Introduction

According to dogma, cartilage has no or only limited regenerative potential, which would explain why initial cartilage damage (for example after joint injury) very frequently progresses to osteoarthriits. However, recent evidence suggest that cartilage indeed possesses at least some regenerative potential. Studies done in rodents, particularly in mice, suggest the presence of precursor cells within cartilage or surrounding tissues (e.g. the synovium) that can help regenerate damaged cartilage. This potential appears to be strain-specific, suggesting that it is regulated by genetic factors. Other factors such as age of animals are also influencing the efficiency of regeneration. This talk will review the current state of knowledge on cartilage regeneration, with particular focus on what we can learn from rodent models.

Content

Studies on cartilage regenration and in particular the underlying molecular mechanisms are almost impossible to do in humans since these studies a) need to be performed using in vivo models with the appropriate tissue interactions, biomechanical loads, oxygen tension etc., which are very hard to mimic in vitro; b) require the collection of biological samples from multiple time points in the process. Therefore, these studies are usually performed in animal models. In particular, mouse models are very useful for these studies due to our ability to manipulate the genome of mice. While CRISPR/Cas9 technology will ultimately allow similar approaches in other mammalian species, at this moment the tools available in the mouse are unmatched by other specieis. I will provide examples of how genetic engineering helps us to provide a better understanding of the molecular and cellular processes invovled in cartilage regeneration.

Using examples from several laboratories (e.g. Linda Sandell, Francesco Dell'Accio, and Roman Krawetz), I will first describe how the use of different mouse strains (all from the same species but with different genetic backgrounds) allows us to understand the large variability in regenerative potential, what the general contribution of genetic factors to this variability is, and how regeneration of articular cartilage correlates with regeneration of other tissues in the body.

I will then discuss an example (from Cosimo de Bari's lab) of how genetic labelling of cells allowed the identification of specific cell types within the joint that contribute to cartilage regeneration in an injury model. Identification of these cell types is crucial to develop strategies for manipulating them when we want to promote cartilage regeneration and endogenous repair.

Finally, I will provide a few examples from our own work, as well as from experiemtns performed by our collaborator Ling Qin, how genetic technology was used to remove or overexpress specific genes in the EGFR pathway in cartilage. These exeriments allowed us to identify a key role of this pathway in the growth (and potentially re-growth after injury) of articular cartilage.

These examples illustrate how we can use mouse models to better understand cartilage biology including regeneration. New insights from these studies will ultimately help to understand the endogenous repair of cartilage and to utilize these mechanisms for therapeutic purposes.

References

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Acknowledgments

I acknowledge the excellent work of my laboratory members and funding form the Canadian Institutes of Health Research and the Canada Research Chair Program.