e. from maxilla and mandible (craniofacial hPDCs, as a potential source for tissue engineered implants for craniofacial applications.

2020-11-07 | GSE149167 | GEO

Expression data from mouse adrenal glands extracted from wild-type and sf1:Cre; Prkar1a Fl/Fl (KO) adrenals

Project description:Prkar1a encodes one of the regulatory subunits of PKA. Prkar1a gene ablation in the adrenal cortex is associated with profound phenotypic alterations, constitutive PKA activation and reciprocal inhibition of WNT signallilng pathway We used microarrays to analyse gene expression in response to Prkar1a gene ablation Adrenal glands were dissected from KO (4) and wild-type littermate (4) mice

2016-02-06 | E-GEOD-77630 | biostudies-arrayexpress

Premature aging of skeletal stem/progenitor cells rather than osteoblasts causes bone loss with mechanosensation decline

Project description:Distinct skeletal stem/progenitor cells (SSPCs) have been identified in the bone marrow, growth plate, and periosteum, which are indispensable for the maintenance and remodeling of the adult skeleton. However, the decline of which cell types are responsible for age-related bone loss and what characteristic changes of these cells during aging remain to be determined. Here, we constructed premature skeletal aging models by depleting metalloproteinase Zmpste24 (Z24) in mice and found that Prx1-dependent, but not Osx-dependent, Z24 deletion caused significant bone loss. Single-cell RNA sequencing (scRNA-seq) revealed that Prx1-expressing cells in the periosteum (pSSPCs) and growth plate (gpSSPCs) significantly declined in progeria mice. Consistent with aggrecan (Acan) expression in gpSSPCs but not pSSPCs, Acan-linked Z24 depletion only caused trabecular bone loss. Chromatin and transcriptional profiling demonstrate that premature aged SSPCs gain apoptotic signaling pathway and mechanosensation decline. Moreover, SSPCs increased after physical exersice and Z24 depletion’s effects on cellular apoptosis and extracellular matrix expression were reverted by mechanical stimuli. Overall, this study identifies that Z24 deficiency-induced impairment of mechanosensation in SSPCs causes bone loss, shedding new insight on how physical exercise can be used to improve bone quality and prevent bone aging.

2023-08-01 | GSE207240 | GEO

Selective endosteal remodeling of blood vessels in acute myeloid leukemia promotes malignancy at the expense of hematopoietic stem cells

Project description:Hematopoietic stem cell (HSC) function requires bone marrow vascular niches, which have been proposed to be co-opted by leukemia cells to support their propagation. Acute myeloid leukemia (AML) cells produce angiogenic factors; however, anti-angiogenic therapies have not improved AML patient outcome. Using intravital microscopy we uncovered hierarchical vascular remodeling with AML progression. AML cells outcompete non-malignant hematopoiesis by gradual elimination of stroma cells, endosteal endothelium, and osteoblastic cells. While central marrow remains vascularized and splenic vascular niches expand, the remodeled endosteal regions lose the ability to retain HSCs. Overall, the endosteal endothelium microenvironment is altered by AML, yet by preserving it we rescue HSC loss and promote chemotherapeutic efficacy. Our findings suggest therapies targeting the endosteal vasculature may improve existing AML therapeutic regimes.

2017-11-01 | GSE105159 | GEO

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