Sc. Manolagas et al., NEW INSIGHTS INTO THE CELLULAR, BIOCHEMICAL, AND MOLECULAR-BASIS OF POSTMENOPAUSAL AND SENILE OSTEOPOROSIS - ROLES OF IL-6 AND GP130, International journal of immunopharmacology, 17(2), 1995, pp. 109-116
It is well established that osteoclasts, the cells responsible for bon
e resorption, are derived from hematopoietic progenitors (CFU-GM), whe
reas the bone-forming osteoblasts are of the same lineage as the mesen
chymal stromal cells of the bone marrow. Moreover, it is widely accept
ed that osteoclast formation depends on cells of the stromal/osteoblas
tic lineage. The appreciation of the ontogeny of osteoclasts and osteo
blasts, the interaction between them, and the role of local factors th
at 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 suggestin
g that a critical cellular change caused by the loss of ovarian, as we
ll 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, w
hich follows the removal of an inhibiting control of estrogens or andr
ogens on IL-6. The inhibiting effect of sex steroids on IL-6 productio
n is mediated by their respective receptors and is exerted indirectly
on the transcriptional. activity of the proximal 225 bp sequence of th
e 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 t
o an upregulation of the gp 130 signal transduction pathway. The osteo
penia associated with aging, however, appears to be due to a decrease
in the ability of the bone marrow to form osteoblastic cells, as evide
nced by a decrease in the number of colony forming units-fibroblasts (
CFU-F), the progenitor of the stromal/osteoblastic cell lineage, end t
he number of colonies exhibiting mineralization, termed colony forming
units-osteoblasts (CFU-OB), in murine models of senescence.