Somatic gene transfer in the development of an animal model for primary hyperparathyroidism.
The overproduction of hormones is associated with a variety of endocrinological disorders. We have used somatic cell gene transfer of human PTH (hPTH) to develop an animal model of hypercalcemia and osteoclastic skeletal resorption. Recombinant retroviruses were used to transduce a functional hPTH gene into cultured rat fibroblasts. The recombinant-derived preproparathyroid hormone peptide was appropriately processed in this ectopic cell, and intact hPTH (1-84) was secreted at a high level (2-5 ng/10(6) cells/24 h). Transplantation of the PTH-secreting cells into syngeneic rat recipients was associated with the development of hypercalcemia mediated by increasing serum concentrations of hPTH. Thyroparathyroidectomy in these hypercalcemic rats producing hPTH did not result in hypocalcemia and tetany, which was observed in control animals undergoing thyroparathyroidectomy. Chronic overproduction of hPTH (60 days) was associated with severe hypercalcemia, metastatic calcification, and histological changes of osteoclastic resorption of bone. This animal model will be useful in studying the pathophysiology of severe hyperparathyroidism in humans and should help in the evaluation of new medical therapies for hypercalcemia.
Wilson
J M
JM
Howard Hughes Medical Institute, University of Michigan, Medical School, Ann Arbor 48109.
Grossman
M
M
Thompson
A R
AR
Lupassikis
C
C
Rosenberg
A
A
Potts
J T
JT
Kronenberg
H M
HM
Mulligan
R C
RC
Nussbaum
S R
SR
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000502:physiology / Q000637:transplantation; D005822:Genetic Vectors; D006801:Humans; D006961:Hyperparathyroidism / Q000503:physiopathology*; D051379:Mice; D010281:Parathyroid Hormone / Q000235:genetics* / Q000502:physiology; D016105:Parathyroidectomy; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012091:Repetitive Sequences, Nucleic Acid; D013539:Simian virus 40 / Q000235:genetics; D012879:Skin Physiological Phenomena; D013965:Thyroidectomy; D014162:Transfection; D014185:Transplantation, Isogeneic
D010281:Parathyroid Hormone; D004247:DNA