Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.
Parathyroid hormone-like adenylate cyclase-stimulating proteins (hACSPs) have been implicated as one of the calcemic, bone-resorbing agents in patients with humoral hypercalcemia of malignancy. We report the synthesis of an amino-terminal hACSP fragment, Tyr36 hACSP (1-36) amide. The synthetic hACSP is a potent agonist of renal membrane adenylate cyclase (Km, 1.7 X 10(-10)) and of bone cell adenylate cyclase (Km 1 X 10(-9)M). It is a potent bone-resorbing agent in vitro, stimulating 45Ca release from fetal rat long bones at a concentration of 10(-9) M. When infused via osmotic minipumps into rats, it is also a potent calcemic factor in vivo, inducing a rise in serum calcium from (mean +/- SD) 10.6 +/- 0.6 to 19.7 +/- 3.2 mg/dl when infused at 1.4 micrograms/h and from 9.9 +/- 0.7 to 11.4 +/- 1.2 mg/dl when infused at 0.14 micrograms/h. These findings indicate that biologically active hACSP fragments can be synthesized. One such synthetic peptide possesses the in vitro and in vivo bioactivities demonstrated in native, tumor-derived hACSPs. It is also a potent calcemic, bone-resorbing agent.
Stewart
A F
AF
Department of Endocrinology, West Haven Veterans Administration Medical Center, Connecticut 06516.
Mangin
M
M
Wu
T
T
Goumas
D
D
Insogna
K L
KL
Burtis
W J
WJ
Broadus
A E
AE
D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D001862:Bone Resorption / Q000187:drug effects*; D003001:Cloning, Molecular; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000494:pharmacology*; D010281:Parathyroid Hormone / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D011994:Recombinant Proteins; C053371:parathyroid hormone-like adenylate cyclase-stimulating protein, human; D000262:Adenylyl Cyclases