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J. Biol. Chem., Vol. 282, Issue 7, 4653-4660, February 16, 2007

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The Effect of Class A Scavenger Receptor Deficiency in Bone^*

Yi-Ling Lin, Willem J. S. de Villiers^¶, Beth Garvy^¶||, Steven R. Post^**, Tim R. Nagy, Fayez F. Safadi, Marie Claude Faugere^¶¶, Guodong Wang^¶¶, Hartmut H. Malluche^¶¶, and John P. Williams^¶¶¶1

From the College of Dentistry, Department of Internal Medicine, Divisions of Digestive Diseases and Nutrition and ^¶¶Nephrology, Bone, and Mineral Metabolism, and Departments of ^||Microbiology, Immunology and Molecular Genetics and ^**Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536, ^¶Lexington Veterans Affairs Medical Center, Lexington, Kentucky 40502, Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294, and Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Class A scavenger receptor (SR-A) is predominantly expressed by macrophages, and because osteoclasts are of monocyte/macrophage lineage, SR-A is of potential interest in osteoclast biology. In addition to modified low density lipoprotein uptake, SR-A is also important in cell attachment and signaling. In this study we evaluated the effect of SR-A deletion on bone. Knock-out animals have 40% greater body weight than wild type. Body composition analyses demonstrated that total lean and fat body mass were greater in knock-out animals, but there was no significant difference in percent fat and lean body mass. Bone mineral density and content were significantly greater in knock-out compared with wild type animals. Micro-computed tomography analyses confirmed that total volume, bone volume as well as trabecular number, thickness, and connectivity were significantly greater in knock-out mice. As expected, trabecular separation was greater in wild type mice. The phenotype appears to be explained by 60% fewer osteoclasts in females and 35% fewer in males compared to wild type mice with a paradoxical increase in nuclei/osteoclast in knock-out animals. Furthermore, there were no differences in adipocyte number and osteoblast number or activity. The addition of the soluble extracellular domain of SR-A to RAW264.7 cells stimulated a concentration-dependent increase in osteoclast differentiation that was receptor activator of nuclear factor-B ligand (RANKL)-dependent. Soluble SR-A had no effect on cell proliferation in the presence of RANKL but stimulated a 40% increase in numbers in the absence of RANKL. We conclude that SR-A plays a role in normal osteoclast differentiation, suggesting a novel role for this receptor in bone biology.

Received for publication, September 5, 2006 , and in revised form, November 13, 2006.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, University of Kentucky, 800 Rose St., MN521, Lexington, KY 40536. Tel.: 859-323-5049 (ext. 231); Fax: 859-323-0232; E-mail: JohnWilliams{at}uky.edu.

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