UC San Diego

The structure of long bones spans multiple scales during skeletal growth. It is organized hierarchically as a whole bone organ with bone and growth plate cartilage zones. During long bone growth by endochondral ossification, chondrocytes proliferate and differentiate longitudinally as bone is formed. The aims of this thesis were to model the altered relationship between bone elongation and cell and tissue dynamics, and to evaluate the model in inherited disease and after injury in mouse models.Governing equations described how changes in cell numbers in tissue and bone structures were related to cell parameters of unit height, self-renewal fraction, and differentiation rate. Zonal growth parameters were further related to longitudinally arranged cell fate properties within each zone. The dynamic and steady-state solutions illustrated zonal dependencies. The steady-state solutions depended on the fraction of self-renewing cells. The time course of dynamic solutions depended additionally on differentiation rate parameters. Normal and achondroplasia mouse tibia exhibited similarities and differences in model parameters. The predicted spatio-temporal course of regeneration from progenitor cells was illustrated. The developed models thus provide quantitative descriptions and linkages between cell, tissue, and organ scale events that can vary during endochondral ossification in health, disease, and after injury.