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J. Biol. Chem., Vol. 280, Issue 17, 16909-16915, April 29, 2005

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P2Y6 Nucleotide Receptors Activate NF-B and Increase Survival of Osteoclasts^*

Jasminka Korcok, Lin N. Raimundo, Xiaobing Du, Stephen M. Sims, and S. Jeffrey Dixon¶

From the Canadian Institutes of Health Research Group in Skeletal Development and Remodeling, Department of Physiology and Pharmacology and Division of Oral Biology, Faculty of Medicine & Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada

Nucleotides, released from cells during inflammation and by mechanical stimulation, act through the P2 family of nucleotide receptors. Previous studies have demonstrated the expression of P2Y1 and P2Y2 receptors in osteoclasts. The aim of this study was to determine whether osteoclast P2Y receptors signal through NF-B, a key transcription factor regulating osteoclastogenesis. Immunofluorescence was used to detect the p65 subunit of NF-B, which upon activation translocates from the cytosol to nuclei. Low levels of NF-B activation were observed in untreated rabbit osteoclasts and in those exposed to 2-methylthio ADP (P2Y1 agonist) or ATP or UTP (P2Y2 agonists). In contrast, UDP or INS48823(P2Y6 agonists) induced a significant increase in the number of cells exhibiting NF-B activation, a process sensitive to the proteasome inhibitor lactacystin. In osteoclasts purified by micromanipulation, reverse transcription-PCR revealed the presence of P2Y1, P2Y2, and P2Y6 receptor transcripts, and application of agonists for these receptors induced the transient rise of cytosolic calcium. Treatment of rat osteoclasts with UDP or INS48823 but not 2-methylthio ADP or UTP, increased osteoclast survival. Osteoprotegerin (a decoy receptor for RANK ligand) did not significantly alter the effects of UDP on NF-B localization or osteoclast survival, consistent with a direct action. Moreover, SN50 (cell-permeable peptide inhibitor of NF-B) suppressed the enhancement of cell survival induced by UDP and INS48823 Our findings demonstrate the presence of functional P2Y6 receptors in osteoclasts. Thus, nucleotides, following their release at sites of inflammation and mechanical stimulation, can act through P2Y6 receptors to initiate NF-B signaling and enhance osteoclast survival.

Received for publication, September 20, 2004 , and in revised form, February 7, 2005.

^* This work was supported by the Canadian Institutes of Health Research and the Canadian Arthritis Network. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Canadian Institutes of Health Research Doctoral Award.

Present address: Aderans Research Institute, Philadelphia, PA.

^¶ To whom correspondence should be addressed. Tel.: 519-661-3769; Fax: 519-850-2459; E-mail: jeff.dixon{at}fmd.uwo.ca.

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