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Characterization of estrogen receptor isoforms in bone

The beneficial influence of estradiol in the maintenance of healthy bone is well recognized. However, the way in which the actions of this hormone are mediated is less clearly understood. We have demonstrated that the well characterised 66kDa ER was only one of the ER? isoforms present in bone. We describe that a 46kDa isoform of ER, expressed at a level similar to the 66kDa isoform, is also present in human primary osteoblasts. This shorter isoform is generated by alternative splicing of an ER gene product, that results in exon 1 being skipped with a start codon in exon 2 used to initiate translation of the protein. Consequently, the transactivation domain AF-1 of this ER isoform is absent.

Functional analysis revealed that hER 46 is able to heterodimerize with the full-length ER and also with Er(beta). We have shown that hER 46 are a strong inhibitor of hER 66 when they are co-expressed in the human osteosarcoma cell line SaOs. As a functional consequence, proliferation of the transfected cells is inhibited when increasing amounts of hER 46 are cotransfected with hER 66. In addition to human bone, the expression of the alternatively spliced ER mRNA variant is also detectable in bone of ER knockout (ERKO) mice.

These data suggest that, in osteoblasts, estradiol can act in part through an ER isoform that is markedly different to the 66kDa receptor. The expression of two ER protein isoforms may account in part for the differential action that estrogens and estrogen analogues have in different tissues. In particular, the current models of the action of estrogens should be re-evaluated to take account of the presence of at least two ER protein isoforms in bone and perhaps in other tissues.

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EMBL - European Molecular Biology Laboratory
Meyerhofstrasse 1PF 102209
69012 Heidelberg
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