Endocrinology, Vol 137, 4685-4690, Copyright © 1996 by Endocrine Society

ARTICLES

Calcitonin-induced changes in the cytoskeleton are mediated by a signal pathway associated with protein kinase A in osteoclasts

H Suzuki, I Nakamura, N Takahashi, T Ikuhara, K Matsuzaki, Y Isogai, M Hori and T Suda
Asahi Chemical Industry Co., Ltd., Laboratory for Pharmacological Research, Shizuoka, Japan.

Calcitonin is known to inhibit osteoclastic bone resorption through its receptor, which is abundantly expressed on the plasma membrane of osteoclasts. Recently, it was reported that calcitonin receptors were coupled to both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). To examine how the PKA and PKC pathways are involved in the effects of calcitonin, we focused on changes in the cytoskeleton of murine osteoclast-like multinucleated cells (OCLs) formed in vitro. When OCLs were cultured on dentine slices, they formed resorption pits and ringed structures of F-actin dots (actin rings). Elcatonin, a synthetic analogue of eel calcitonin, disrupted actin rings and inhibited pit formation in a dose-dependent manner. Forskolin and dibutyryl cAMP, both of which have the ability to activate PKA, mimicked the effects of elcatonin. Phorbol myristate acetate and phorbol 12,13-dibutyrate, both of which have the ability to activate PKC, also inhibited pit-forming activity, but little affected actin rings of OCLs. The inhibitory effects of elcatonin on the pit formation and actin ring formation were partially restored by the treatment with Rp-cAMPs, a cAMP antagonist. Elcatonin induced a rapid increase in PKA activity within a few minutes, and its activation by elcatonin occurred in a dose-dependent manner. The time- and dose-dependent profiles of elcatonin for the activation of PKA were similar to those for the disruption of actin rings. Moreover, microinjection of activated PKA into OCLs disrupted actin rings within 10 min on culture dishes. Actin rings were little affected by the microinjection of the PKA preincubated with a cAMP-dependent protein kinase inhibitor (IP-20) into OCLs. These results suggest that PKA activation, rather than PKC activation, is involved in mediating the effects of calcitonin, through the disruption of actin organization.

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