Doctoral Dissertation Improvement Grant: The Effect of Interactions between Estradiol and Mechanical Loading on Human Longitudinal and Periosteal Bone Growth

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This study tests a hypothesized mechanism for two well-documented trends in human skeletal evolution: that recent humans are less robust than earlier modern humans, and that humans from warm climates have longer, less robust limbs than humans from cold climates. The general hypothesis is that there is a relationship between limb proportions and skeletal robusticity, because the processes by which bones grow in length and in thickness are both influenced by the hormone estrogen during skeletal growth. The specific prediction is that variation in estrogen levels among individuals alters 1) the expression of the estrogen receptor, which affects how bones respond to mechanical loading (e.g. from exercise), and 2) the activity of cartilage cells in the growth plate, which affects how bones grow in length. If the extent to which bones respond to mechanical loading varies among individuals or populations, then patterns of human skeletal robusticity may reflect both loading history and changes in the levels of hormones such as estrogen. Similarly, if interactions between estrogen levels and mechanical loading affect bone length, then patterns of limb length may reflect habitual activity as well as adaptations to climate. Distinguishing among these alternatives is crucial for improving our interpretations of human adaptation and behavior.The 45-day experiment will use 24 sheep (Ovis aries), divided into low, normal and high estrogen treatment groups. Half of each group will be sedentary, and half will exercise daily. Fluorochrome dyes will label bone growth. Real-time reverse transcriptase polymerase chain reaction (rtPCR) will quantitatively measure estrogen receptor-a expression. Proliferating cell nuclear antigen (PCNA) immunoreactivity will measure cartilage cell proliferation. The preliminary experimental results support the hypothesis that variation in estrogen level influences epiphyseal growth and diaphyseal responses to loading, and thus may affect patterns of skeletal robusticity in humans. In a small sample of juvenile sheep, differences in estrogen level and exercise had significant and dramatic effects on periosteal growth rate in the femur and tibia. For example, mean daily apposition rate in the femora of exercised animals is 44% higher in high-estrogen than in low-estrogen animals (p.05), and 26% higher than in sedentary, high-estrogen animals (p.05). Epiphyseal height also varies with estrogen level and exercise: the height of the metatarsal growth plate is 41% greater (p.025), and there are 29% more proliferative chondrocytes (p.05), in high-estrogen exercised vs. sedentary animals, and the height of the distal tibia growth plate is 25% greater in low-estrogen exercised vs. sedentary animals (p.025). This project will promote the integration of graduate training and research in physical anthropology with experimental physiology and skeletal endocrinology. The experiments will address a number of basic biological questions about how interactions between estrogen and strain affect longitudinal and periosteal bone growth. The specific effects of interactions between hormone levels and environmental stimuli on human bone growth have never been studied, but are quite relevant to a number of clinical issues, including the attainment of peak bone density and prevention of osteoporosis. For this reason, the results of this study will be disseminated in biomedical as well as anthropological journals.