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This version published online on April 3, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0021
Molecular Endocrinology Vol. 0, No. 2003 200300211-
doi:10.1210/me.2003-0021
Copyright © 2003 by the Endocrine Society.
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Submitted on January 21, 2003
Accepted on March 28, 2003

Deletion of the P2X7 Nucleotide Receptor Reveals Its Regulatory Roles in Bone Formation and Resorption

Hua Zhu Ke1*, Hong Qi1, A. Frederik Weidema1, Qing Zhang1, Nattapon Panupinthu1, D. Todd Crawford1, William A. Grasser1, Vishwas M. Paralkar1, Mei Li1, Laurent P. Audoly1, Christopher A. Gabel1, Webster S.S. Jee1, S. Jeffrey Dixon1, Stephen M. Sims1, and David D. Thompson1

1 Pfizer, Inc. Global Research and Development, Groton Laboratories, Groton, CT 06340, USA, CIHR Group in Skeletal Development and Remodeling, and Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada N6A 5C1, Radiobiology Division, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.

* To whom correspondence should be addressed. E-mail: huazhu_ke{at}groton.Pfizer.com.

The P2X7 nucleotide receptor is an ATP-gated ion channel expressed widely in cells of hematopoietic origin. Our purpose was to explore the involvement of P2X7 receptor in bone development and remodeling by characterizing the phenotype of mice genetically modified to disrupt the P2X7 receptor (KO). Femoral length did not differ between KO and wild-type (WT) littermates at 2 or 9 months of age, indicating that the P2X7 receptor does not regulate longitudinal bone growth. However, KO mice displayed significant reduction in total and cortical bone content and periosteal circumference in femurs, and reduced periosteal bone formation and increased trabecular bone resorption in tibiae. Patch clamp recording confirmed expression of functional P2X7 receptors in osteoclasts from WT but not KO mice. Osteoclasts were present in vivo and formed in cultures of bone marrow from KO mice, indicating that this receptor is not essential for fusion of osteoclast precursors. Functional P2X7 receptors were also found in osteoblasts from WT, but not KO mice, suggesting a direct role in bone formation. P2X7 receptor KO mice demonstrate a unique skeletal phenotype, which involves deficient periosteal bone formation together with excessive trabecular bone resorption. Thus, the P2X7 receptor represents a novel therapeutic target for the management of skeletal disorders such as osteoporosis.
Key words: ATP • osteoporosis • osteoclast • osteoblast • P2X7 receptor




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