ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2012; 8(10):1398-1407. doi:10.7150/ijbs.5079 This issue Cite
Research Paper
TRAF Family Member-Associated NF-κB Activator (TANK) Induced by RANKL Negatively Regulates Osteoclasts Survival and Function
1. Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Blvd, Birmingham AL 35294-2182, USA.
2. Institute of Genetics, Life Science College, Zhejiang University, 388 Yuhang Road, Hangzhou 310058, People's Republic of China.
3. Shanghai Key laboratory, Shanghai Institute of Trauma and Orthopaedics, Ruijin Hospital, School of Medicine, Shanghai Jiao-Tong University, 197 Rui Jin Er Road, Shanghai 200025, P.R.China.
Abstract
Osteoclasts are the principle bone-resorbing cells. Precise control of balanced osteoclast activity is indispensable for bone homeostasis. Osteoclast activation mediated by RANK-TRAF6 axis has been clearly identified. However, a negative regulation-machinery in osteoclast remains unclear. TRAF family member-associated NF-κB activator (TANK) is induced by about 10 folds during osteoclastogenesis, according to a genome-wide analysis of gene expression before and after osteoclast maturation, and confirmed by western blot and quantitative RT-PCR. Bone marrow macrophages (BMMs) transduced with lentivirus carrying tank-shRNA were induced to form osteoclast in the presence of RANKL and M-CSF. Tank expression was downregulated by 90% by Tank-shRNA, which is confirmed by western blot. Compared with wild-type (WT) cells, osteoclastogenesis of Tank-silenced BMMs was increased, according to tartrate-resistant acid phosphatase (TRAP) stain on day 5 and day 7. Number of bone resorption pits by Tank-silenced osteoclasts was increased by 176% compared with WT cells, as shown by wheat germ agglutinin (WGA) stain and scanning electronic microscope (SEM) analysis. Survival rate of Tank-silenced mature osteoclast is also increased. However, acid production of Tank-knockdown cells was not changed compared with control cells. IκBα phosphorylation is increased in tank-silenced cells, indicating that TANK may negatively regulate NF-κB activity in osteoclast. In conclusion, Tank, whose expression is increased during osteoclastogenesis, inhibits osteoclast formation, activity and survival, by regulating NF-κB activity and c-FLIP expression. Tank enrolls itself in a negative feedback loop in bone resorption. These results may provide means for therapeutic intervention in diseases of excessive bone resorption.
Keywords: TANK, RANKL, NF-κB, Osteoclast.
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