The research focus of this dissertation deals with two major issues relevant to osteoporosis, the most common metabolic bone disease. These two aspects are:​ 1) mechanisms that are involved in the regulation o f peak bone density, and 2) evaluation of the in vivo effects of Insulin-like Growth Factor Binding Protein-5 (IGFBP-5) as a potential means to treat osteoporosis.

The first study compared two strains of inbred mice, one with high bone density and one with low bone density, to determine when and to what extent bone density accumulation during postnatal and pubertal growth contributed to the observed differences in bone density between the two strains. We found that the high density strain gained more bone faster than the low density strain, from as early as postnatal day 7 through day 35 at the end of puberty. The future identification of the differences in gene expression between the two strains during these periods of skeletal growth will be helpful in identifying genes that determine peak bone density in mice.

In the second study we treated inbred mice with local or systemic doses of a novel growth factor, IGFBP-5. It is one o f six high affinity binding proteins that belong to the IGF system. Compared to the other IGFBPs IGFBP-5 has several unique characteristics:​ 1) IGFBP-5 has been shown to consistently enhance the mitogenicity of IGFs in osteoblasts;​ 2) it accumulates in bone, along with its bound IGFs. due to its ability to bind some extracellular matrix proteins and hydroxyapatite in bone;​ and 3) it has the potential to increase cell proliferation via its specific receptor. Therefore, IGFBP-5 has the potential to increase bone formation via IGF-dependent and independent mechanisms. IGFBP-5 administration alone or in combination with IGF-I increased several bone formation parameters in serum and in bone extracts more than an equimolar dose o f IGF-I alone. This effect was independent o f changes in serum IGF-I levels. This is the first in vivo study to show the potential bone forming action of IGFBP-5 and these findings suggest that IGFBP-5 might be a potential anabolic therapy that increases bone formation in vivo.