| Institution: | 1. Institute for Pharmacology and Toxicology, University of Bonn, Bonn, Germany
Contribution: Data curation (equal), Formal analysis (equal), Investigation (equal), Methodology (equal), Writing - review & editing (equal);2. R&D, Drug Metabolism & Pharmacokinetics, Sanofi-Aventis Deutschand GmbH, Frankfurt, Germany;3. Institute for Pharmacology and Toxicology, University of Bonn, Bonn, Germany |
| Abstract: | Excessive pressure or overload induces and aggravates osteoarthritic changes in articular cartilage, but the underlying biomechanical forces are largely ignored in existing pharmacological in vitro models that are used to investigate drugs against osteoarthritis (OA). Here, we introduce a novel in vitro model to perform pathophysiological and pharmacological investigations, in which cartilage explants are subjected to intermittent cyclic pressure, and characterize its ability to mimic OA-like tissue reactivity. Mechanical loading time-dependently increased the biosynthesis, content and retention of fibronectin (Fn), whereas collagen metabolism remained unchanged. This protocol upregulated the production and release of proteoglycans (PGs). The release of PGs from explants was significantly inhibited by a matrix metalloproteinase (MMP) inhibitor, suggesting the involvement of such proteinases in the destruction of the model tissue, similar to what is observed in human OA cartilage. In conclusion, the metabolic alterations in our new biomechanical in vitro model are similar to those of early human OA cartilage, and our pharmacological prevalidation with an MMP-inhibitor supports its value for further in vitro drug studies. |
