NEW INSIGHTS INTO THE CELLULAR, BIOCHEMICAL, AND MOLECULAR-BASIS OF POSTMENOPAUSAL AND SENILE OSTEOPOROSIS - ROLES OF IL-6 AND GP130

It is well established that osteoclasts, the cells responsible for bone resorption, are derived from hematopoietic progenitors (CFU-GM), whereas the bone-forming osteoblasts are of the same lineage as the mesenchymal stromal cells of the bone marrow. Moreover, it is widely accepted that osteoclast formation depends on cells of the stromal/osteoblastic lineage. The appreciation of the ontogeny of osteoclasts and osteoblasts, the interaction between them, and the role of local factors that regulate their development has led to the emergence of new insights into the pathophysiology of the osteopenias associated with estrogen deficiency and senescence. Consistent with histomorphometric data from humans, there is now evidence from studies in animal models suggesting that a critical cellular change caused by the loss of ovarian, as well as testicular, function is an increase in osteoclastogenesis. This change is apparently mediated by an increase in the production of the osteoclastogenic cytokine interleukin-6 by cells of the bone marrow, which follows the removal of an inhibiting control of estrogens or androgens on IL-6. The inhibiting effect of sex steroids on IL-6 production is mediated by their respective receptors and is exerted indirectly on the transcriptional. activity of the proximal 225 bp sequence of the IL-6 gene promoter. Besides its effects on IL-6 production, loss of gonadal function may also cause an increase in the sensitivity of the osteoclastic precursors to the action of cytokines such as IL-6, due to an upregulation of the gp 130 signal transduction pathway. The osteopenia associated with aging, however, appears to be due to a decrease in the ability of the bone marrow to form osteoblastic cells, as evidenced by a decrease in the number of colony forming units-fibroblasts (CFU-F), the progenitor of the stromal/osteoblastic cell lineage, end the number of colonies exhibiting mineralization, termed colony forming units-osteoblasts (CFU-OB), in murine models of senescence.