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

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; (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.

Type

Journal article

Department

Description

Provenance

Subjects

Cartilage, Articular, Knee Joint, Cell Line, Chondrocytes, Stem Cells, Mesenchymal Stem Cells, Humans, Osteoarthritis, Knee, Hypertrophy, Homeodomain Proteins, Transcription Factors, Apoptosis, Cell Differentiation, Up-Regulation, Adolescent, Adult, Aged, Female, Male, Biomarkers

Citation

Published Version (Please cite this version)

10.3390/ijms21144823

Publication Info

Twomey-Kozak, John, Salomi Desai, Wenguang Liu, Neill Y Li, Nicholas Lemme, Qian Chen, Brett D Owens, Chathuraka T Jayasuriya, et al. (2020). Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells. International journal of molecular sciences, 21(14). p. E4823. 10.3390/ijms21144823 Retrieved from https://hdl.handle.net/10161/26068.

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Scholars@Duke

Li

Neill Yun Li

Assistant Professor of Orthopaedic Surgery

I lead a peripheral nerve regeneration lab that strives to understand the genetic, cellular, and immunologic responses and interactions that occur following nerve injury and during nerve regeneration. With our aging population, we are further interested in understanding how these change in the context of aging. Through this understanding, we are seeking to develop immunomodulatory interventions and biologics that enhance nerve regeneration and preserve muscle viability for reinnervation to provide our patients with debilitating nerve injuries the best chance for recovery through the advent of cutting-edge therapies.


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