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Bioactivity of Parathyroid Hormone and Parathyroid Hormone-Like Peptide: Agonist and Antagonist Activities of Amino-Terminal Fragments as Assessed by the Cytochemical Bioassay and in Situ Biochemistry^*

N. LOVERIDGE, V. DEAN, D. GOLTZMAN and G. N. HENDY

Bone Growth and Metabolism Unit (N.L., V.D.), Rowett Research Institute, Aberdeen AB2 9SB, Scotland, and Departments of Medicine and Physiology (D.G., G.N.H.), McGill University and Royal Victoria Hospital, Montreal H3A 1A1 Quebec, Canada

Address all correspondence and requests for reprints to: Dr. Nigel Loveridge, Bone Growth and Metabolism Unit, Rowett Research Institute, Greenburg Road, Aberdeen AB2 9SB, Scotland.

Abstract

Parathyroid hormone-like peptide (PLP) is elaborated from certain tumors and is thought to play a role in the etiology of humoral hypercalcemia of malignancy. The amino-terminal portion of this peptide has a sequence homology with parathyroid hormone PTH. We have compared the agonist potency of the synthetic human amino-terminal 1–34 peptide [human (h)PLP-(l–34)] with that of intact PTH and its amino terminal fragment [hPTH-(l–34)] in the renal and metatarsal cytochemical bioassays (CBA). Furthermore, the antagonist activity of the truncated amino terminal molecule [hPLP-(3–34)] has been compared to that of [Norleu^8,18,Tyr³⁴]bovine PTH-(3–34)NH2, and we have also tested their ability to stimulate enzyme activities thought to be associated with bone formation and resorption. In the renal CBA, both PLP-(l–34) and hPTH-(l–34) were equipotent with intact hPTH. In the metatarsal CBA, although the two amino-terminal peptides were equipotent, they elicited an earlier response than the intact PTH molecule. In both assay systems the truncated PLP analog [hPLP-(3–34)] was a more potent antagonist of both PTH and PLP activity than was [Norleu^8,l8,Tyr³⁴]bovine PTH-(3–34)NH2. In acute studies, hPLP-(l–34) and hPTH-(l–34) stimulated alkaline phosphatase and glucose 6-phosphate dehydrogenase activity in osteoblasts to a similar extent, and both peptides stimulated tartrate-resistant acid phosphatase and succinate dehydrogenase activity in osteoclasts. Longer exposure to the peptides resulted in stimulation of enzyme activity in osteoclasts but not osteoblasts, although there was no difference in potency between the two molecules. (Endocrinology 128: 1938–1946,1991)

Footnotes

^* This work was supported by Nato Grant 0804/7 (to N.L. and G.N.H.) and Medical Research Council of Canada Grant MA-9315 (to G.N.H.). Presented in part at the 10th International Conference on Calcium Regulating Hormones, Montreal, Quebec, Canada, 1989.

Recipient of a Scholarship Award from the Medical Research Council of Canada.

Received September 17, 1990.

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