Functional expression of beta-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.
The expression and functions of receptors for the beta-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-kappa 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 alpha (but not macrophage inflammatory protein-1 beta) 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.
Yano
Shozo
S
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine and Membrane Biology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mentaverri
Romuald
R
Kanuparthi
Deepthi
D
Bandyopadhyay
Sanghamitra
S
Rivera
Alicia
A
Brown
Edward M
EM
Chattopadhyay
Naibedya
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D020287:In Situ Nick-End Labeling; D007457:Iodine Radioisotopes; D051379:Mice; D010006:Osteoblasts / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515301:Ccr1 protein, mouse; C515302:Ccr1 protein, rat; C515351:Ccr3 protein, mouse; C515352:Ccr3 protein, rat; C515355:Ccr4 protein, mouse; C515356:Ccr4 protein, rat; D018946:Chemokine CCL5; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D019869:Phosphatidylinositol 3-Kinases