DT56a stimulates gender-specific human cultured bone cells in vitro.
DT56a found to have SERM-like properties is used for the treatment of menopausal symptoms and osteoporosis. In vivo experiments demonstrated that DT56a displayed selective estrogenic activity; it stimulated creatine kinase (CK) specific activity in the skeletal tissues but not on the uterus of ovariectomized rats. DT56a, when applied together with estradiol-17beta (E(2)), completely inhibited the E(2)-stimulated CK, as demonstrated by other SERMs. DT56a stimulated bone formation in a rat model as measured by histological and histomorphometrical parameters. In a clinical study, administration of DT56a (Femarelle) resulted in a considerable elevation of bone mineral density and relief of menopausal symptoms. The aim of the present study was to analyze the effects of DT56a in vitro on human-derived bone cultured osteoblasts (Ob), by measuring its effects, at different concentrations, on DNA synthesis, CK and alkaline phosphatase (ALP) specific activities as well as changes in intracellular [Ca(2+)](i) concentrations. DT56a stimulated CK and DNA synthesis in both pre- and post-menopausal female Ob with maximal effect at 100 ng/ml for both age groups. In addition, DT56a stimulated ALP in Ob from both pre- and post-menopausal women with maximal effect at lower dose of 50 ng/ml, with higher response of pre-menopausal cells. Raloxifene (Ral) inhibited all DT56a-stimulated changes in Ob from both age groups. DT56a, when given together with E(2), completely antagonized E(2)-stimulated effects demonstrating its nature as a phyto-SERM. DT56a also, dose dependency, stimulated the intracellular levels of [Ca(2+)](i) with maximal effect at 10 ng/ml. Male-derived Ob did not respond to DT56a in any parameter. In summary, DT56a stimulated sex-specifically female-derived Ob, indicating its unique nature compared to the compounds currently used for postmenopausal osteoporosis by being bone-forming and not only an anti-resorptive agent.
Somjen
Dalia
D
Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel. dalis@tasmc.health.gov.il
Katzburg
Sara
S
Lieberherr
M
M
Hendel
David
D
Yoles
Israel
I
D000469:Alkaline Phosphatase / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004338:Drug Combinations; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology; D010936:Plant Extracts / Q000494:pharmacology*; D017698:Postmenopause; D017697:Premenopause; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D017678:Sex Distribution
C478341:DT56a; D004338:Drug Combinations; D010936:Plant Extracts; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D004247:DNA; D003402:Creatine Kinase; D000469:Alkaline Phosphatase; D002118:Calcium