TGF-β Inducible Early Gene-1 (TIEG1) is a Krüppel-like transcription factor 
(KLF10) that was originally cloned from human osteoblasts as an early response 
gene to TGF-β treatment. As reported previously, TIEG1(-/-) mice have decreased 
cortical bone thickness and vertebral bone volume and have increased spacing 
between the trabeculae in the femoral head relative to wildtype controls. Here, 
we have investigated the role of TIEG1 in osteoclasts to further determine their 
potential role in mediating this phenotype. We have found that TIEG1(-/-) 
osteoclast precursors differentiated more slowly compared to wildtype precursors 
in vitro and high RANKL doses are able to overcome this defect. We also 
discovered that TIEG1(-/-) precursors exhibit defective RANKL-induced 
phosphorylation and accumulation of NFATc1 and the NFATc1 target gene DC-STAMP. 
Higher RANKL concentrations reversed defective NFATc1 signaling and restored 
differentiation. After differentiation, wildtype osteoclasts underwent apoptosis 
more quickly than TIEG1(-/-) osteoclasts. We observed increased AKT and MEK/ERK 
signaling pathway activation in TIEG1(-/-) osteoclasts, consistent with the 
roles of these kinases in promoting osteoclast survival. Adenoviral delivery of 
TIEG1 (AdTIEG1) to TIEG1(-/-) cells reversed the RANKL-induced NFATc1 signaling 
defect in TIEG1(-/-) precursors and eliminated the differentiation and apoptosis 
defects. Suppression of TIEG1 with siRNA in wildtype cells reduced 
differentiation and NFATc1 activation. Together, these data provide evidence 
that TIEG1 controls osteoclast differentiation by reducing NFATc1 pathway 
activation and reduces osteoclast survival by suppressing AKT and MEK/ERK 
signaling.