Elucidating the Molecular Regulation of PTHrP+ and Fgfr3+ Chondrocytes in Diverse Endochondral Tissues

Abstract

Diseases affecting development and growth of the skeleton pose a massive healthcare burden and require invasive surgical treatment to repair. Of the many cell types involved in endochondral ossification, skeletal stem and progenitor cells (SPPCs) have profound roles in facilitating the development, maintenance and regeneration of skeletal tissues. SSPCs are mainly comprised of precursors of osteoblasts, adipocytes and chondrocytes, which are housed within specific niches throughout the embryonic and postnatal skeletons. Chondrocytes not only form a rudimentary anlage, which will eventually give rise to organized bone, but they also persist throughout adulthood at the articular surface to provide mechanical resistance during locomotion in bipedal mammals. Yet, the molecular regulation of this specialized cell type within the appendicular and craniofacial skeletons remains incompletely understood. The endochondral skeleton contains several unique tissues that are controlled by shared as well as site-specific mechanisms. For example, the long bone growth plate, a cartilaginous structure housed within the epiphysis of the femur and tibia among other endochondral tissues, is comprised of layers of chondrocytes, which are eventually replaced by bone during skeletal maturation in humans. The organization of the growth plate is unidirectional in nature, facilitating growth accordingly. Conversely, housed within the craniofacial skeleton is the cranial base, an endochondral-derived tissue that functions to promote anteroposterior growth of the craniofacial complex. Importantly, the various bones that comprise the cranial base are separated by cartilaginous growth center synchondroses. Like the long bone growth plate, the synchondroses are comprised of distinct layers of chondrocytes. However, synchondrosis chondrocytes are organized bilaterally in a mirror-imaged manner, thus facilitating bidirectional growth of the cranial base. The developmental regulation of the synchondroses has only recently been subject to scientific investigation. The overall goal of this dissertation is to better define the molecular regulation of epiphyseal growth plate and cranial base synchondrosis chondrocytes. Ultimately, these findings aim to provide novel therapeutic targets to regenerate congenitally malformed or damaged endochondral tissues.