TGF-I2 Inducible Early Gene 1 Regulates Osteoclast Differentiation and Survival by Mediating the NFATc1, AKT, and MEK/ERK Signaling Pathways

• Published in: PloS one Vol. 6; no. 3
• Main Authors: Cicek, Muzaffer, Vrabel, Anne, Sturchio, Catherine, Pederson, Larry, Hawse, John R, Subramaniam, Malayannan, Spelsberg, Thomas C, Oursler, Merry Jo
• Format: Journal Article
• Language: English
• Published: 14.03.2011
• Subjects: AKT protein; Apoptosis; Bone (cortical); Data processing; DC-STAMP protein; Extracellular signal-regulated kinase; Femur; Osteoblasts; Osteoclastogenesis; Osteoclasts; Osteoprogenitor cells; Phosphorylation; Signal transduction; siRNA; Survival; TRANCE protein; Transcription factors; Vertebrae
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0017522

TGF-I2 Inducible Early Gene-1 (TIEG1) is a KrA14ppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-I2 treatment. As reported previously, TIEG1a/a 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 TIEG1a/a 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 TIEG1a/a 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 TIEG1a/a osteoclasts. We observed increased AKT and MEK/ERK signaling pathway activation in TIEG1a/a osteoclasts, consistent with the roles of these kinases in promoting osteoclast survival. Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1a/a cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1a/a 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.