Regulation of Articular Cartilage Zonal Emergence: Harnessing Developmental Pathways to Enhance Regeneration

Introduction

Articular cartilage (AC) has a complex zonal structure and composition, providing it with its essential functional properties. However, when cartilage is damaged, the zonal complexity does not regenerate, leaving an inferior tissue which is prone to degeneration. As a result, cartilage injury commonly leads to pain and the eventual need for joint replacement.

Background

Progress towards true regeneration of AC requires an advance in understanding how zonal complexity (and corresponding function) emerge over development. The most promising clue to understanding zonal emergence is that mechanical forces are known to be important for normal AC development.

Project Overview

ReZone will reveal the mechanisms underlying zonal emergence through a novel goat model in which a common veterinary procedure is repurposed to create a radically altered mechanical environment in the developing joint.

Methodology

By comparing gene activity between normal and altered states of zonal emergence, I will identify pathways likely to be involved in zonal emergence. I will leverage my expertise in cartilage explant culture and mechanostimulation bioreactors to develop a novel in vitro explant model, and use this model to validate candidate pathways.

Therapeutic Potential

Finally, I will demonstrate the therapeutic potential of molecular regulators of zonal emergence using gene-activated biomaterials to regenerate zonal emergence in an in vivo, large-animal model of cartilage repair.

Expected Outcomes

ReZone will provide a step-change in our understanding of how zonal AC develops postnatally, including the role of mechanical loading. The project’s ambitious aim is to bring about enhanced regeneration of AC through activation of the developmental processes which form functional cartilage in early life.

Conclusion

Revealing key mechanisms underlying zonal emergence in immature AC will enable true regeneration of injured AC, improving quality of life for patients with articular cartilage defects worldwide.