These results suggest that Asian males should be offered testing for defects in ACE I/D polymorphisms, especially if they are hypertensive. We suggest that physicians should provide specific protection to D-allele carriers, for example by administering ACE inhibitors to hypertensive patients. The insulin-like growth factor system, formed by insulinlike peptides, their receptors and binding proteins, plays a central role in the regulation of cell growth and differentiation. Human homozygous loss-of-function IGF1 gene mutations cause intrauterine and postnatal growth failure and severe sensorineural deafness. Treatment with recombinant human IGF-I has been shown to improve short stature in patients with severe IGF-I deficiency, supporting the key role of IGF-I in skeletal development. Moreover, decrease in IGF-I production and/or activity has been suggested to contribute to age-related osteopenia and low bone formation. Mice with a homozygous Igf1 gene deletion display a 30% size reduction and an aberrant bone phenotype with shortened femoral length and reduction in cortical bone size, and also sensorial impairment, MG132 as compared to wild type littermates. These bone changes are related to a decrease in both bone formation and bone resorption with a low number of osteoblasts and osteoclasts, and also a reduced capacity for osteoblastogenesis and osteoclastogenesis in the bone marrow of Igf1-null mice. Thus, the observation of an increased trabecular bone volume in the proximal tibia of these mice was suggested to be a consequence of the IGF-I effect on osteoclast formation and/or activity at this skeletal site, which is absent in Igf1-null mice. Mice with a homozygous deletion of the gene encoding the IGF-I high affinity receptor show a delayed ossification in the cranial and facial bones, inner ear alterations and die shortly after birth. Furthermore, partial deletion of the Igf1r gene causes postnatal growth retardation in humans. IGF1R activation recruits insulin receptor substrates. Mice with homozygous deletion or spontaneous mutation in Irs1 show sensory alterations,MK-1775 severe bone growth impairment and low-bone turnover osteopenia. In addition, gain-of-function mouse mutants of IGF-I binding proteins that reduce IGF-bioavailability also consistently show a low cortical and trabecular bone mineral density and alterations in bone formation rates. The bulk of current studies performed in rodents support the notion that the IGF system plays a paramount role in the bone anabolic actions of PTH. Thus, neither Igf1-null nor Igf1r-null mice show the bone anabolic response triggered by transient administration of PTH in normal mice. IGF1R in mature osteoblasts seems to be a critical PTH target for its skeletal actions. Cells of the osteoblastic lineage are a rich source of PTHrelated protein, an important modulator of bone development and bone remodelling. PTH and PTHrP interact with the same PTH type 1 receptor in osteoblasts. Similarly to PTH, intermittent administration of the N-terminal PTHrP fragment induces bone anabolic features in mice and humans.