Investigating the role of in vivo cell cycle activation within mesenchymal stem cells in the regenerative potential of articular cartilage after injury

Purpose: Cartilage has intrinsic poor healing capacity after injury, which can lead to the development of degenerative diseases such as osteoarthritis (OA). Current treatments for OA are unable to effectively stop or delay disease progression. Hence, the development of methods for regenerating cartilage with sustained effects is clinically relevant. Deletion of the p21CIP1/WAF1 gene in mice results in these animals having the ability to regenerate cartilage after injury, however, the underlying mechanisms of this phenomenon remains unclear. p21 is a critical cell cycle regulator, and its absence facilitates cell cycle progression. Whether this is implicit in cartilage regeneration is not known, and difficult to elucidate since p21 is tightly regulated and involved in other intricate cellular processes, such as inflammation and apoptosis. Therefore, to discriminate the potential role of cell cycle activation on cartilage regeneration, we focused downstream of p21 and investigated E2F1, a transcription factor previously linked to cartilage and bone development. In the p21 pathway, inhibition of p21 leads to enhanced activity of E2F1, and as a result, cell cycle progression. Thus, we examined the in vivo role of cell cycle activation on cartilage regeneration after injury by conditionally overexpressing E2F1 in quiescent mesenchymal stem cells (MSCs); as MSCs have the unique ability to differentiate into chondrocytes and therefore are a likely contributor to this cartilage regeneration phenotype.