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Hormone-Specific Suppression of Adenosine 3',5'-Monophosphate Responses in Bone in Vitro during Prolonged Incubation with Parathyroid Hormone, Prostaglandin E_1, and Calcitonin

Medical Research Council Group in Periodontal Physiology (J.N.M.H., B.N.), Faculty of Dentistry, University of Toronto Toronto, Ontario, Canada
the Laboratory of Cell Biology, Faculty of Medicine, University of Leiden Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. J. N. M. Heersche, 4384 Medical Sciences Building, University of Toronto, Taddle Creek Road, Toronto, Ontario M5S 1A8, Canada.

Abstract

Incubation of fetal rat calvaria with parathyroid hormone (PTH, 2 U/ml) causes an initial rise in cAMP concentration in the tissue at 15 min, followed by a decrease upon further incubation, but concentrations remain above control levels for at least 120 min. The decrease in cAMP levels could not be explained by hormone inactivation or by secretion into the medium of a hormone inhibitor. Calvaria incubated for 60 min with PTH did not respond to the addition of new PTH, but addition of salmon calcitonin (sCT, 100 mU/ml) or prostaglandin E₁ (PGE₁, 2.5 µg/ml) at this point clearly resulted in a further increase in cAMP concentration. Prolonged incubation of calvaria with sCT, PGE₁, and PGE₂ also caused a significant increase in concentration of cAMP at 15 min, followed by a decrease thereafter. Tissue incubated with sCT for 60 min did not respond to the addition of new sCT, but responded to newly added PTH. Similarly, tissue incubated for 60 min with PGE₁, did not respond to addition of new PGE₁, but responded well to newly added PTH. The effect of lower but still effective concentrations of PTH and PEG, (i.e. 0.3, 0.6, and 1.25 U/ml PTH and 0.3, 0.6, and 1.25 µg/ml PGE_>1) is similar: tissue cAMP levels rise during the first 15 min of incubation and decrease thereafter to levels slightly above control levels after 1–2 h. Incubation of bone tissue for 1 h with the lower concentrations of PTH and PGE₁ resulted in a considerably decreased responsiveness of the tissue to a newly added higher dose of the same hormone. These results indicate that the decreased responsiveness to PTH, PGE₁, and sCT after prolonged exposure to these hormones is hormone-specific and occurs at all hormone concentrations that cause a rise in tissue cAMP levels. The results suggest the existence to bone tissue of a cellular mechanism to compensate for overexposure to PTH, PGE₁, and sCT.

Received August 11, 1976.