TNF inhibits production of stromal cell-derived factor 1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood.
BACKGROUND
The objective of the present study was to investigate the role of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis in TNF-induced mobilization of osteoclast precursors (OCPs) from bone marrow.


METHODS
OCPs were generated from bone marrow cells of TNF-transgenic mice or wild-type mice treated with TNF or PBS. The percentage of CD11b+/Gr-1-/lo OCPs was assessed by fluorescence-activated cell sorting. OCP migration to the SDF-1 gradient and the osteoclast forming potency were assessed in chemotaxis/osteoclastogenic assays. SDF-1 expression was assessed by real-time RT-PCR, ELISA and immunostaining in primary bone marrow stromal cells, in the ST2 bone marrow stromal cell line, and in bones from TNF-injected mice.


RESULTS
OCPs generated in vitro from wild-type mice migrated to SDF-1 gradients and subsequently gave rise to osteoclasts in response to RANKL and macrophage colony-stimulating factor. TNF reduced SDF-1 expression by ST2 cells. Bone marrow stromal cells from TNF-transgenic mice produced low levels of SDF-1. TNF treatment of wild-type mice decreased the SDF-1 concentration in bone marrow extracts and decreased the SDF-1 immunostaining of bone marrow stromal cells, and it also increased the circulating OCP numbers. The percentage of bone marrow CXCR4+ OCPs was similar in TNF-transgenic mice and wild-type littermates and in TNF-treated and PBS-treated wild-type mice.


CONCLUSIONS
Systemically elevated TNF levels inhibit bone marrow stromal cell production of SDF-1 and increase the release of bone marrow OCPs to the peripheral blood. Disruption of the SDF-1/CXCR4 axis by TNF may play an important role in mediating OCP mobilization from the bone marrow cavity in chronic inflammatory arthritis.
Zhang
Qian
Q
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642, USA. qianzhang@urmc.rochester.edu
Guo
Ruolin
R
Schwarz
Edward M
EM
Boyce
Brendan F
BF
Xing
Lianping
L
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D053245:RANK Ligand; D019718:Receptors, CXCR4; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha