tgf-β inducible early gene 1 regulates osteoclast differentiation and survival by mediating the nfatc1, akt, and mekerk signaling pathwaystgf-β诱导早期基因1调节破骨细胞分化和生存通过调停nfatc1,akt,mekerk信号通路.pdfVIP

TGF-b Inducible Early Gene 1 Regulates Osteoclast Differentiation and Survival by Mediating the NFATc1, AKT, and MEK/ERK Signaling Pathways 1 2 2 2 1 Muzaffer Cicek *, Anne Vrabel , Catherine Sturchio , Larry Pederson , John R. Hawse , Malayannan 1 1 1,2 Subramaniam , Thomas C. Spelsberg , Merry Jo Oursler 1 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America, 2 Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America Abstract ¨ TGF- b Inducible Early Gene-1 (TIEG1) is a Kruppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-b treatment. As reported previously, TIEG12/ 2 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 TIEG12/ 2 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 TIEG12/ 2 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 TIEG12/ 2 osteoclasts. We observed incre