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Targeting Meniscus Degradation in Osteoarthritis

Periodic Reporting for period 2 - TARGETMENISCUS (Targeting Meniscus Degradation in Osteoarthritis)

Reporting period: 2020-02-01 to 2021-07-31

Osteoarthritis (OA), a chronic degenerative joint disease, is one of the leading causes of disability worldwide. The disease affects more than 25% of the population over the age of 45, resulting in stiffness, chronic pain, and reduced function of the joint. The prevalence of OA increases dramatically with age, and the proportion of elderly continues to increase in most populations. Moreover, obesity, a significant risk factor for OA, is also an increasingly frequent condition in most countries. Thus, the burden of OA is expected to surge, not only in the elderly, but even in the working-age population.

Today, the diagnosis of OA primarily relies on the presence of symptoms combined with the detection of degenerative changes in the joint visible on x-rays. However, by the time OA is visible in joint x-rays, the disease is at a late stage, when it is difficult to halt its progression. Traditionally the focus in research has been on the hyaline cartilage. However, the focus of this project is on an another feature of knee OA - the degeneration of the knee meniscus, which may come early. The meniscus is a key load-distributing tissue in the knee, whose degeneration is one of the most potent risk factors for future OA.

Here, we aim to understand the molecular and structural degeneration of the meniscus during OA in order to discover meniscus-specific biomarkers for early-diagnosis of OA, as well as to identify potential molecular targets for future disease-modifying treatments for OA.
We use mass spectrometry-based proteomics to understand the molecular changes during meniscal degeneration. Using this approach we have analysed healthy human meniscus, identifying 600+ proteins and mapping their spatial distribution in the tissue. We have also compared the meniscal proteomes of persons with and without OA, identifying protein pathways whose activation differs between the two groups. We have also compared the global interplay of proteins in the synovial fluid (i.e. the fluid inside the knee) from persons without OA or with early or late OA, finding that this interplay was disrupted in late-stage OA.

Towards tracking structural changes in the meniscus during OA, we have conducted computed tomography-based structural imaging of healthy and OA meniscal samples. Furthermore, we are in the process of imaging the knees of volunteers and patients at risk for OA, using advanced magnetic resonance imaging (MRI) to follow the earliest structural progression of OA in vivo. This approach allows us to discern early changes in tissue composition during OA development, even before explicit structural changes become visible.
Our project is unique to apply a combination of cutting-edge molecular and structural analyses to understand the degeneration of the human meniscus during OA, using ample sample material from an in-house knee tissue biobank. So far, this approach has allowed a comprehensive understanding of the molecular and structural degeneration of the meniscus during OA. As we progress further, we plan to link data from these different approaches to each other, as well as to longitudinal MRI changes in knees of human volunteers at risk for OA, to identify potential molecular and structural biomarkers that may predict risk for progression of knee OA.