Regulatory T cells protect from local and systemic bone destruction in arthritis
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Regulatory T cells protect from local and systemic bone destruction in arthritis. / Zaiss, Mario M; Frey, Benjamin; Hess, Andreas; Zwerina, Jochen; Luther, Julia; Nimmerjahn, Falk; Engelke, Klaus; Kollias, George; Hünig, Thomas; Schett, Georg; David, Jean-Pierre.
in: J IMMUNOL, Jahrgang 184, Nr. 12, 15.06.2010, S. 7238-46.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Regulatory T cells protect from local and systemic bone destruction in arthritis
AU - Zaiss, Mario M
AU - Frey, Benjamin
AU - Hess, Andreas
AU - Zwerina, Jochen
AU - Luther, Julia
AU - Nimmerjahn, Falk
AU - Engelke, Klaus
AU - Kollias, George
AU - Hünig, Thomas
AU - Schett, Georg
AU - David, Jean-Pierre
PY - 2010/6/15
Y1 - 2010/6/15
N2 - We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-alpha-induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-kappaB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.
AB - We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-alpha-induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-kappaB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.
KW - Animals
KW - Arthritis, Experimental
KW - Arthritis, Rheumatoid
KW - Bone Resorption
KW - Cell Differentiation
KW - Cell Separation
KW - Enzyme-Linked Immunosorbent Assay
KW - Flow Cytometry
KW - Forkhead Transcription Factors
KW - Humans
KW - Immunohistochemistry
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Osteoclasts
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - T-Lymphocytes, Regulatory
KW - Tomography, X-Ray Computed
KW - Tumor Necrosis Factor-alpha
U2 - 10.4049/jimmunol.0903841
DO - 10.4049/jimmunol.0903841
M3 - SCORING: Journal article
C2 - 20483756
VL - 184
SP - 7238
EP - 7246
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 12
ER -