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Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells.

Publication ,  Journal Article
Twomey-Kozak, J; Desai, S; Liu, W; Li, NY; Lemme, N; Chen, Q; Owens, BD; Jayasuriya, CT
Published in: Int J Mol Sci
July 8, 2020

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; (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.

Duke Scholars

Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

July 8, 2020

Volume

21

Issue

14

Location

Switzerland

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • Stem Cells
  • Osteoarthritis, Knee
  • Mesenchymal Stem Cells
  • Male
  • Knee Joint
  • Hypertrophy
  • Humans
  • Homeodomain Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Twomey-Kozak, J., Desai, S., Liu, W., Li, N. Y., Lemme, N., Chen, Q., … Jayasuriya, C. T. (2020). Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells. Int J Mol Sci, 21(14). https://doi.org/10.3390/ijms21144823
Twomey-Kozak, John, Salomi Desai, Wenguang Liu, Neill Y. Li, Nicholas Lemme, Qian Chen, Brett D. Owens, and Chathuraka T. Jayasuriya. “Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells.Int J Mol Sci 21, no. 14 (July 8, 2020). https://doi.org/10.3390/ijms21144823.
Twomey-Kozak J, Desai S, Liu W, Li NY, Lemme N, Chen Q, et al. Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells. Int J Mol Sci. 2020 Jul 8;21(14).
Twomey-Kozak, John, et al. “Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells.Int J Mol Sci, vol. 21, no. 14, July 2020. Pubmed, doi:10.3390/ijms21144823.
Twomey-Kozak J, Desai S, Liu W, Li NY, Lemme N, Chen Q, Owens BD, Jayasuriya CT. Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells. Int J Mol Sci. 2020 Jul 8;21(14).

Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

July 8, 2020

Volume

21

Issue

14

Location

Switzerland

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • Stem Cells
  • Osteoarthritis, Knee
  • Mesenchymal Stem Cells
  • Male
  • Knee Joint
  • Hypertrophy
  • Humans
  • Homeodomain Proteins