ICF: Promotion of intrinsic cartilage repair to treat osteoarthritis

The articular cartilage is an essential tissue that protects the ends of long bones and allows near friction-free movement as we use our joints. It has long been regarded as a tissue with little repair capability, accounting for why over 40% of us will develop osteoarthritis (OA) as we age. OA is driven by mechanical stess on the joint and work that we have done over 20 years has shown that rather than wearing down like a rubber tyre, the cartilage cells, called chondrocytes, respond to this stress directly by activating pathways that drive different tissue responses. One response is to activate enzymes that will degrade the cartilage, causing further destruction. Another response is to release growth factors that are trapped within the substance (extracellular matrix) of the tissue and which are released when the tissue is damaged. Our work, recently submitted for publication, shows that the growth factors (5 identified by us to date) work cooperatively to drive cartilage to repair. Excitingly, our data indicate that the chondrocyte becomes its own repair cell by reprogramming into a cell that now migrates and proliferates in the damaged tissue before turning back into a chondrocyte which will restore the extracellular matrix and build back the tissue. We have called these cells "mechano-activated chondroprogenitors" (MACs). Our work is supported by three additional pieces of evidence: (i) demonstration that osteoarthritic cartilage can repair itself if the joint is mechanically 'off-loaded' which is best demonstrated by a procedure called surgical joint distraction, (ii) evidence that has emerged from genetic studies in which the same growth factors have been identified as being genetic determinants of OA risk (iii) demonstration that core MAC pathways are chronically turned on in OA as measured in the joint fluid (synovial) of individuals with OA. The latter comes from a large human study in which over 7000 proteins were measured in the synovial fluid of over 1300 patients (STEpUP OA). This programme of work is divided into three main aims: (i) To define the molecular mechanisms that convert the chondrocyte into a MAC and then return it to chondrocyte. This will include exploring the other, less well understood, growth factors. It will also include cutting edge imaging to visualise the cells making this transition inside the tissue. (ii) Explore patient factors that influence the ability of OA cartilage to repair. This will look at how genetics, age and biological sex affect MAC biological pathways, using human OA cartilage and synovial fluid protein profiles from STEpUP OA in which patient demographic factors such as age, sex can be examined across a large patient population. This will help understand impediments to cartilage repair that may, for instance, occur with age. (iii) Identify and test potential targets that will help to switch chronically activated MACs back into chondrocytes again. A number of putative targets are identified that will be tested in vivo. Several of these have drugs already in use in humans. This ambitious programme seeks not only to arrest cartilage loss in OA, but potentially to restore it.