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  • The estrogen receptor ER dependent

    2019-09-09

    The estrogen receptor(ER)-dependent signaling pathway plays an important role in bone metabolism by restoring the balance between osteoblastic bone formation and osteoclastic bone resorption [21]. ER has two major isoforms, ERalpha (ER-α) and ERbeta (ER-β), which mediate the effect of estrogen and other biologically active substances through genomic or non-genomic methods [22]. Mitogen-activated protein kinase (MAPK) pathways are also central signal transducers in the regulation of bone metabolism. The MAPKs, mainly including extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal of stress-activated protein kinases (JNK) and the p38 protein kinases, are critically involved in cell growth, differentiation, and apoptosis [23]. ERK1/2 and p38 signaling pathways have been shown to have a pivotal role in the differentiation of osteoblasts by phosphorylating runt-related transcription factor 2 (RUNX2), the master regulator of osteoblast differentiation [24]; however, studies have also suggested that osteoblast differentiation is inhibited by ERK1/2 pathway activation [25]. ICT has a chemical structure similar to estrogen, and previous studies have indicated estrogen-like activity [26], [14]. ICT can also activate the ERK or p38 pathways in different ISCK03 clinical [5], [6], [7], [8]. However, it is unclear whether ICT can influence the activity of osteoblasts through the ER-dependent pathway or the MAPK pathway. In the present study, we investigated the effect of ICT on the differentiation and mineralization of MC3T3-E1 subclone 14 preosteoblast cells. The role of the ER-dependent, ERK1/2 and p38 pathways in the process of differentiation was explored.
    Materials and methods
    Results
    Discussion Estrogen is involved in bone physiology and pathology through the ER, which is very important for bone growth, maturation and bone mass maintenance. ICI182780 (Fulvestrant, Faslodex) is a steroidal selective ER modulator that can downregulate ER by accelerating ER degradation [28]. Phytoestrogens are plant-derived compounds that have affinity to the ER and are able to act as either estrogen agonists or antagonists. Because of their structural similarity to 17-beta-estradiol, they have been studied extensively for their role in the prevention of postmenopausal bone loss [26]. Phytoestrogens are often present in plants as glycoside and then hydrolyzed into aglycone via biological activity by intestinal bacterial glycosidases in the body [29]. ICT is a product of icariin via the metabolism of intestinal bacteria with an estrogen-like chemical structure where the C-3 and C-7 are hydroxylated [29], and exhibits estrogen-like activities [26], [14]. Therefore, we hypothesized that ICT had estrogen-like effects to modulate the differentiation of osteoblasts. Two distinct ER isoforms, ER-α and ER-β, have been described in MC3T3 E1 cells [30]. In this study, we also identified that MC3T3-E1subclone 14 cells expresses the ER-α and ER-β proteins and that ICT can increase ER-α expression. After blocking ER with ICI182780, the effects of ICT on cell differentiation were decreased significantly. Therefore, we suggest that ER mediates the role of ICT in cell differentiation. MAPK pathways are major information highways from the cell surface to the nucleus. Studies have determined that MAPKs regulate bone formation by osteoblasts [24], [31]. Mice with a germline deletion of Erk1 and a conditional deletion of Erk2 in limb mesenchyme (Erk1−/−Erk2Prx1 mice), including osteoblasts, display substantially reduced bone mineralization [32]. The p38 pathway is also required for normal skeletogenesis in mice, as mice with deletion of p38a or p38b display profoundly reduced bone mass, secondary to defective osteoblast differentiation [31]. The JNK pathway is by far the least understood MAPK pathway in osteoblasts for several inconsistent results in vitro studies [33], [34].