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  • br Acknowledgments br Introduction Postmenopausal osteoporos


    Introduction Postmenopausal osteoporosis, which is primarily caused by Nutlin 3 deficiency, has been a worldwide health problem and threatens postmenopausal women of all races. An estimated 80% of osteoporosis patients in the United States are women, and approximately 30% of postmenopausal women in developed countries have osteoporosis (Reginster and Burlet, 2006, Sweet et al., 2009). The risk of suffering from an osteoporotic fracture in white American women older than 50 has been estimated to be 40% (Tella and Gallagher, 2014). The health care expenditure of postmenopausal osteoporosis has generated substantial burdens on patients and society (Hoerger et al., 1999). Therefore, more extensive research on osteoporosis is necessary and urgent, especially regarding the development of specific molecular drugs. Compared with other types of osteoporosis, postmenopausal osteoporosis is distinguished by the high turnover phenotype with upregulated bone resorption and formation (Michael et al., 2005). Additionally, the increased bone resorption, which is mediated by osteoporotic osteoclasts, overwhelms osteoblast-mediated bone formation and that is considered to be the primary cause of bone loss in postmenopausal osteoporosis (Rodan and Martin, 2000). Regarding to bone resorption, estrogen suppresses osteoclastogenesis and promotes osteoclast apoptosis (Chen et al., 2014, Imai et al., 2009, Kameda et al., 1997, Nakamura et al., 2007). Therefore, in postmenopausal osteoporosis, excessive bone resorption is caused by dysregulated osteoclast formation and apoptosis, which are sequences in the reduction of estrogen’s protective effect on bone mass. In addition to the heated discussion of mature osteoclast-mediated bone resorption, pre-osteoclasts, the precursor of mature osteoclasts, have been highlighted for their unique functions, such as their pro-angiogenesis effect in bone remodeling (Xie et al., 2014). In light of this information, we are interested in the proliferation, differentiation and apoptosis of osteoclasts in postmenopausal osteoporosis. The hedgehog signaling pathway (Hh signaling pathway) has important and pleiotropic roles in the development and maintenance of embryonic and adult tissues (Briscoe, 2006). The Hh pathway can be divided into two distinct signaling modules according to the participation of Gli transcription factors: canonical and noncanonical Hedgehog signaling (Robbins et al., 2012). Canonical Hedgehog signaling, which engages the PTCH1, SMO and Gli family of transcription factors, is referred to here as Hedgehog-Gli (HH-Gli) signaling. At the initiation of its activation in vertebrates, Hedgehog ligands, including Sonic Hedgehog (SHH), India Hedgehog (IHH) and Desert Hedgehog (DHH) (Echelard et al., 1993), bind to a 12-transmembrane receptor known as Patched1 (PTCH1). Upon interaction with Hedgehog ligands, PTCH1 migrates away from the cell membrane and derepresses Smoothened (SMO). SMO translocates onto the primary cilium and activates downstream molecules to release the full-length activator form of Gli, referred to as GliA. Subsequently, GliA translocates to the nucleus where it binds the promoters of Hedgehog target genes and activates their transcription (Aberger et al., 2012). An essential role in this process is played by Gli1, a widely used biomarker in the activation of the HH-Gli signaling pathway (Wang and Holmgren, 2000). Mammals possess three Gli transcription factors (Gli1, Gli2 and Gli3). Gli1 and Gli2 principally act as transcriptional activators; while Gli3 is a repressor (Robbins et al., 2012). Gli transcription factors are essential in canonical Hedgehog signaling. However, noncanonical Hedgehog pathways do not require Gli transcription factors. Thus, the commonly used Hedgehog signaling agonist purmorphamine and antagonist vismodegib which both target on SMO, are effective in both canonical and noncanonical Hedgehog pathways. While GANT61, another antagonist targeting on Gli1 and Gli2, only block canonical Hedgehog signaling pathway.