The development and growth of the long bones of the skeleton involves the coordinated interaction of numerous epigenetic factors, including local and systemic growth factors and hormones, as well as mechanical loading environment. This thesis consists of three primary components which investigate the influence of various epigenetic factors, including both mechanical and physiochemical agents, on long bone growth, development, and evolution.

In the first component, the role of one particular growth factor, Bone Morphogenetic Protein-5 (BMP-5), was examined by studying the growth characteristics and the biomechanical properties of the long bones of the BMP-5 deficient short ear mouse. The results of this investigation indicate that BMP-5, by itself, does not appear to play a crucial role in establishing the net rates of femoral growth in length or girth in the mouse. However, an apparent elevation in short ear cortical bone material strength in 4-week old animals suggests that BMP-5 may continue to play a role in the postnatal skeleton.

In the second component, two approaches to mathematically modeling endochondral growth and ossification of the long bones were developed:​ a surface growth and a volumetric growth approach. Postnatally, endochondral growth at the proximal and distal growth plates and spherical physes was modeled as the progression of four bone surfaces, each associated with its own growth rate. It was found that, to adequately capture the subtle characteristics of a longitudinal bone growth curve, time-dependent epigenetic influences associated with infancy, childhood, and puberty must be incorporated within the model. While the surface growth approach was able to accurately simulate postnatal long bone growth in length, endochondral growth is actually a volumetric growth process in which the growth of the cartilage tissue is tightly coupled to tissue maturity at a given location. A one-dimensional mathematical formulation of a volumetric approach to endochondral growth and ossification was developed. The volumetric model was able to accurately predict not only postnatal rudiment growth, but also prenatal growth and progression of the primary bone front. These models demonstrate that to accurately simulate longitudinal bone growth it is not necessary to explicitly include the direct influence of mechanical stresses and strains, although the dominant hormonal events associated with infancy, childhood, and puberty must be included. However, without the explicit incorporation of mechanobiologic influences, the appearance of the secondary ossific nucleus is not predicted.

Lastly, in the third component, finite element models of the developing chondroepiphyses in primitive tetrapods and mammals were constructed to investigate species-specific differences in the development of the secondary ossific nucleus. The results of these analyses indicate that both genetic and epigenetic mechanobiologic factors must be considered to fully explain the various ossification pattern observed in different animals.

The work in this thesis suggests that, in order to fully understand the processes of skeletal growth and development, as well as the evolutionary history of these processes, physiochemical and mechanical phenomenon should not be considered in isolation, but the interaction of these epigenetic factors must be examined.