Matrix metalloprotease inhibitors suppress initiation and progression of chondrogenic differentiation of mesenchymal stromal cells in vitro
| Autor: | Wiltrud Richter, Helge Bertram, Michael W. Hofmann, Stephane Boeuf, Sandra Boehmer, Dorothea Piecha, Christian Heisel, Jasper Wachters |
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| Rok vydání: | 2009 |
| Předmět: |
Proteases
Matrix metalloproteinase Biology Matrix Metalloproteinase Inhibitors Gene Expression Regulation Enzymologic Cell therapy Tissue engineering Catalytic Domain Humans Protease Inhibitors RNA Messenger Dose-Response Relationship Drug Mesenchymal stem cell Cell Differentiation Mesenchymal Stem Cells Cell Biology Hematology Chondrogenesis Alkaline Phosphatase In vitro Matrix Metalloproteinases Cell biology Adipose Tissue Immunology Alkaline phosphatase Stromal Cells Developmental Biology |
| Zdroj: | Stem cells and development. 18(6) |
| ISSN: | 1557-8534 |
| Popis: | Mesenchymal stromal cells (MSC) are an attractive source for cell therapy and tissue engineering of joint cartilage. Common chondrogenic in vitro protocols, however, induce hypertrophic markers like COL10A1, matrix metalloproteinase 13 (MMP13), and alkaline phosphatase (ALP) reminiscent of endochondral bone formation. To direct MSC toward articular chondrocytes more specifically, a better understanding of the regulatory steps is desirable. Proteases are important players in matrix remodeling, display inhibitory effects on growth plate development and MMP13 inhibition prevented hypertrophy of bovine chondrocytes. The aim of this study was to evaluate whether the activity of proteases and MMPs, especially MMP13, is crucial for the transition of MSC toward mature chondrocytes and could allow to selectively influence aspects of early and late chondrogenic differentiation. Protease inhibitors were added during MSC chondrogenesis and stage-specific markers were assessed by histology, qPCR, and ALP quantification. Chondrogenesis was little affected by leupeptin, pepstatin, or aprotinin. In contrast, broad spectrum pan-MMP inhibitors dose dependently suppressed proteoglycan deposition, collagen type II and type X staining, ALP activity, and reduced SOX9 and COL2A1 expression. A selective MMP13 inhibitor allowed chondrogenesis and showed only weak effects on ALP activity. In conclusion, transition of MSC toward mature chondrocytes in vitro depended on molecules suppressed by pan-MMP inhibitors identifying chondrogenic differentiation of MSC as a sophistically regulated process in which catabolic enzymes are capable to directly influence cellular fate. In future therapeutic applications of diseased joints, the tested MMP13-specific inhibitor promises suppression of collagen type II degradation without imposing a risk to impair MSC-driven regeneration processes. |
| Databáze: | OpenAIRE |
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