Dataset Information

Mouse Articular chondrocyte LC-MSMS of wild-type, miR-26a -/- and cartilage-specific miR-23ab clusters knockout mice

ABSTRACT: To reveal the potential regulation target genes of miR-26a and miR-23a/b clusters in articular chondrocytes, we performed a multi-omics analysis of LC-MSMS and RNA-seq using cultured chondrocytes samples, which were primarily isolated from 3-week-old wild-type, miR-26a -/- (with or without miR-26a mimic transfection afterwards) or miR-23a/b cluster flox/flox;Col2a1-cre mice. For LC-MSMS, protein from TRIZOL reagent was extracted, nanoLC-MSMS was performed. An expression list was made to further explore the regulation targets of miR-26a and miR-23a/b clusters.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Articular Chondrocyte

SUBMITTER: Chenyang Ding

LAB HEAD: Shigeru Miyaki

PROVIDER: PXD031868 | Pride | 2023-01-25

REPOSITORIES: Pride

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Publications

miR-23a/b clusters are not essential for the pathogenesis of osteoarthritis in mouse aging and post-traumatic models.

Fujiwara Yusuke Y Ding Chenyang C Sanada Yohei Y Yimiti Dilimulati D Ishikawa Masakazu M Nakasa Tomoyuki T Kamei Naosuke N Imaizumi Kazunori K Lotz Martin K MK Akimoto Takayuki T Miyaki Shigeru S Adachi Nobuo N

Frontiers in cell and developmental biology 20230104

Osteoarthritis (OA), the most prevalent aging-related joint disease, is characterized by insufficient extracellular matrix synthesis and articular cartilage degradation and is caused by various risk factors including aging and traumatic injury. Most microRNAs (miRNAs) have been associated with pathogenesis of osteoarthritis (OA) using <i>in vitro</i> models. However, the role of many miRNAs in skeletal development and OA pathogenesis is uncharacterized <i>in vivo</i> using genetically modified m ...[more]

PMID: 36684425

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Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.

			Action	DRS
	CartmiR23KO.raw	Raw
	Result.xml	Xml
	Wild.raw	Raw
	checksum.txt	Txt
	miR-26KOplusMimic.raw	Raw