Parathyroid hormone-related peptide transiently increases cytosolic calcium in osteoblast-like cells: comparison with parathyroid hormone.
PTH-related protein (PTHrP), similarly to PTH, stimulates cAMP production in target tissues. However, different potencies have been observed for the two peptides in some biological assays, suggesting that cAMP-independent second messenger pathways might be involved in PTHrP signal transduction. This hypothesis was tested in the osteogenic sarcoma cell line UMR 106-01. Addition of PTHrP-(1-34) to cell suspensions loaded with the Ca2+ indicator indo-1 produced a transient dose-dependent increase in intracellular calcium ([Ca2+]i), with a maximal effect at 2 x 10(-7) M and an ED0.5 at about 4 x 10(-8) M. The amplitude and duration of the transients were similar to those induced by equimolar concentrations of bovine PTH-(1-34) (bPTH), and the dose-responses of the two peptides completely overlapped. Both full-length peptides, PTHrP-(1-141) and bPTH-(1-84), produced effects identical to those observed with the 1-34 fragments. Homologous and heterologous desensitization to both PTHrP-(1-34) and PTHrP-(1-141) occurred when the cells were prestimulated with equimolar or 10-fold lower doses of either PTHrP-(1-34) or bPTH-(1-34). Desensitization to bPTH-(1-34) was also observed when cells were prestimulated with PTHrP-(1-34). Furthermore, pretreatment with either bPTH-(3-34) or [Nle8,18, Tyr34]bPTH-(3-34) amide did not affect [Ca2+]i, but reduced the response to PTHrP-(1-34) by 55 +/- 10% (n = 3) and 67 +/- 8% (n = 3), respectively. The PTHrP-(1-34)-induced [Ca2+]i transient was not substantially affected by either extracellular Ca2+ chelation by EGTA or pretreatment with diltiazem, and nitrendipine only partially inhibited the [Ca2+]i response to PTHrP-(1-34) by about 10%. These results indicate that in osteoblastic cells PTHrP mobilizes Ca2+ from an intracellular storage pool with potency equal to that of PTH, and that the two hormones interact with the same receptor.
Civitelli
R
R
Division of Endocrinology, Jewish Hospital of St. Louis, Washington University Medical Center, Missouri 63110.
Martin
T J
TJ
Fausto
A
A
Gunsten
S L
SL
Hruska
K A
KA
Avioli
L V
LV
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005456:Fluorescent Dyes; D007211:Indoles; D007700:Kinetics; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009568:Nitrendipine / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D012516:Osteosarcoma; D010281:Parathyroid Hormone / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein
D005456:Fluorescent Dyes; D007211:Indoles; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D004533:Egtazic Acid; D009568:Nitrendipine; D004110:Diltiazem; C048960:indo-1; D002118:Calcium