Retinoids and Indian Hedgehog Orchestrate Long Bone Development

Abstract

Long bone formation is a complex process that has been studied for decades (1–3). It initiates with the emergence, at specific times and sites, of mesenchymal cell condensations that are patterned by the concerted action of the zone of polarizing activity (ZPA), apical ectodermal ridge, and dorsal ectoderm. The condensed cells differentiate into chondrocytes that produce characteristic cartilage matrix components and give rise to readily identifiable cartilaginous elements. The chondrocytes within each element start a process of maturation, which includes a proliferative, prehypertrophic, hypertrophic, and post-hypertrophic phase, and become organized in growth plates. At the same time, diarthrodial synovial joints develop at each epiphyseal end. Once formed, hypertrophic cartilage is invaded by bone, marrow, and vascular progenitor cells from adjacent perichondrial tissues, is eroded, and is finally replaced by endochondral bone and marrow. In addition, perichondrial cells give rise to an intramembranous bone collar surrounding the elements, which is critical to determine diameter and shape of the shaft (1).Maturation, hypertrophy, blood vessel invasion, and ossification first occur in the diaphyseal region and then spread toward the opposing epiphyses with increasing developmental time. Thus, long bone formation requires multiple and topographically restricted events within the cartilaginous elements as well as coordinated events in perichondrial tissues. It is not fully understood how all these processes are set and regulated, what signaling molecules mediate cartilage-perichondrium communication and interactions, and how events in cartilage are coordinated with those in perichondrium.