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Lubricating Cartilage: exploring the relation between lubrication and gene-regulation to alleviate osteoarthritis

Periodic Reporting for period 4 - CartiLube (Lubricating Cartilage: exploring the relation between lubrication and gene-regulation to alleviate osteoarthritis)

Reporting period: 2022-03-01 to 2023-08-31

The main issue being addressed by this project is to determine whether, by lubricating articular cartilage of osteoarthritic joints, it is possible to alleviate the disease (osteoarthritis, OA)).

It is important for society because OA is a very widespread, painful and debilitating disease, with over 30M sufferers in the EU alone, which imposes a high burden both in terms of human suffering and in socio-economic terms. As it is a disease which afflicts mostly the elderly population (>50% of people over 70) it reduces their mobility and ability to participate in society, while at the same time imposing a high medical and economic cost in terms of expending of treatment resources and lost working ability.

The project consists on the one hand of developing and improving suitable lubricants for injection into joints (intra-articular or IA injections), and in parallel developing means of evaluating whether such IA administration of lubricants leads to changes in the cartilage that indicate the lubrication is having a beneficial effect, as well as relieving pain. Experiments are carried out on a mouse model. The overall objectives are to determine the optimum lubricant and means of applying it to joints while maximizing its beneficial effects on the OA joints.

In conclusion of the project, we made excellent progress towards all our aims. We were able to create and apply liposome-based lubricants and see their effect on cartilage in induced OA, and also to examine their deeper effects in terms of gene regulation arising from biolubrication. Many publications (28 to date) describe this progress, and several more are in the pipeline. In the nature of things publications involving animals which are a central part of this project take longer to summarize and publish. The success of the project may also be judged not only through its academic publications but also through the fact that a successful start-up company, Liposphere, for treating and alleviating osteoarthritis was established directly due to developments that arose from the projects achievements. Moreover, and not least, it led to 3 ERC Proof of Concept grants to follow up discoveries made as a result of the project.
In the project as a whole we have made extensive progress on many of the aims of the project, and 28 papers (acknowledging have so far been published. This is despite the serious obstacles due to the covid-19 pandemic over the period of the project which not only affected our work directly (lockdowns etc) but also meant that contact with our Oxford team members was severely curtailed.

The work in the project focused on elucidating the microscopic details of hydration lubrication in systems relevant to joint lubrication. These included direct surface force balance (SFB) studies on different boundary layer combinations, including those of lipid and lipid mixtures that are believed to be active in articular cartilage boundary lubrication; the synergy between hyaluronan (hyaluronic acid) and lipids which is believed to be central for such boundary effects; the effect of different biomedically-important molecules such as polyethylene oxide on lubrication by lipids; very importantly, the nature of phosphocholinated liposomes which are both sterically-stabilized and also provide excellent lubrication, and are the major candidates for our work with the Oxford group (team-member Tonia Vincent and her co-workers). We demonstrated that our ideas on cartilage lubrication could be used also in synthetic hydrogels to create extremely well-lubricated surfaces, of partocular interest for biomedical devices including artificial cartilage to help in OA affected joints. We also commenced looking at lubrication afforded by lipid mixtures, in particular mixtures of lipids known to be present in synovial joints and on cartilage, and on lipid mixtures derived from the synovial fluid of actual OA patients. Likewise the role of hyaluronic acid in cartilage boundary lubrication was investigated, and more fundamental effects related to lubrication by thin fluid films, as well as the question of the slip plane in boundary lubrication by polymers, were directly examined using the surface force balance. Towards the end of the project we discovered the unexpected effect of polyphosphocholination of liposomes in greatly extending their retention lifetime when IA injected into (mice) joints. We considerably extended also our work with the Oxford group using a novel technique based on direct fluorescence signal detection of gene regulation in chondrocytes embedded in cartilage, thought to underlie OA pathogenesis. Indeed some of our most exciting (soon to be published) results were obtained in connection with gene regulation in chondrocytes by our IA injected lubricants with the Oxford team, especially in the latter period of the project.

Finally but not least, our project led directly to the establishmment of a successful start-up company, Liposphere, for treating and alleviating osteoarthritis, perhaps the most widespread and debilitating joint disease (and affecting hundreds of millions world-wide), based on findings and developments arising from this project. Moreover, despite the fact that much of the work was basic and strove towards understanding at a fundamental molecular level of the effects that lead to osteoarthritis and its alleviation, nonetheless during the project period we were awarded 3 ERC Proof of Concept grants - the maximal number allowed - to follow up for practical and commercialization purposes discoveries made as a result of the project.
We have progressed well beyond the state-of-the-art in determining the effect of lipid mixtures as opposed to single component lubricating vesicles; in creating superlubrication vectors stabilized by novel polyphophocholinated moeities; in demonstrating the effect of these on gene regulation in the cartilage cells (chondrocytes); in proving that ideas from cartilage lubrication could lead to novel means of lubricating synthetic hydrogels; and in discovering that much longer retention of liposomic lubricants in joints could be achieved by their polyphosphocholination.

Expected results to be obtained by the end of the project include our current work on the effect of lubricants IA-injected into mice with OA, from the point of view both of morphology and gene regulation, and examination of reduction in pain level when suitable lipid-based lubricants are IA delivered, all on murine models.
Functionalized liposomes injected intra-articularly may reduce cartilage friction and alleviate OA