Involvement of SOCS3 in Regulation of CD11c⁺ Dendritic Cell-Derived Osteoclastogenesis and Severe Alveolar Bone Loss

• Published in: Infection and Immunity Vol. 77; no. 5; pp. 2000 - 2009
• Main Authors: Zhang, Xiaoxia, Alnaeeli, Mawadda, Singh, Bhagirath, Teng, Yen-Tung A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.05.2009; American Society for Microbiology (ASM)
• Subjects: Actinobacillus Infections - immunology; Actinobacillus Infections - pathology; Adult; Aggregatibacter actinomycetemcomitans - immunology; Alveolar Bone Loss - immunology; Animals; Biological and medical sciences; Bone Resorption - immunology; CD4-Positive T-Lymphocytes - immunology; Dendritic Cells - immunology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Host Response and Inflammation; Humans; Mice; Mice, Inbred BALB C; Mice, SCID; Microbiology; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - physiology; Young Adult; Dendritic cell; Microbiology; Immunity; Osteopenia; Diseases of the osteoarticular system
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.01070-08

To investigate the role of suppressor of cytokine signaling (SOCS) molecules in periodontal immunity and RANKL-mediated dendritic cell (DC)-associated osteoclastogenesis, we analyzed SOCS expression profiles in CD4⁺ T cells and the effect of SOCS3 expression in CD11c⁺ DCs during periodontal inflammation-induced osteoclastogenesis and bone loss in nonobese diabetic (NOD) versus humanized NOD/SCID mice. Our results of ex vivo and in vitro analyses showed that (i) there is significantly higher SOCS3 expression associated with RANKL⁺ T-cell-mediated bone loss in correlation with increased CD11c⁺ DC-mediated osteoclastogenesis; (ii) the transfection of CD11c⁺ DC using an adenoviral vector carrying a dominant negative SOCS3 gene significantly abrogates TRAP and bone-resorptive activity; and (iii) inflammation-induced TRAP expression, bone resorption, and SOCS3 activity are not associated with any detectable change in the expression levels of TRAF6 and mitogen-activated protein kinase signaling adaptors (i.e., Erk, Jnk, p38, and Akt) in RANKL⁺ T cells. We conclude that SOCS3 plays a critical role in modulating cytokine signaling involved in RANKL-mediated DC-derived osteoclastogenesis during immune interactions with T cells and diabetes-associated severe inflammation-induced alveolar bone loss. Therefore, the development of SOCS3 inhibitors may have therapeutic potential as the target to halt inflammation-induced bone loss under pathological conditions in vivo.