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The Chemokine Cxcl1 Is a Novel Target Gene of Parathyroid Hormone (PTH)/PTH-Related Protein in Committed Osteoblasts

Bone Joint and Cancer Unit (D.O., E.H.A., J.M.W.Q., J.H.G., S.P., N.A.S., M.T.G., T.J.M.), St. Vincent’s Institute, and Department of Medicine (J.M.W.Q., J.H.G., S.P., N.A.S., M.T.G., T.J.M.), St. Vincent’s Hospital, The University of Melbourne, Fitzroy, Victoria 3065, Australia

Address all correspondence and requests for reprints to: Professor T. J. Martin, St. Vincent’s Institute, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. E-mail: jmartin{at}svi.edu.au.

The PTH receptor (PTHR1) is expressed on osteoblasts and responds to PTH or PTHrP in an endocrine or autocrine/paracrine manner, respectively. A microarray study carried out on PTHR1-positive osteoblasts (Kusa 4b10 cells) identified the cysteine-X-cysteine (CXC) family chemokine ligand 1 (Cxcl1) as a novel immediate PTH/PTHrP-responsive gene. Cxcl1 is a potent neutrophil chemoattractant with recognized roles in angiogenesis and inflammation, but a role in bone biology has not been described. Cxcl1 mRNA levels were up-regulated 1 h after either PTH or PTHrP treatment of differentiated Kusa 4b10 osteoblasts (15-fold) and mouse calvarial osteoblasts (160-fold) and in rat metaphyseal bone (5-fold) 1 h after a single sc injection of PTH. Furthermore, PTH treatment stimulated a 10-fold increase in secreted Cxcl1 protein by both Kusa 4b10 cells and calvarial osteoblasts. Immunohistochemistry and PCR demonstrated that CXCR2, the receptor for Cxcl1, is highly expressed in osteoclast precursors (hemopoietic cells) but is predominantly undetectable in the osteoblast lineage, suggesting that osteoblast-derived Cxcl1 may act as a chemoattractant for osteoclast precursors. Confirming this hypothesis, recombinant Cxcl1 dose-dependently stimulated migration of osteoclast precursors in cell culture studies, as did conditioned media from Kusa 4b10 cells treated with PTH. These data indicate that local action through the PTHR1 could stimulate cells of the osteoblast lineage to release a chemokine capable of attracting osteoclast precursors to the bone environment.