TNF inhibits production of stromal cell-derived factor 1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood

Qian Zhang,Edward M Schwarz,Lianping Xing,Brendan F Boyce,Ruolin Guo

doi:10.1186/ar2391

Qian Zhang, Edward M Schwarz + Show 3 more

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https://doi.org/10.1186/ar2391

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Abstract

IntroductionThe 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.MethodsOCPs 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.ResultsOCPs 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.ConclusionSystemically 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.

Highlights

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
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
SDF-1 has a chemotaxic effect on bone marrow OCPs We and other workers have demonstrated that patients or mice with chronic inflammatory arthritis have an increased frequency of OCPs in peripheral blood and spleens, and that TNF promotes the release of bone marrow OCPs into the bloodstream [3,4,5]

Summary

Introduction

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. Patients with psoriatic arthritis [3] and mice with TNF-induced arthritis [4,5] have increased numbers of circulating OCPs, which correlate with systemically increased TNF concentrations and are reduced by anti-TNF therapy in association with clinical improvement. These findings suggest that OCP mobilization from the marrow may be involved in the pathogenesis of inflammatory arthritis. SDF-1 and CXCR4 have been implicated in OCP migration in vitro, and SDF-1 treatment of OCPs increases osteoclastogenesis and subsequent osteoclast bone-resorbing capacity [12,13]

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