Agrin: harnessing mechanisms of limb development for joint regeneration in patients

Osteoarthritis is a degenerative joint disease characterised by the loss of articular cartilage.

There is currently no cure of osteoarthritis and patients must ultimately undergo joint replacement surgery to regain joint function. Despite the function of the joint largely being restored, the symptoms associated with osteoarthritis rarely are.

A common predisposing factor for osteoarthritis is cartilage injury, which in many cases does not heal and begins the breakdown cascade. We previously identified a molecule called agrin to possess homeostatic properties when applied to chondrocytes.

Treatment with agrin resulted in enhanced cartilage formation both in vitro and in vivo, without inducing ectopic bone formation, as molecules such as BMPs have in the past.

Our most recent findings uncovered that the effect of agrin is achieved by orchestrating the activation of the CaMKII/CREB pathways and simultaneous inhibition of the canonical WNT pathway.

The result of this combination of events led agrin to induce the expression GDF5 in synovium derived stem cells – but not in bone marrow derived stem cells.

We showed these stem cells were recruited to the site of osteochondral defects in mice and sheep and repaired the bone-cartilage architecture as well as restoring function and relieving pain. Additionally, when agrin was knocked out in the developing limb bud, only 54% of embryos were carried to term.

Suggesting a major role for agrin in the limb bud stem cells.

This fellowship aims to identify a molecular-signature of agrin in stem cells at different stages of their differentiation during development to ascertain which stem-cell lineage agrin affects.

This molecular-signature will be screened against signature-databases of existing FDA approved drugs which could be repurposed and test these drugs (alongside agrin) in vivo in a model of osteoarthritis.