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Originally published online as doi:10.2353/ajpath.2007.060930 on May 10, 2007

Published online before print May 10, 2007
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(American Journal of Pathology. 2007;171:116-123.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060930

Osteogenic Responses in Fibroblasts Activated by Elastin Degradation Products and Transforming Growth Factor-ß1

Role of Myofibroblasts in Vascular Calcification

Agneta Simionescu, Dan T. Simionescu and Narendra R. Vyavahare

From the Department of Bioengineering, Clemson University, Clemson, South Carolina

Our objective was to establish the role of fibroblasts in medial vascular calcification, a pathological process known to be associated with elastin degradation and remodeling. Rat dermal fibroblasts were treated in vitro with elastin degradation products and transforming growth factor (TGF)-ß1, factors usually present in deteriorated matrix environments. Cellular changes were monitored at the gene and protein level by reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence, and von Kossa staining for calcium deposits. By 21 days, multicellular calcified nodules were formed in the presence of elastin degradation products and TGF-ß1 separately and to a significantly greater extent when used together. Before mineralization, cells expressed {alpha}-smooth muscle actin and large amounts of collagen type I and matrix metalloproteinase-2, characteristic features of myofibroblasts, key elements in tissue remodeling and repair. Stimulated cells expressed increased levels of core-binding factor {alpha}1, osteocalcin, alkaline phosphatase, and osteoprotegerin, representative bone-regulating proteins. For most proteins analyzed, TGF-ß1 synergistically amplified responses of fibroblasts to elastin degradation products. In conclusion, elastin degradation products and TGF-ß1 promote myofibroblastic and osteogenic differentiation in fibroblasts. These results support the idea that elastin-related calcification involves dynamic remodeling events and suggest the possibility of a defective tissue repair process.




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