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Endocrinology Vol. 141, No. 12 4711-4719
Copyright © 2000 by The Endocrine Society

ARTICLES

Intracellular Calcium and Protein Kinase C Mediate Expression of Receptor Activator of Nuclear Factor-{kappa}B Ligand and Osteoprotegerin in Osteoblasts

Masamichi Takami, Naoyuki Takahashi, Nobuyuki Udagawa, Chisato Miyaura, Koji Suda, Je-Tae Woo, T. John Martin, Kazuo Nagai and Tatsuo Suda

Department of Biochemistry, School of Dentistry, Showa University (M.T., N.T., N.U., T.S.), Tokyo 142-8555, Japan; Department of Bioengineering, Tokyo Institute of Technology (K.S., J.-T. W., K.N.), Yokohama 226-8501, Japan; Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science (C.M.), Tokyo 192-0392, Japan; and St. Vincent’s Institute of Medical Research (T.J.M.), Fitzroy, Victoria 3065, Australia

Address all correspondence and requests for reprints to: Dr. Tatsuo Suda, Department of Biochemistry, School of Dentistry, Showa University, 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail: suda{at}dent.showa-u.ac.jp

Receptor activator of nuclear factor-{kappa}B ligand (RANKL) and osteoprotegerin (OPG) produced by osteoblasts/stromal cells are involved as positive and negative regulators in osteoclast formation. Three independent signals have been proposed to induce RANKL expression in osteoblasts/stromal cells: vitamin D receptor-, cAMP-, and gp130-mediated signals. We previously reported that intracellular calcium-elevating compounds such as ionomycin, cyclopiazonic acid, and thapsigargin induced osteoclast formation in cocultures of mouse bone marrow cells and primary osteoblasts. Increases in calcium concentration in culture medium also induced osteoclast formation in cocultures. Treatment of primary osteoblasts with these compounds or with high calcium medium stimulated the expression of both RANKL and OPG messenger RNAs (mRNAs). 1,2-Bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)-tetra(acetoxymethyl)ester, an intracellular calcium chelator, suppressed both ionomycin-induced osteoclast formation in cocultures and expression of RANKL and OPG mRNAs in primary osteoblasts. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, also stimulated osteoclast formation in these cocultures and the expression of RANKL and OPG mRNAs in primary osteoblasts. Protein kinase C inhibitors such as calphostin and staurosporin suppressed ionomycin- and PMA-induced osteoclast formation in cocultures and expression of RANKL and OPG mRNAs in primary osteoblasts. Ionomycin stimulated RANKL mRNA expression in ST2 and MC3T3-G2/PA6 cells, but not in MC3T3-E1 or NIH-3T3 cells. These effects were closely correlated with osteoclast formation in response to ionomycin in cocultures with these stromal cell lines. OPG strongly inhibited osteoclast formation induced by calcium-elevating compounds and PMA in cocultures, suggesting that RANKL expression in osteoblasts is a rate-limiting step for osteoclast induction. Forskolin, an activator of cAMP signals, also stimulated osteoclast formation in cocultures. Forskolin enhanced RANKL mRNA expression but suppressed OPG mRNA expression in primary osteoblasts. These results suggest that the calcium/protein kinase C signal in osteoblasts/stromal cells is the fourth signal for inducing RANKL mRNA expression, which, in turn, stimulates osteoclast formation.




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