Clinically important bone loss is a sum of Type I osteoporosis, Type II osteoporosis and the secondary causes. In women, maximum bone mass is attained before age 35 and evidence of trabecular bone loss is already apparent at age 40, before the onset of menopause. During the post- menopausal period, the rate of bone loss is increased (Type I) for approximately 5-10 years, and after this period, bone loss continues at a decreased rate due to Type II osteoporosis. In men, the rate of bone loss is not as rapid as that of women, it is persistent and due solely to Type II osteoporosis as well as secondary causes. Longitudinal studies of vertebral bone loss reveal relatively rapid rates of osteoporosis, approaching that seen in women. The differences between the types of osteoporosis is clear but the relative importance is less clear. If estimates are correct then 1 in every 3 women will have had a hip fracture by age ninety compared to 1 in 6 men. The mortality associated with hip fracture in men aged greater than 75 years is 30%, triple that reported for women. Therefore Type II osteoporosis is a very important public health issue, not only for the impact on the healthspan of men, but also for the additive role it plays in women as well. In this condition of bone loss there is normal to slightly decreased osteoclastic activity in conjunction with greatly decreased bone forming ability. This form of osteoporosis is thought to be caused by decreased osteoblast activity/function and has been attributed to various factors such as deficits in recruitment, proliferation and differentiation of these cells at needed sites, as well as changes in the milieu as a result of other age- related processes. It has been shown that there is no bone formation in mice in which the gene encoding the transcription factor for osteocalcin (a gene expressed only in osteoblasts) OSF2/Cbfal has been inactivated. We here propose to test the hypothesis that deficits in differentiated function and/or decreased proliferative ability due to cell senescence occurs with aging in osteoblast cells and contributes to age related osteoporosis. We will test this by determining OSF2/Cbfal expression, and expression of senescence related genes in bone tissue from young and old donors and proliferation potential as well as expression of these genes in osteoblasts derived from the bone. We will also determine whether osteoblasts can form tissue in a transplatation model system in vivo. The results will provide the preliminary data and evidence that we can perform these techniques for an R01 proposal.
