Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice.

Arthritis Rheum 2004 Jan;50(1):265-76

University of Rochester Medical Center, Rochester, New York 14642, USA.

Objective: To investigate the mechanisms whereby tumor necrosis factor alpha (TNFalpha) increases osteoclastogenesis in vivo.

Methods: TNFalpha-transgenic (TNF-Tg) and wild-type mice injected with TNFalpha were studied. In vitro osteoclastogenesis assays, monocyte colony-forming assays, and fluorescence-activated cell sorting were performed using splenocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells to quantify and characterize osteoclast precursors (OCPs). Etanercept, a TNFalpha antagonist, was used to block TNFalpha activity in vivo. The effects of TNFalpha on proliferation, apoptosis, and differentiation of OCPs were assessed using 5-bromo-2'-deoxyuridine labeling, annexin V staining, and reverse transcriptase-polymerase chain reaction.

Results: OCP numbers were increased 4-7-fold in PBMCs and spleen, but not in bone marrow of TNF-Tg mice. The OCPs in spleen were in the CD11b(high) population and contained both c-Fms- and c-Fms+ cells. The increased number of OCPs correlated with the initiation of detectable TNFalpha in serum and the onset of inflammatory arthritis in TNF-Tg mice. Etanercept eliminated the increase in peripheral OCPs. TNFalpha did not affect proliferation, survival, or differentiation of CD11b(high) splenocytes in vivo or in vitro, but caused a rapid increase in CD11b+ cells in blood within 4 hours of a single injection and an accumulation of CD11b(high) OCPs in spleen after 3 days of multiple injections.

Conclusion: Systemic TNFalpha induces a marked increase in circulating OCPs that is reversible by anti-TNF therapy and may result from their mobilization from bone marrow. Our findings provide a new mechanism whereby TNFalpha stimulates osteoclastogenesis in patients with inflammatory arthritis, suggesting that CD11b+ PBMCs could be used to evaluate a patient's potential for erosive disease and the efficacy of anti-TNF therapy.

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.11419DOI Listing
January 2004
43 Reads

Publication Analysis

Top Keywords

necrosis factor
12
bone marrow
12
tumor necrosis
12
tnfalpha
9
anti-tnf therapy
8
tnf-tg mice
8
increase peripheral
8
inflammatory arthritis
8
factor alpha
8
osteoclast precursors
8
ocps spleen
8
ocps
7
number ocps
4
increased number
4
ocps correlated
4
c-fms+ cells
4
contained c-fms-
4
c-fms- c-fms+
4
correlated initiation
4
cells increased
4

Altmetric Statistics

References

(Supplied by CrossRef)

Teitelbaum et al.
Science 2000

Goldring et al.
Arthritis Res 2000

Hofbauer et al.
J Bone Miner Res 2000

Feldmann et al.
Cell 1996

Douni et al.
J Inflamm 1996

Campbell et al.
J Clin Invest 2001

Childs et al.
J Bone Miner Res 2001

Suda et al.
J Bone Miner Res 1997

Karsenty et al.
Genes Dev 1999

Lacey et al.
Cell 1998

Yasuda et al.
Proc Natl Acad Sci U S A 1998

Similar Publications