IntroductionEstrogens and androgens exert regulatory influences on a wide variety of biological processes by signaling through highly specialized proteins belonging to the superfamily of nuclear receptors: the estrogen receptors (ERs) α and β and the androgen receptor (AR) (1-3). Binding of the hormone to the receptor causes homo-or heterodimerization of the protein and changes its conformation in such a way that it allows the dimer to interact with several coactivator proteins. The receptor-coactivator(s) complex attaches to specific DNA response elements (estrogen response elements [EREs] and androgen response elements [AREs]) and the basal transcription machinery, causing histone acetylation, decondensation of the chromatin, and initiation of transcription. Estrogens and androgens also regulate the transcription of genes that do not contain EREs or AREs. In this case the ligandactivated receptors form protein-protein complexes with other transcription factors, thus preventing them from interacting with their target gene promoters (4).Nonetheless, numerous effects of estrogens and androgens cannot be explained by the established models of transcriptional regulation resulting from cis-or trans-interactions of their classical nuclear receptor proteins with DNA. To distinguish them from the classical, It has been found that 4-estren-3α,17β-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17β-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-β (C/EBPβ), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/ c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligandbinding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17β-estradiol or 4-estren-3α,17β-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPβ, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.

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Purpose of review To describe the current knowledge on the cross-talk between connexins and microRNAs (miRs) in bone cells. Recent findings Connexins play a crucial role on bone development and maintenance, and disruptions in their abundance or localization can affect how bone perceives and responds to mechanical, hormonal, and pharmacological stimuli. Connexin expression can be modified by miRs, which modulate connexin mRNA and protein levels. Recently, different manners by which miRs and connexins can interact in bone have been identified, including mechanisms that mediate miR exchange between cells in direct contact through gap junctions, or between distant cells via extracellular vesicles (EVs). Summary We bring to light the relationship between miRs and connexins in bone tissue, with special focus on regulatory effects of miRs and connexins on gene expression, as well as the mechanisms that mediate miR exchange between cells in direct contact through gap junctions, or between distant cells via EVs.