Osteoclasts and transforming growth factor-beta: estrogen-mediated isoform-specific regulation of production.
Estrogen deficiency induced by menopause leads to an increase in bone resorption that is not compensated for by a comparable increase in bone formation, resulting in excessive bone loss. Clinically, estrogen replacement reverses these processes, but the mechanisms by which this takes place are not completely understood. Both osteoclasts and osteoblasts contain functional estrogen receptors and, therefore, may be directly involved in these responses. Because both osteoclasts and osteoblasts secrete transforming growth factor-beta (TGF beta), and because 17 beta-estradiol (E2) treatment increases TGF beta production by osteoblast-like cells in vitro, we have investigated the possibility that E2 also may increase the production of TGF beta by isolated osteoclasts in vitro. Highly purified avian osteoclasts were treated with either vehicle or E2, and TGF beta protein accumulation in culture was measured by bioassay. Although an E2 dose-dependent increase in TGF beta protein accumulation in osteoclast-conditioned medium was measured at 4 h of treatment, a steroid dose-dependent decrease in the accumulation of active TGF beta was measured after 18 h of estrogen treatment. The steroid specificity of the increased TGF beta accumulation was confirmed by demonstrating that the E2-induced increase in TGF beta protein levels in the medium was inhibited by cotreatment with a specific E2 antagonist. Interestingly, E2 treatment induced a TGF beta isoform change from TGF beta 2 to predominantly TGF beta 3. Thus, the data suggest that a direct action of E2 on osteoclasts to lower resorption activity may be mediated by autocrine/paracrine production and activation of TGF beta, perhaps including modulation of specific isoform production.
Robinson
J A
JA
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Riggs
B L
BL
Spelsberg
T C
TC
Oursler
M J
MJ
D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology*; D007536:Isomerism; D009994:Osmolar Concentration; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D004967:Estrogens; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta