Differential regulation of receptor-stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3-E1 osteoblasts

James E. Hartle, Veronica Prpic, Suresh R. Siddhanti, Robert F. Spurney, Leigh Quarles

Research output: Contribution to journalArticle

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Abstract

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 E1 (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 PGE1- 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 (Gd3+) from attenuating PGE1- 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 Gd3+-mediated suppression of PGE1-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.

Original languageEnglish (US)
Pages (from-to)789-799
Number of pages11
JournalJournal of Bone and Mineral Research
Volume11
Issue number6
StatePublished - Jun 1 1996
Externally publishedYes

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Osteoblasts
Cyclic AMP
Cations
Alprostadil
Parathyroid Hormone
Poisons
Gadolinium
Protein Kinase C
Calcium
Phosphoinositide Phospholipase C
Inositol Phosphates
Neomycin
Cholera Toxin
Pertussis Toxin
Colforsin
Aluminum
GTP-Binding Proteins
Adenylyl Cyclases
Signal Transduction
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Differential regulation of receptor-stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3-E1 osteoblasts. / Hartle, James E.; Prpic, Veronica; Siddhanti, Suresh R.; Spurney, Robert F.; Quarles, Leigh.

In: Journal of Bone and Mineral Research, Vol. 11, No. 6, 01.06.1996, p. 789-799.

Research output: Contribution to journalArticle

Hartle, James E. ; Prpic, Veronica ; Siddhanti, Suresh R. ; Spurney, Robert F. ; Quarles, Leigh. / Differential regulation of receptor-stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3-E1 osteoblasts. In: Journal of Bone and Mineral Research. 1996 ; Vol. 11, No. 6. pp. 789-799.
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