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Functional Expression of ß-Chemokine Receptors in Osteoblasts: Role of Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) in Osteoblasts and Regulation of Its Secretion by Osteoblasts and Osteoclasts

Division of Endocrinology, Diabetes, and Hypertension (S.Y., R.M., D.K., E.M.B., N.C.), Department of Medicine and Membrane Biology Program, Brigham and Women’s Hospital and Department of Laboratory Medicine (A.R.), Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and Genetics and Aging Unit (S.B.), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

Address all correspondence and requests for reprints to: Naibedya Chattopadhyay, Ph.D., Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: naibedya{at}rics.bwh.harvard.edu.

The expression and functions of receptors for the ß-chemokine, regulated upon activation, normal T cell expressed, and secreted (RANTES)/CCL5, were investigated in osteoblasts. Both primary osteoblasts and the MC3T3-E1 osteoblast cell line express the RANTES receptors, CCR1, 3, 4, and 5 (by RT-PCR), which encode functional receptors in osteoblasts as shown by [¹²⁵I]-RANTES binding followed by Scatchard analysis. Expression of all four RANTES receptor mRNAs in osteoblast is in contrast to the reports of expression of CCR1 being the only RANTES receptor expressed by osteoclasts. Exogenous RANTES elicits chemotaxis of osteoblasts and promotes cell survival via phosphatidylinositol 3-kinase with attendant phosphorylation of Akt. Osteoclastic RANTES, obtained from the conditioned medium of receptor activator of nuclear factor-B ligand-differentiated RAW264.7 cells also induces chemotaxis of MC3T3-E1 cells. Incubating the conditioned medium with an anti-RANTES neutralizing antibody attenuated this effect. RANTES secretion from osteoblast is inhibited by differentiation promoting hormones, e.g. 1,25 (OH)₂D₃ and dexamethasone, whereas macrophage inflammatory protein-1 (but not macrophage inflammatory protein-1ß) and elevated calcium induce it. Elevated calcium also stimulated RANTES secretion by osteoclasts. Therefore, RANTES is an osteoblast chemoattractant and a survival-promoting molecule whose regulation in osteoblast is varied. Furthermore, RANTES secreted from osteoclasts induces osteoblast chemotaxis. Therefore, expression of RANTES and its receptors in both osteoblasts and osteoclasts could enable this chemokine to act in autocrine/paracrine modes.

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