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Parathyroid Hormone-Related Peptide Transiently Increases Cytosolic Calcium in Osteoblast-Like Cells: Comparison with Parathyroid Hormone^*

Divisions of Endocrinology and Metabolism St. Louis, Missouri 63110
Nephrology, The Jewish Hospital of St. Louis, Washington University Medical Center St. Louis, Missouri 63110
St. Vincent's Institute of Medical Research Melbourne, Victoria, Australia

Address all correspondence and requests for reprints to: Roberto Civitelli, M.D., Division of Endocrinology and Metabolism, The Jewish Hospital of St. Louis, 216 South Kingshighway Boulevard, St. Louis, Missouri 63110.

Abstract

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 ED₀₅ 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 [Nle⁸¹⁸,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.

Footnotes

^* Part of this work has been presented in abstract form at the Tenth Annual Meeting of the American Society for Bone and Mineral Research, New Orleans, LA, June 4-7,1988 (Abstract 14). This work was supported in part by NIH Grants AR-32087 (to R.C., A.F., S.L.G., K.A.H., and L.V.A.) and AR-3956 (to K.A.H.), and a grant from Shriners Hospitals for Crippled Children (to K.A.H. and L.V.A.).

Received March 17, 1989.

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