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Control of Cyclic Adenosine 3',5'-Monophosphate Production in Osteoclasts: Calcitonin-Induced Persistent Activation and Homologous Desensitization of Adenylate Cyclase^*

G. C. NICHOLSON, J. M. MOSELEY, A. J. P. YATES and T. J. MARTIN

University of Melbourne, Department of Medicine, Repatriation General Hospital Heidelberg, Victoria 3081, Australia

Abstract

Hormonal control of cAMP production in the osteoclast has not been investigated in detail because this boneresorbing cell has been difficult to isolate. We have used osteoclasts freshly isolated by disaggregation from neonatal rat long bones and settled onto coverslips (100–150 cells per coverslip) to examine the effects of calcitonin and prostaglandin E2 on osteoclast cAMP levels and cytoplasmic spreading. Salmon, eel, and human calcitonin (CT), and various analogs, stimulated cAMP production in a dose-dependent manner with relative potencies as seen in other response systems. Forskolin (10^-7 M) increased the sensitivity and amplitude of the response. Pretreatment with pertussis toxin (200 ng/ml for 3 h) had no effect suggesting that CT does not act through N_i, the inhibitory guanine nucleotide regulatory unit of adenylate cyclase. CT treatment was associated with rapid and dose-dependent induction of a persistent activated state of adenylate cyclase and homologous desensitization, the former being a particular feature of CT action previously observed in nonosteoclastic cells. Quantitative histomorphometry demonstrated a sensitive, dose dependent, and prolonged (>2 h) reduction in osteoclast plan area after exposure to salmon CT. Although prostaglandin E₂ also stimulated cAMP production and resulted in cell contraction in osteoclasts this was not associated with persistent activation of adenylate cyclase nor with prolonged contraction. Persistent activation of adenylate cyclase may be an important mechanism in CT inhibition of osteoclast function. (Endocrinology 120: 1902–1908,1987)

Footnotes

^* This work was supported by a grant from the National Health and Medical Research Council of Australia.

National Health and Medical Research Council of Australia Postgraduate Medical Research Scholar.

To whom correspondence and requests for reprints should be addressed.

Received September 18, 1986.

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