LINKAGE OF DECREASED BONE MASS WITH IMPAIRED OSTEOBLASTOGENESIS IN A MURINE MODEL OF ACCELERATED SENESCENCE

Bone marrow is the principal site for osteoclastogenesis and osteoblas togenesis; and an increase in the former has been linked with bone los s caused by acute loss of gonadal steroids, We have now used an establ ished murine model of accelerated senescence and osteopenia (SAMP6) to test the hypothesis that reduced osteoblastogenesis is linked with de creased bone mass. At 1 mo of age, the number of osteoblast progenitor s in SAMP6 marrow was indistinguishable from controls; however a three fold decrease was found at 3-4 mo of age, Impaired osteoblast formatio n was temporally associated with decreased bone formation and decrease d bone mineral density, as determined by histomorphometric analysis of tetracycline-labeled cancellous bone and dual-energy x-ray absorptiom etry, respectively, Osteoclastogenesis determined in ex vivo bone marr ow cultures was also decreased in these mice, as was the number of ost eoclasts in histologic sections, Moreover, unlike controls, senescence -accelerated mice failed to increase osteoclast development after gona dectomy, The osteoclastogenesis defect was secondary to impaired osteo blast formation as evidenced by the fact that osteoclastogenesis could be restored by addition of osteoblastic cells from normal mice. These findings provide the first demonstration of a link between low bone m ineral density and decreased osteoblastogenesis in the bone marrow and validate the senescence-accelerated mouse as a model of involutional osteopenia.