Parathyroid hormone-related protein (PTHrP) is initially translated as a preprohormone which is posttranslationally processed to yield a family of mature secretory forms. Most attention has focused on the aminoterminal portion of the molecule which is homologous to parathyroid hormone. It is clear, however, that a midregion species of PTHrP is posttranslationally cleaved from the highly conserved mid-region of PTHrP, and that the amino terminus of this peptide is Ala 38 . The purposes of the current study were three: 1) to confirm that Arg 37 immediately preceding Ala 38 serves as a posttranslational processing site in the PTHrP precursor, 2) to determine the carboxyl terminus of the mid-region secretory species of PTHrP, and 3) to synthesize this authentic mid-region secretory form of PTHrP and determine whether it is biologically active. The results indicate that: 1) Arg 37 is indeed a processing site in the PTHrP precursor; 2) three distinct mid-region PTHrP species are generated by posttranslational processing, PTHrP(38 -94)amide, PTHrP(38 -95), and most likely, PTHrP(38 -101); and 3) synthetic mid-region PTHrP(38 -94)amide is active in four different biological systems. These studies confirm the finding that PTHrP is a prohormone. More importantly, they define a novel, biologically active highly conserved mid-region secretory form of PTHrP.Parathyroid hormone-related protein (PTHrP) 1 was initially discovered through its structural and functional homology with parathyroid hormone (for a review, see Refs.

SUMMARYPerfusion in situ of the placenta of intact or previously parathyroidectomized fetal lambs has been used to assess the ability of three mid-molecule fragments of the human parathyroid hormone-related protein (PTHrP)

SUMMARYPerfusion in situ of the placenta of previously thyroparathyroidectomized fetal lambs has been used to compare the ability of various forms of parathyroid hormone-related protein (PTHrP) to stimulate placental calcium transport. Whereas PTHrP (1-34) was without effect, PTHrP (1-141) was active but usually after a delay of up to 1 h, in common with the effect noted when using extracts of fetal parathyroid glands. In contrast, PTHrP (1-84) and PTHrP (1-108), tended to show a more rapid stimulatory action. It is suggested that post-translational processing of PTHrP (1-141) may occur as an activating step in the placenta in vivo.

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A radioimmunoassay based on an antiserum to human parathyroid hormone-related protein PTHrP(1-16) was used with PTHrP(1-34) standard to measure the concentration of immunoreactive PTHrP in extracts of fetal parathyroid glands from lambs and calves and also placental membranes obtained from several species, including man. Dilution curves from these sources were parallel to those obtained for PTHrP(1-34) standard. It was demonstrated that this parallelism was not the result of tracer damage caused by enzymic activity in the tissue extracts. Extracts of human placental membranes were subjected to high-pressure liquid chromatography with a linear acetonitrile gradient. Co-elution of cytochemical biological activity with 125I-labelled PTHrP(1-34) was noted. These results provide further evidence for both the fetal parathyroid glands and the placenta containing material resembling PTHrP which may be responsible for sustaining the activity of the placental calcium pump which maintains the fetus hypercalcaemic relative to its mother.