Endocrine Abstracts

Wnt ligands are secreted proteins that bind to Frizzled receptors. During normal development Wnt signalling plays essential roles in the regulation of patterning, fate determination, and cell proliferation. In the ‘canonical’ Wnt/ß-catenin signalling pathway, binding of Wnt ligand to Frizzled and LRP5 receptors normally leads to inhibition of a ‘destruction complex’ consisting of APC/Axin/GSK-3ß/Ck1/Dvl and other factors, with subsequent accumulation of non-phosphorylated active ß-catenin, and regulation of its target genes. The pathway is strongly implicated in tumorigenesis, where aberrant accumulation of active ß-catenin in the cytoplasm/nucleus plays an important role in a variety of human cancers. Accumulation of ß-catenin can be caused by mutations in CTNNB1 (ß-catenin), APC, Axin, or ß-Trcp.

Primary hyperparathyroidism is characterized by hypersecretion of parathyroid hormone and generally also hypercalcemia, due to one or several parathyroid tumors. Secondary hyperparathyroidism develops in patients with uremia, because of phosphate retention, hypocalcemia, and reduced 1,25-dihydroxyvitamin D₃ levels, causing parathyroid hyperplasia and eventually development of parathyroid tumors and hypercalcemia. Activation of CCND1 expression or inactivation of the MEN1 gene contributes to deregulated growth control in a fraction of sporadic parathyroid adenomas.

I will describe our findings that ß-catenin is accumulated in parathyroid adenomas as well as in secondary hyperplastic glands, and that this is caused by expression of an aberrantly spliced internally truncated LRP5 receptor (LRP5Δ) or by a stabilizing mutation in exon 3 of CTNNB1. Several lines of evidence from experiments in a human parathyroid tumor cell line, support a fundamental role of the LRP5Δ receptor in regulating aberrant ß-catenin driven transcription in parathyroid tumor cells. An autocrine regulatory role for the Wnt3 ligand in parathyroid tumors will be presented. Our work suggests that dysregulated Wnt/ß-catenin signalling is a common pathogenic pathway for primary – and secondary hyperparathyroidism and that the LRP5Δ receptor presents a potential target for therapeutic intervention.