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STEM CELL GENETICS AND GENOMICS

Glucocorticoids Promote Chondrogenic Differentiation of Adult Human Mesenchymal Stem Cells by Enhancing Expression of Cartilage Extracellular Matrix Genes

^a Cartilage Biology and Orthopaedics Branch,
^b Cartilage Genetics Group, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, NIH, Department of Health and Human Services, Bethesda, Maryland, USA

Key Words. Differentiation • Human mesenchymal stem cells • Glucocorticoid • Cartilage

Correspondence: Rocky S. Tuan, Ph.D., Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, NIH, 50 Center Drive, Room 1523, MSC 8022, Bethesda, Maryland 20892-8022, USA. Telephone: 301-451-6854; Fax: 301-435-8017; e-mail: tuanr{at}mail.nih.gov

Received August 26, 2005; accepted for publication February 2, 2006.

In the adult human, mesenchymal stem cells (hMSCs) resident in the bone marrow retain the capacity to proliferate and differentiate along multiple connective tissue lineages, including cartilage. Glucocorticoids (GCs) are required for chondrogenic differentiation of hMSCs in vitro; however, the exact role of GCs in this process is not known. In this study, we examined the effects of dexamethasone (DEX) on chondrogenic differentiation of hMSCs in the presence or absence of DEX, transforming growth factor-ß (TGF-ß), or DEX plus TGF-ß. GC treatment upregulated gene expression of cartilage matrix components aggrecan, dermatopontin, and collagen type XI; enhanced TGF-ß-mediated upregulation of collagen type II and cartilage oligomeric matrix protein; and increased aggrecan and collagen type II production as well as cartilage matrix-sulfated proteoglycans as assessed by immunohistochemistry and alcian blue staining. Inclusion of an antagonist of GCs inhibited expression of chondrogenic differentiation markers, suggesting that the GC effects during chondrogenesis are mediated by the GC receptor (GR). Steady levels of the major active form of GR, GR, were detected in both undifferentiated and differentiating hMSCs, whereas the dominant-negative isoform GRß, present at low levels in undifferentiated hMSCs, was downregulated during chondrogenesis. In the presence of DEX and TGF-ß, expression of a collagen type II gene promoter luciferase reporter construct in hMSCs was upregulated. However, coexpression of GRß dramatically inhibited promoter activity, suggesting that GR is required for GC-mediated modulation of chondrogenesis and that GCs may play an important role in the maintenance of cartilage homeostasis.

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