SFEBES2009 Oral Communications Bone and Calcium (8 abstracts)
Mice deleted for the hyperparathyroidism-jaw tumour (HPT-JT) syndrome allele have abnormal parathyroids with increased proliferation rates
G Walls 1 , M Bowl 1 , J Jeyabalan 1 , A Reed 1 , B Harding 1 , A Ali 1 , K Bradley 1 , P Wang 2 , J Chen 2 , B Williams 3 , B Teh 2 & R Thakker 1
1Academic Endocrine Unit, OCDEM, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, Oxon, UK; 2Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan, USA; 3Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, Michigan, USA.
The hyperparathyroidism-jaw tumour (HPT-JT) syndrome, an autosomal dominant disorder, is characterised by the occurrence of parathyroid tumours, often carcinomas, and ossifying fibromata of the jaw. The HPT-JT gene, referred to as HRPT2, is located on chromosome 1q25 and consists of 17 exons that encode a 531 amino-acid protein designated parafibromin. To explore the role of HRPT2 in parathyroid tumourigenesis, we generated two mouse models that comprised a conventional knockout (Hrpt2+/−) and a conditional knockout that was generated by mating a Hrpt2-floxed mouse (Hrpt2L/L) with a parathyroid hormone (PTH)-Cre transgenic mouse to obtain mice deleted for both Hrpt2 alleles in the parathyroids (PTH-Cre/Hrpt2−/−), and investigated these for parathyroid tumours. Mice were kept in accordance with welfare guidelines and project licence restrictions. All heterozygous knockout mice were viable and fertile, and were studied at eighteen months of age. Both conventional (Hrpt2+/−) and conditional (PTH/Cre-Hrpt2−/−) knockout mice had histological abnormalities in their parathyroids, that included enlargement, organisation of cells in solid sheets, and/or increased fibrous septation. These abnormal features would be consistent with parathyroid adenomas. To assess parathyroid proliferation, drinking water containing 5-bromo-2-deoxyuridine (BrdU) at 1 mg/ml was given to Hrpt2+/−, PTH/Cre-Hrpt2−/− and wild-type (Hrpt2+/+) littermates for 2 weeks. Parathyroid sections were immunofluorescently labelled for the calcium-sensing receptor (CaSR), BrdU and with DAPI, and parathyroid glands from each of four animals per genotype were analyzed to determine the percent of BrdU-positive cells. The mean daily proliferation rate (±S.E.M.) of parathyroid cells in the conventional Hrpt2+/− (0.31±0.08%) and conditional PTH-Cre/Hrpt2−/− (0.56±0.02%) mice was significantly (P<0.001) increased when compared to wild-type mice (0.08±0.02% per day), respectively. Thus, these mice have abnormal parathyroids with a greater than four fold increased in vivo proliferation rate when compared to wild-type, and provide a useful model to investigate the molecular pathways involved in parathyroid tumourigenesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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