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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0166v1 200/2/199    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lemus, A. Articles by Perez-Palacios, G. Search for Related Content PubMed PubMed Citation Articles by Lemus, A. Articles by Perez-Palacios, G.

A Lemus, Reproductive Biology (S-301), Universidad Autonoma Metropolitana, Mexico, 09340, Mexico
J Enriquez, Instituto Nacional de Ciencias Medicas y Nutricon, Mexico, Mexico
A Hernandez, Universidad Autonoma Metropolitana Iztapalapa, Mexico, Mexico
R Santillan, Medical Research, Instituto Nacional de Perinatologia Isidro Espinosa de los Reyes, Mexico, Mexico
G Perez-Palacios, General Direction, Instituto Nacional de Perinatologia Isidro Espinosa de los Reyes, Mexica, Mexico

Correspondence: Ana Lemus, Email: anaelenalemus{at}prodigy.net.mx

Abstract

A number of clinical studies have demonstrated that norethisterone (NET), a potent synthetic progestin, restores postmenopausal bone loss, although its mode of action on bone cells is not fully understood, while the effect of naturally occurring progesterone in bone has remained controversial. A recent report claims that the potent effects of NET on osteoblastic cell proliferation and differentiation, mimicking the action of estrogens, are mediated by non-phenolic NET derivatives. To determine whether osteoblasts possess the enzymes required to bioconvert a progesterone receptor (PR) agonist into A-ring reduced metabolites with affinity to bind estrogen receptor (ER), we studied the in vitro metabolism of [3H]-labelled NET in cultured neonatal rat osteoblasts and the interaction of its metabolic conversion products with cytosol osteoblast ER, employing a competition analysis. Results indicated that NET was extensively bioconverted (36.4 %) to 5-reduced metabolites, including 5-dihydro NET, 3,5-tetrahydro NET (3,5-NET) and 3β,5-tetrahydro NET (3β,5-NET), demonstrating the activities of 5-steroid reductase and two enzymes of the aldo-keto reductases family. Expression of Srd5a1 in neonatal osteoblast was well demonstrated, whereas Srd5a2 expression was not detected. The most striking finding was that 3β,5-NET and 3,5-NET were efficient competitors of [3H]-estradiol for osteoblast ER binding sites, exhibiting affinities similar to that of estradiol.

The results support the concept that the interplay of 5-steroid reductase and aldo-keto reductases in osteoblastic cells, acting as an intracrine modulator system is capable to bioconvert a PR agonist into ER agonists, offering an explanation of the molecular mechanisms NET uses to enhance osteoblastic cell activities.