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Submitted on October 5, 2004
Accepted on December 21, 2004
School of Animal and Microbial Sciences, The University of Reading, Whiteknights, Reading, RG6 6AJ, UK
* To whom correspondence should be addressed. E-mail: p.g.knight{at}reading.ac.uk.
We reported recently that bovine theca interna cells in primary culture express several type-I and type-II receptors for bone morphogenetic proteins (BMPs). The same cells express at least two potential ligands for these receptors (BMP-4 and -7) while bovine granulosa cells and oocytes express BMP-6. Therefore BMPs of intrafollicular origin may exert autocrine/paracrine actions to modulate theca cell function. Here we report that BMP-4, -6 and -7 potently suppress both basal (P < 0.0001; respective IC50 values 0.61, 0.25, 1.13ng/ml) and LH-induced (P < 0.0001; respective IC50 values 5.00. 0.55, 4.55 ng/ml) androgen production by bovine theca cells while having only a moderate effect on progesterone production and cell number. Semi-quantitative RT-PCR showed that all three BMPs markedly reduced steady-state levels of mRNA for P450c17 levels of mRNA encoding StAR and P450scc and 3
HSD were also reduced but to a much lesser extent. Immunocytochemistry confirmed a marked reduction in cellular content of P450c17 protein following BMP treatment (P < 0.001). Exposure to BMPs led to cellular accumulation of phosphorylated Smad1, but not Smad2, confirming that the receptors signal via a Smad1 pathway. The specificity of the BMP response was further explored by co-incubating cells with BMPs and several potential BMP antagonists, chordin, gremlin and follistatin. Gremlin and chordin were found to be effective antagonists of BMP-4 and -7 respectively and the observation that both antagonists enhanced (P < 0.01) androgen production in the absence of exogenous BMP suggests an autocrine/paracrine role for theca-derived BMP-4 and -7 in modulating androgen production. Collectively, these data indicate that an intrafollicular BMP signaling pathway contributes to the negative regulation of thecal androgen production and that ovarian hyperandrogenic dysfunction could be due to a defective autoregulatory pathway involving thecal BMP signaling.
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