Activin A belongs to the TGF-β family of growth factors involved in control of tissue
formation by growth inhibition and to a family of hormones involved in human reproduction.
Serum levels of dimeric activin A display a sexual dimorphism with significantly higher
circulating hormone concentrations in men than in women after menopause. Since goiter
is far more frequent in women than in men, we investigated the role of this sex-related
growth factor in the human thyroid. Primary cultures were obtained from 3 patients
with goiter, and 4 with recurrent goiter. Activin A significantly inhibited the proliferation
of human thyroid follicular epithelial cells in vitro in concentrations between 0.5 and 50 ng/ml and was almost as potent as TGFβ-1. Analysis
in native tissues from 12 normal thyroids, 16 goiters, and 5 Graves thyroids demonstrated
mRNA expression of the activin subunit βA, TGFβ-receptor type I and II, activin receptors
type I receptors alk2 and alk4, and activin type II receptors actRII and actRIIb.
Isoform analysis of the major functional type I activin receptor alk4 revealed the
full-length transcript SKR2-1 and transcripts for the partially truncated proteins
SKR2-2 and SKR2-3 in normal thyroids and goiters. Semi-quantitative RT-PCR revealed
a significant 2.5-fold decrease of mRNA for alk4-1 type I activin receptors in goiter
as compared to normal thyroid (p < 0.05), whereas expression of the type II receptor actRII was unchanged. These data
identify a novel growth inhibitory pathway by activin in the human thyroid. Down-regulation
of activin receptor type lb in goiter hints towards end-organ changes which could
contribute to deficient growth inhibition. These data provide a mechanistic model
how the sexually dimorphic hormone activin A may protect males from goitrogenesis.
Key words
Activin A - Inhibin A - Alk - Receptor - Thyroid - Cancer - Goiter
