Translating protection of cell-surface receptor LRP1 into potential disease-modifying therapies for osteoarthritis.

Importance Osteoarthritis (OA) causes pain and disability and is the most prevalent age-related joint disorder worldwide but there are no disease-modifying drugs available. The hallmark of OA is loss of cartilage in the joints, impairing joint function. The development of new drugs to halt the cartilage breakdown is a major unmet clinical need.

Such drugs could reduce OA symptoms, slow disease progression, and reduce the requirement for joint replacement surgery.

Background I have shown that a protein which sits on the surface of cells, low-density lipoprotein receptor-related protein 1 (LRP1), plays a vital role in maintaining healthy cartilage.

In healthy joints, LRP1 maintains the correct proportion of cartilage-degrading enzymes to ensure a balance between cartilage breakdown and renewal. In OA cartilage, LRP1 is removed from the cell surface by membrane-bound enzymes, called sheddases. I have evidence that inhibiting sheddases protects LRP1 from removal and prevents human OA cartilage destruction.

I recently discovered that LRP1 also regulates inflammation, tissue regeneration and cellular metabolism. Thus, the loss of LRP1 function has serious consequences for cartilage health, playing a key role in OA development.

My vision My goal in this proposal is to determine the potential of LRP1 protection/restoration in preventing/slowing OA progression, an essential step on the pathway to new OA therapies.

My team consists of two sponsors and five collaborators with varied expertise to ensure that I can successfully complete the project and exploit new developments. Objective 1: Evaluate whether inhibiting removal of LRP1 prevents the onset or chronic development of OA in mice.

Global deletion of LRP1 sheddases, MMP14 and ADAM17, in mice results in abnormal development or lethality, respectively. I will genetically delete these enzymes postnatally in cartilage cells in mouse joints. I will use standard models to induce knee OA, and then determine OA severity by examining the whole joint tissues.

I will also use genetic techniques to prevent LRP1 sheddases being made in various type of the cells in a knee joint to understand where LRP1 is most important.

I will follow LRP1 loss by measuring the amount of LRP1 at the cell surface and in synovial fluid in the joint and investigate whether this correlates with OA severity.

Objective 2: Generate agents able to prevent loss of LRP1 function without interfering with the physiological function of LRP1 sheddases.

I aim to generate a soluble “decoy LRP1”, that inhibits LRP1 shedding without directly interfering with the activity of LRP1 sheddases, and to test whether it reduces cartilage degradation in human OA cartilage. Each soluble mini version of LRP1 (subdomain) binds to selective molecules and changes their proportion.

Thus, there is a possibility that such subdomain selectively increases cartilage-protecting molecules.

I will investigate whether LRP1 subdomain is capable of compensating for reduced capacity of LRP1, as a potential alternative therapeutic approach.

Impact This work will establish the potential of inhibiting LRP1 removal as a therapeutic strategy for OA and generate agents potentially able to restore function of LRP1 without side-effects, paving the way to disease-modifying drugs for OA.