Osteoarthrtis may be treated as an environmental ciliopathy

Osteoarthritis (OA) is a widespread, painful and debilitating condition that affects the synovial joints such as the hip and knee. The disease is associated with breakdown of the articular cartilage which, in healthy joints, provides a smooth, low friction load-bearing surface. This painful and debilitating condition affects over 8 million people in the UK alone and is a major burden to the health services and UK economy. Furthermore, this disease is likely to become more prevalent with the trend toward an aging population. Treatment of severe OA is restricted to total joint replacement, however, the current implants have a limited lifetime as well as problems associated with wear debris. It is therefore clear that an alternative approach for the treatment of cartilage degradation and OA is desperately needed.

The cartilage is composed of living cells, a hundredth of a millimeter in diameter, which reside within an abundant extracellular matrix. This provides the tissue with its mechanical integrity which is critical to its function in the joint. The individual cartilage cells, called chondrocytes, each poses a single tiny hair-like projection called a primary cilium (plural cilia) which is involved in various cellular activities or signalling pathways. Our group and others have shown that primary cilia are important for cartilage development and health. Further studies indicate that OA is associated with changes in primary cilium dependent cellular signalling pathways and that this leads to degradation of the cartilage. Interestingly OA is also associated with changes in primary cilia length. We have recently found that environmental factors which predispose to OA, such as increased mechanical loading and the presence of inflammatory molecules, also alter cilia length and that this leads to changes in cilia function which may cause tissue degradation. We therefore aim to test the hypothesis that OA is associated with disruption of the joint environment causing changes in primary cilia structure and function leading to further destruction of the cartilage extracellular matrix. If this is found to be true it will open the way to novel therapeutic approaches for the treatment of OA through pharmaceutical manipulation of primary cilia structure and function.

The work will involve testing of bovine cartilage cartilage cells as well as human cells obtained from patients undergoing total joint replacement surgery. This will allow us to determine the role of specific environmental regulation of primary cilia length on the function of the primary cilium and the subsequent degradation of the cartilage and progression of OA. In addition we will conduct a wide-spread screen of potential pharmaceutical molecules which regulate chondrocyte primary cilia length. We will then test to see if molecules which alter cilia length can be used to successfully reduce cartilage degradation. These tests will initially be conducted using both bovine and human cartilage tissue. However we will ultimately test the most promising therapeutic molecules using a well-established in vivo rat model of arthritis. In this way we will determine the efficacy of pharmaceutical manipulation of primary cilia in preventing cartilage degradation .

Thus by the end of the project we will have identified the role of environmental regulation of primary cilia length in cartilage degradation and determined the efficacy of a totally novel treatment for OA in the form of pharmaceutical regulation of primary cilia structure and function.

The primary cilium is a microtubule-based structure that functions as a centre for hedgehog, Wnt and mechanotransduction signalling. Increasing evidence suggests that primary cilia and the associated signalling pathways are critical for the health of articular cartilage and that dysregulation is involved in the pathogenesis of osteoarthritis (OA). Recently we have shown that environmental/pathological stimuli regulate primary cilia length and that this modulates cilia function. We therefore hypothesise that pathological alterations in the cartilage microenvironment regulate chondrocyte primary cilia structure leading to fundamental changes in cilia signalling which drive cartilage degradation.
Human articular chondrocytes will be subjected to three types of environmental stimuli, namely mechanical trauma, exposure to inflammatory cytokines and exposure to fibroblast growth factor (FGF-2). The first two factors are associated with development of OA, whilst FGF-2 appears to be anti-catabolic and protect against cartilage degradation. Importantly all three have previously been linked to changes in primary cilia length. Cilia will be imaged using confocal/super resolution microscopy and downstream changes in cilia signalling and matrix catabolism investigated using a combination of biochemical assays, molecular biology, imaging and biomechanical evaluation. A parallel set of work packages will identify existing FDA approved small molecules which regulate primary cilia length. We will then use these to determine whether pharmaceutical modulation of primary cilia length reduces catabolic signalling and cartilage degradation in both in vitro and in vivo models. Thus by the end of the project we will have identified the role of environmental regulation of primary cilia length in cartilage degradation and determined the efficacy of a totally novel treatment for OA in the form of small molecule regulation of primary cilia structure-function

This research programme is aimed at identifying the role of environmental and pharmaceutical modification of primary cilia structure in the pathogenesis of osteoarthritis (OA). As such this research will have long term impact on a variety of different stakeholders including: project staff, other academic beneficiaries, biotechnology companies, patients and clinicians and wider society.

The ultimate goal is to aid the development of an effective treatment for OA and associated cartilage degradation through pharmaceutical manipulation of primary cilia structure. Although the realisation of this aim is beyond the scope of the 3-year project, we will provide the innovative step change and take appropriate actions to ensure future clinical societal and commercial impact. For example, in the final year of the grant we will attract and engage pharmaceutical industrial partners with the support of the fulltime knowledge transfer team within QMUL (Queen Mary Innovation). We will ensure that potentially commercially valuable data are protected whilst maintaining a policy of data sharing and publication in line with MRC best practice which will beneficially impact the wider research community.

One of our key areas of societal impact that we will achieve within the 3 year programme centres on our communications plans for public engagement for which the PI and the host institution have an extensive track record. We will deliver an innovative and substantial programme of public engagement activities linked with this research programme. Dissemination will be primarily through the award winning 'Centre of the Cell' science centre at QMUL and at major UK science festivals including The Big Bang 2016. In addition, at the end of the grant period, we will deliver a public seminar and reception disseminating our research findings to the general public and in particular those patients that donated tissue for our research.

Within the timeframe of the grant we will also provide beneficial impact on staff associated with the research, namely, the two PDRAs, the investigators and other members of their respective research groups. In particular this will involve multidisciplinary internationally leading research training for the PDRAs as well as a broader cross fertilisation of ideas, techniques and expertise valuable to all. This will provide long term benefit to the research community as well as the staff themselves.