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Differential regulation of receptor‐stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3‐E1 osteoblasts
Author(s) -
Hartle James E.,
Prpic Veronica,
Siddhanti Suresh R.,
Spurney Robert F.,
Quarles L. Darryl
Publication year - 1996
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.5650110610
Subject(s) - forskolin , parathyroid hormone , medicine , endocrinology , chemistry , protein kinase c , cyclic adenosine monophosphate , pertussis toxin , phospholipase c , second messenger system , adenosine , protein kinase a , cholera toxin , signal transduction , extracellular , receptor , microbiology and biotechnology , g protein , biology , calcium , biochemistry , kinase
Extracellular cations have paradoxical trophic and toxic effects on osteoblast function. In an effort to explain these divergent actions, we investigated in MC3T3‐E1 osteoblasts if polyvalent cations differentially modulate the agonist‐stimulated cyclic adenosine monophosphate (cAMP) pathway, an important regulator of osteoblastic function. We found that a panel of cations, including gadolinium, aluminum, calcium, and neomycin, inhibited prostaglandin E 1 (PGE)‐stimulated cAMP accumulation but paradoxically potentiated parathyroid hormone (PTH)‐stimulated cAMP production. In contrast, these cations had no effect on forskolin‐ or cholera toxin–induced increases in cAMP, suggesting actions proximal to adenylate cyclase and possible modulation of receptor interactions with G proteins. Phorbol 12‐myristate 13‐acetated (PMA) mimicked the effects of cations on PGE 1 ‐and PTH‐stimulated cAMP accumulation in MC3T3‐E1 cells, respectively, diminishing and augmenting the responses. Moreover, down‐regulation of protein kinase C (PKC) by overnight treatment with PMA prevented gadolinium (Gd 3+ ) from attenuating PGE 1 ‐ and enhancing PTH‐stimulated cAMP production, indicating involvement of PKC‐dependent pathways. Cations, however, activated signal transduction pathways not coupled to phosphatidylinositol‐specific phospholipase C (PI‐PLC), since there was no corresponding increase in inositol phosphate formation or intracellular calcium concentrations. In addition, pertussis toxin treatment failed to prevent Gd 3+ ‐mediated suppression of PGE 1 ‐Stimulated cAMP, suggesting actions independent of G αi . Thus, polyvalent cations may either stimulate or inhibit hormone‐mediated cAMP accumulation in osteoblasts. These differential actions provide a potential explanation for the paradoxical trophic and toxic effects of cations on osteoblast function that occur in vivo under different hormonal conditions.