Insights from molecular pathways: potential pharmacologic targets of benign thyroid nodules

To describe molecular pathways that might be of relevance for a potential pharmacologic therapy of benign thyroid nodules.

Constitutively activating thyrotropin receptor mutations have been found in about 60% of hot nodules. Its predominant role for signaling in hot nodules has been confirmed by in-vitro mutagenesis studies, thyrotropin receptor modeling and microarray studies. In contrast, the basic molecular cause of cold thyroid nodules is so far largely unknown. Defective sodium/iodide symporter trafficking, accumulation of T4-deficient, insufficiently iodinated thyroglobulin, increased oxidative stress and differential expression of several Gqalpha-protein kinase C pathway-associated genes have, however, recently been identified in cold thyroid nodules.

As disturbed thyrotropin receptor signaling plays a central role in hot thyroid nodules, the identification of effective low-molecular-weight thyrotropin receptor ligands, such as thyrotropin receptor agonists, inverse agonists and antagonists has a pharmacologic potential in the diagnosis and treatment of thyroid cancer, Graves' disease and hot thyroid nodules, respectively. Further studies have to clarify the pharmacologic potential of the enhancement of antioxidative mechanisms and the inhibition of Gqalpha-protein kinase C signaling in cold thyroid nodules.