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Comparison of Parathyroid Hormone (PTH) (1‐34) and PTH (7‐34) Effects on Cell Signaling and Proliferation in Saos‐2 Osteoblast‐like Cells
Author(s) -
Mamidanna Gayatri,
Cole Judith
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.772.10
Subject(s) - parathyroid hormone , bone resorption , chemistry , endocrinology , medicine , protein kinase b , osteoblast , resorption , agonist , cell growth , signal transduction , receptor , microbiology and biotechnology , calcium , in vitro , biology , biochemistry
In bone, PTH (1‐34) (P134) regulates formation and resorption, but the molecular mechanisms are not fully defined. The ability of P134 to increase bone formation has made it beneficial therapeutically, but its impact on bone resorption limits its usefulness. Studies in mice have shown that bovine PTH (7‐34) (P734) produces G protein‐independent increases in bone formation without stimulating bone resorption. For P734 to be therapeutically useful as a promoter of bone formation, its impact on PTH receptor (PTHR) signaling and bone function must be compared to that produced by P134 and assessed in the presence of endogenous PTH. In this study, we examined the effects P134, P734 and P134 +P734 on cAMP production, calcium (Ca) signaling, Akt activation and DNA synthesis in Saos2 cells. P134 dose‐dependently increased cAMP production (EC50 =15 pM) while P734 reduced basal cAMP production, indicating that PTH734 is an inverse agonist in these cells. P734 also competitively antagonized P134‐dependent cAMP production, reducing its EC50 to 339 nM. P134 dose‐dependently increased intracellular Ca levels (EC50 = 37 nM) while P734 had no effect. However, 1 uM P734 enhanced the effect of PTH134 on Ca at each dose of the peptide, suggesting that it sensitizes the cells to the effect of PTH134. A 24 h treatment with P134 stimulated proliferation, while P734 had no effect alone and blocked the responses to P134. Interestingly, P134 decreased while P734 increased Akt, suggesting that P134 does not use Akt to increase proliferation and may induce apoptosis while P734 may promote cell survival by activating Akt. Taken together, these data suggest that the in vivo data reported in mouse may reflect modification of the endogenous PTH signaling rather than P734 alone.