Human parathyroid hormone-related peptide-(107-111) does not inhibit bone resorption in neonatal mouse calvariae.
Recent analysis of the structure-function relationship of human PTH-related peptide (hPTHrP) has led to the discovery that its direct inhibitory activity on osteoclastic bone resorption resides fully in the 107-111 sequence of the peptide, as assessed by a bone resorption assay using isolated rat osteoclasts. Here we report that hPTHrP-(107-111) is inactive in neonatal mouse calvariae in culture. hPTHrP-(107-111), at doses of 10(-12)-10(-6) M and incubation periods up to 96 h, did not affect either basal or agonist-stimulated 45Ca release from prelabeled neonatal mouse calvariae, while salmon calcitonin was a potent and powerful inhibitor of both basal and stimulated 45Ca release from bone. Moreover, salmon calcitonin, but not hPTHrP-(107-111), inhibited the increase in osteoclast number in hPTHrP-(1-34)-treated bones. Furthermore, hPTHrP-(107-139) also failed to inhibit 45Ca release and the hPTHrP-(1-34)-induced increase in osteoclast number in this organ culture model when tested under conditions identical to those for hPTHrP-(107-111). The addition of indomethacin to hPTHrP-(107-111)- or hPTHrP-(107-139)-treated bones was without effect, excluding the possibility that the direct inhibitory activity of these peptides on osteoclasts is ablated by a prostaglandin-mediated mechanism. Although the mechanism underlying the apparent inability of the carboxyl-terminal PTHrP fragments to inhibit osteoclastic bone resorption in neonatal mouse calvariae is unknown, it may involve the complex microenvironment of osteoclasts in intact bone, which contains a large variety of cell types other than osteoclasts.
Sone
T
T
Department of Radiology and Nuclear Medicine, Kyoto University Hospital, Japan.
Kohno
H
H
Kikuchi
H
H
Ikeda
T
T
Kasai
R
R
Kikuchi
Y
Y
Takeuchi
R
R
Konishi
J
J
Shigeno
C
C
D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002116:Calcitonin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D009924:Organ Culture Techniques; D010010:Osteoclasts / Q000502:physiology*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*
D002132:Calcium Radioisotopes; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C071784:parathyroid hormone-related protein (107-111); C054296:parathyroid hormone-related protein (1-34); C071097:parathyroid hormone-related protein (107-139); C028815:salmon calcitonin; D002116:Calcitonin; D002118:Calcium; D007213:Indomethacin