Bone loss occurs when the amount of bone formed during each remodeling cycle does not exactly replace the bone removed during the preceding resorption phase. Recent studies provide evidence that the involutional osteopenia that occurs with advancing age is associated with defective recruitment of osteoblasts relative to the demand for them. This deficit could be due to a reduction in the number of osteoblasts that differentiate from progenitors in the marrow; or to a defect in the processes that cause the newly recruited team of differentiated osteoblasts to arrive at the remodeling site at the correct plate and time; or to inappropriate programmed cell death (apoptosis) of mature or differentiating osteoblasts. We have obtained evidence that the low turnover osteopenia that characterizes the SAMP6 mouse, an animal model of early senescence, is associated with a decrease in the number of osteoblast progenitors in the bone marrow. In addition, we have demonstrated a chronologic linkage between impaired osteoblastogenesis in the bone marrow, decreased bone formation rate and low bone mineral density in these mice. Based on the above, we propose the hypothesis that decreased osteoblast progenitor formation in the bone marrow, and increased apoptosis of osteoblasts or osteoblast progenitors, are fundamental cellular changes responsible for the decreased rate of bone formation and decreased bone mass associated with aging. The following specific aims are proposed to test this hypothesis, and to establish a causal relationship between changes in osteoblastogenesis and the rate of bone formation. First, determine the effect of aging on relationships among osteoblast progenitors in the marrow, bone formation in remodeling cancellous bone, and bone mass, using ex-vivo bone marrow cultures, quantitative bone histomorphometry, and dual energy X-ray absorptiometry (DEXA). These studies will be performed in osteopenic SAMP6 mice as well as Balb/c mice. Second, determine the effect of age on the ability of stimulators of osteoblastogenesis to cause an increase in the rate of bone formation in remodelling cancellous bone in SAMP6 mice and Balb/c mice. Third, determine whether an increase in programmed death (apoptosis) of osteoblasts, or osteoblast progenitors, contributes to the reduction in the rate of bone formation observed during aging in Balb/c mice and SAMP6 mice; and determine the effect of anabolic agents and gonadectomy on apoptosis of osteoblasts.
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