Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption.
Inflammatory bone resorption mediated by osteoclasts is a major cause of morbidity and disability in many inflammatory disorders, including rheumatoid arthritis (RA). The mechanisms that regulate osteoclastogenesis and bone resorption in inflammatory settings are complex and have not been well elucidated. In this study, we identify the immunoregulator differentially expressed in FDCP 6 homolog (Def6) as a novel inhibitor of osteoclastogenesis in physiological and inflammatory conditions. Def6 deficiency inDef6-/-mice enhanced the sensitivity of osteoclast precursors to the physiological osteoclastogenic inducer receptor activator for NF-κB ligand, andDef6-/-osteoclasts formed actin rings. Furthermore, Def6 deficiency markedly increased TNF-α-induced osteoclastogenesis in vitro and in vivo and enhanced bone resorption in an inflammatory osteolysis mouse model. TNF-α serum levels correlated negatively with Def6 expression levels in osteoclast precursors obtained from RA patients, and the osteoclastogenic capacity of the osteoclast precursors was significantly inversely correlated with their Def6 expression levels, indicating that Def6 functions as an inhibitor of excessive osteoclast formation and bone destruction in RA. Mechanistically, Def6 suppressed osteoclastogenesis and the expression of key osteoclastogenic factors NFATc1, B lymphocyte-induced maturation protein-1, and c-Fos by regulating an endogenous IFN-β-mediated autocrine feedback loop. The Def6-dependent pathway may represent a novel therapeutic target to prevent pathological bone destruction.
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
Nikolaus
0000-0002-1237-8102
N
Binder
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
Christine
0000-0003-2176-9516
C
Miller
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
Masaki
M
Yoshida
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
Kazuki
K
Inoue
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
Shinichi
S
Nakano
Institute for Immunology, Tsinghua University, Beijing 100084, China.|School of Medicine, Tsinghua University, Beijing 100084, China.
Xiaoyu
X
Hu
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.|Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021.
Lionel B
LB
Ivashkiv
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
Georg
G
Schett
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.|Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021.|Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021; and.
Alessandra
A
Pernis
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
Steven R
SR
Goldring
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
F Patrick
FP
Ross
Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021; zhaob@hss.edu.|Department of Medicine, Weill Cornell Medical College, New York, NY 10021.
Baohong
B
Zhao
D000199:Actins / Q000378:metabolism; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D019898:Autocrine Communication; D001862:Bone Resorption / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics; D010014:Osteolysis / Q000235:genetics / Q000276:immunology*; D053245:RANK Ligand / Q000276:immunology
D000199:Actins; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D053245:RANK Ligand; C473249:Def6 protein, mouse