The Emerging Role of Cell Transdifferentiation in Skeletal Development and Diseases

The vertebrate musculoskeletal system is known to be formed by mesenchymal stem cells condensing into tissue elements, which then differentiate into cartilage, bone, tendon/ligament, and muscle cells. These lineage-committed cells mature into end-stage differentiated cells, like hypertrophic chondrocytes and osteocytes, which are expected to expire and to be replaced by newly differentiated cells arising from the same lineage pathway. However, there is emerging evidence of the role of cell transdifferentiation in bone development and disease. Although the concept of cell transdifferentiation is not new, a breakthrough in cell lineage tracing allowed scientists to trace cell fates in vivo. Using this powerful tool, new theories have been established: (1) hypertrophic chondrocytes can transdifferentiate into bone cells during endochondral bone formation, fracture repair, and some bone diseases, and (2) tendon cells, beyond their conventional role in joint movement, directly participate in normal bone and cartilage formation, and ectopic ossification. The goal of this review is to obtain a better understanding of the key roles of cell transdifferentiation in skeletal development and diseases. We will first review the transdifferentiation of chondrocytes to bone cells during endochondral bone formation. Specifically, we will include the history of the debate on the fate of chondrocytes during bone formation, the key findings obtained in recent years on the critical factors and molecules that regulate this cell fate change, and the role of chondrocyte transdifferentiation in skeletal trauma and diseases. In addition, we will also summarize the latest discoveries on the novel roles of tendon cells and adipocytes on skeletal formation and diseases.