Project 462022

Osteoarthritis is a debilitating, progressive disease affecting cartilaginous tissues, such as the knees and spine. Currently no cure exists. We recently discovered that cartilage can change its properties, and established how these changes predispose to osteoarthritis-like outcomes. These changes are induced in precursor cells that reside in specific locations deep in the cartilage close to the bone. By changing one factor in this area, cartilage cells change their identity and start producing cartilage with altered properties. These altered properties are less resilient to the wear-and-tear predisposing joints to osteoarthritis development. Having found evidence that similar changes also occur in individuals with osteoarthritis, we believe that at least some forms of osteoarthritis are initiated deep inside the cartilage (where stem cells are located) rather than the cartilage surface. In this project we will systematically explore this possibility and test ways to manipulate these stem cells to 'restore' the correct type of cartilage. We will combine state-of-the-art technological approaches with specific mouse mutant models to identify how changes to this factor affects cartilage precursor cells and to show that cellular changes leading to degeneration occur before osteoarthritis can be clinically detected. In a next step, we will compare findings from these mouse models with human osteoarthritis. To do so, we will systematically analyze osteoarthritic cartilage from joint replacement surgeries for similar cartilage changes as observed in the mouse model. Lastly, we will attempt to restore the 'normal' cartilage differentiation in the mouse and test if this restores normal cartilage properties in otherwise osteoarthritic cartilage. This project we will show how osteoarthritis starts in stem cells long before clinical symptoms appear. This study will pave the way towards restoring healthy cartilage, potentially illuminating a path to a cure for osteoarthritis.