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Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells
- Source :
- International Journal of Molecular Sciences, Volume 21, Issue 14, International Journal of Molecular Sciences, Vol 21, Iss 4823, p 4823 (2020)
- Publication Year :
- 2020
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2020.
-
Abstract
- Chondrocyte hypertrophy is a hallmark of osteoarthritis (OA) pathology. In the present study, we elucidated the mechanism underlying the relationship between the hypertrophy/apoptotic phenotype and OA pathogenesis in bone marrow-derived mesenchymal stem cells (BM-MSCs) via gene targeting of distal-less homeobox 5 (DLX5). Our primary objectives were (1) to determine whether DLX5 is a predictive biomarker of cellular hypertrophy in human osteoarthritic tissues<br />(2) To determine whether modulating DLX5 activity can regulate cell hypertrophy in mesenchymal stem/progenitor cells from marrow and cartilage. Whole transcriptome sequencing was performed to identify differences in the RNA expression profile between human-cartilage-derived mesenchymal progenitors (C-PCs) and bone-marrow-derived mesenchymal progenitors (BM-MSCs). Ingenuity Pathway Analysis (IPA) software was used to compare molecular pathways known to regulate hypertrophic terminal cell differentiation. RT-qPCR was used to measure DLX5 and hypertrophy marker COL10 in healthy human chondrocytes and OA chondrocytes. DLX5 was knocked down or overexpressed in BM-MSCs and C-PCs and RT-qPCR were used to measure the expression of hypertrophy/terminal differentiation markers following DLX5 modulation. Apoptotic cell activity was characterized by immunostaining for cleaved caspase 3/7. We demonstrate that DLX5 and downstream hypertrophy markers were significantly upregulated in BM-MSCs, relative to C-PCs. DLX5 and COL10 were also significantly upregulated in cells from OA knee joint tissues, relative to normal non-arthritic joint tissues. Knocking down DLX5 in BM-MSCs inhibited cell hypertrophy and apoptotic activity without attenuating their chondrogenic potential. Overexpression of DLX5 in C-PCs stimulated hypertrophy markers and increased apoptotic cell activity. Modulating DLX5 activity regulates cell hypertrophy and apoptosis in BM-MSCs and C-PCs. These findings suggest that DLX5 is a biomarker of OA changes in human knee joint tissues and confirms the DLX5 mechanism contributes to hypertrophy and apoptosis in BM-MSCs.
- Subjects :
- Cartilage, Articular
Male
Knee Joint
Cellular differentiation
Cell
Chondrocyte hypertrophy
Muscle hypertrophy
lcsh:Chemistry
cartilage
lcsh:QH301-705.5
Spectroscopy
apoptosis
Cell Differentiation
General Medicine
progenitor cells
Osteoarthritis, Knee
DLX5
gene therapy
Up-Regulation
Computer Science Applications
medicine.anatomical_structure
embryonic structures
Female
Stem cell
Adult
Adolescent
Biology
Article
Catalysis
Cell Line
Inorganic Chemistry
Chondrocytes
stem cells
medicine
Humans
Physical and Theoretical Chemistry
Progenitor cell
Molecular Biology
Aged
Homeodomain Proteins
cellular hypertrophy
Organic Chemistry
Mesenchymal stem cell
Mesenchymal Stem Cells
Hypertrophy
osteoarthritis
lcsh:Biology (General)
lcsh:QD1-999
Cancer research
Biomarkers
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....58f8f7445e2e129170adf7ca241f2ee1
- Full Text :
- https://doi.org/10.3390/ijms21144823