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Increase in ALK1/ALK5 Ratio as a Cause for Elevated MMP-13 Expression in Osteoarthritis in Humans and Mice¹

Esmeralda N. Blaney Davidson^2,*, Dennis F. G. Remst^*, Elly L. Vitters^*, Henk M. van Beuningen^*, Arjen B. Blom^*, Marie-Jose Goumans, Wim B. van den Berg^* and Peter M. van der Kraan^*

^* Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Department of Molecular Biology, University Medical Center Leiden, Leiden, the Netherlands

During osteoarthritis (OA) chondrocytes show deviant behavior resembling terminal differentiation of growth-plate chondrocytes, characterized by elevated MMP-13 expression. The latter is also a hallmark for OA. TGF-β is generally thought to be a protective factor for cartilage, but it has also displayed deleterious effects in some studies. Recently, it was shown that besides signaling via the ALK5 (activin-like kinase 5) receptor, TGF-β can also signal via ALK1, thereby activating Smad1/5/8 instead of Smad2/3. The Smad1/5/8 route can induce chondrocyte terminal differentiation. Murine chondrocytes stimulated with TGF-β activated the ALK5 receptor/Smad2/3 route as well as the ALK1/Smad1/5/8 route. In cartilage of mouse models for aging and OA, ALK5 expression decreased much more than ALK1. Thus, the ALK1/ALK5 ratio increased, which was associated with changes in the respective downstream markers: an increased Id-1 (inhibitor of DNA binding-1)/PAI-1 (plasminogen activator inhibitor-1) ratio. Transfection of chondrocytes with adenovirus overexpressing constitutive active ALK1 increased MMP-13 expression, while small interfering RNA against ALK1 decreased MMP-13 expression to nondetectable levels. Adenovirus overexpressing constitutive active ALK5 transfection increased aggrecan expression, whereas small interfering RNA against ALK5 resulted in increased MMP-13 expression. Moreover, in human OA cartilage ALK1 was highly correlated with MMP-13 expression, whereas ALK5 correlated with aggrecan and collagen type II expression, important for healthy cartilage. Collectively, we show an age-related shift in ALK1/ALK5 ratio in murine cartilage and a strong correlation between ALK1 and MMP-13 expression in human cartilage. A change in balance between ALK5 and ALK1 receptors in chondrocytes caused changes in MMP-13 expression, thereby causing an OA-like phenotype. Our data suggest that dominant ALK1 signaling results in deviant chondrocyte behavior, thereby contributing to age-related cartilage destruction and OA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Dutch Arthritis Association "National Reumafonds".

² Address correspondence and reprint requests to Dr. Esmeralda N. Blaney Davidson, Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands. E-mail address: e.blaneydavidson{at}reuma.umcn.nl

³ Abbreviations used in this paper: OA, osteoarthritis; Ad-caALK, adenovirus overexpressing constitutive active ALK; ALK, activin-like kinase; DMM, destabilization of the medial meniscus; Id-1, inhibitor of DNA binding-1; PAI-1, plasminogen activator inhibitor-1; shRNA, short hairpin RNA.