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Both Breast and prostate cancers are dependent on the actions of sex hormones mediated through their nuclear receptors in onset and development of the cancers. Nuclear estrogen and androgen receptors(ER and AR)are DNA-binding transcription factors and regulate expressions of the target mRNA genes by modulating chromatin structure and function. In this short review, the function of nuclear sex hormone receptors in sex hormone-depend cancers are overviewed in the chromatin reorganization for target gene regulations. Moreover, the role of enhancer RNA(eRNA), one of the non-coding RNAs, in chromatin reconfiguration is discussed for enhancer function in tumor development.

Environment and structure of chromatin underlie epigenetics, and they also facilitate transcriptional regulations by nuclear receptors including VDR. In this short review, the molecular basis of chromatin remodeling and post-translational modifications of histone proteins are illustrated with characterization of their regulators, providing mechanisms for co-regulation of epigenetics and transcription on chromatin. Moreover, the role of enhancer RNA (eRNA), one of the non-coding RNAs, in chromatin configuration is discussed for gene regulation by VDR.

Most of vitamin D actions mediate expression of target genes regulated by nuclear vitamin D receptor (VDR). Regulation of chromatin environment has emerged to underlie gene regulation by liganded VDR. Active state of chromatin is defined by specific combination of post-translational modification of histone proteins, and chromatin remodelers as nuclear complexes conduct dynamic shift of chromatin sate. Among histone modifications, methylations of specific lysine residues located in the N-terminal tails of histone H3 are known to play pivotal roles in directing chromatin state, and the methylated lysine 4 and 9 in the histone H3 (H3K4me and H3K9me) are widely used as indicators of chromatin state. The histone modifying enzymes and chromatin remodelers are thus regulators for chromatin environment, and overtly co-regulate transcriptional regulations of a particular set of target genes by nuclear receptors including VDR. In this review, the molecular mechanism of regulated chromatin configuration is described by illustrating modifications of histone proteins and rearrangements of nucleosome array and their regulators.

Osteoclasts are differentiated from hematopoietic stem cells and become multinucleated giant cells through cell-fusion by a number of regulators. Among such regulators, transcription factors play pivotal roles by reorganizing gene networks. Recently, epigenetic regulators like histone modifiers and chromatin remodelers have emerged to be prerequisite for gene regulations by transcriptional factors. However, little is known about epigenetic controls during osteoclastogenesis and osteoclastic maturation. To address this issue, we tried to identify novel epigenetic regulators for fine control of NFATc1 function through biochemical approaches. Here, we summarize the new epigenetic regulation mechanism and epigenetic regulator which are required for normal osteoclastogenesis.

Fat-soluble ligands like steroid hormones exert their actions through nuclear receptor-mediated transcriptional controls. Nuclear receptors are hormone-dependent transcription factors, and their ligand-dependent function is facilitated by transcriptional co-regulators, that were initially considered to bridge nuclear receptors with transcription initiation complex. However, recent progress in epigenome and chromatin research has uncovered that hormone-dependent transcriptional controls by nuclear receptors require a number of epigenetic/transcriptional co-regurators facilitating chromatin reorganization.

Vitamin D is one of the best established hormone to exert beneficial action for bone mass control and bone metabolism. Such vitamin D action for bone tissue is recapitulated in intact animals, while vitamin D is well known to potentiate bone resorption by inducing gene of RANKL an osteoclastic inducer. By genetic characterization of VDR in mice, VDR was found to serve as a negative regulator in intact bone. Moreover, RANKL gene expression level in intact bone was down-regulated in osteoblast-specific VDR KO mice. Thus, these findings indicate that VDR in bone tissue is a negative regulator for bone mass control.

Sex steroid hormones play important roles in bone metabolism through the functions of its specific nuclear receptors, estrogen receptors(ERs) and androgen receptor (AR). From the results of analyses of bone tissue specific sex steroid hormone receptors knockout mice, it has been clarified that sex steroids can directly function in bone tissue as well as indirect endocrine influences. These recent researches may promote the investigations of novel strategies to treat osteoporosis, which could be induced by deficiency of sex steroid hormones in the old population regardless of gender.

Fat-soluble ligands like steroid hormones serve to activate nuclear receptors. Nuclear receptors are ligand-dependent transcription factors to transcriptionally activate sets of target genes, and such ligand-dependent transcription mediates a number of transcriptional coregulators. Since nuclear receptors form a gene superfamily, their protein structures are divided into several functional domains. The C-terminal ligand binding domain is structurally altered upon ligand binding, and switches interaction of co-transcriptional regulators; from co-repressors to co-activators. Likewise, owing to ligand-dependent structure alteration of the entire receptor proteins, the N-terminal domains of receptors become accessible to co-activators. Synthetic agonists/antagonists are potent to induce structural alteration in ligand-type dependent manner, resulting in pharmacological association with transcriptional co-regulators.

The bone mass, which is controlled by the balances between bone formation and bone resorption can be reduced by estrogen deficiency in post-menopausal osteoporosis. Reduced bone mass can be recovered by hormone replacement therapy (HRT) , however, HRT has various side effects. Although SERMs can rescue the bone mass with less side effect compared to HRT, the precise mechanisms of this effect is still elusive. From the results of the analyses for osteoclast specific estrogen receptor (ER) alphaknockout mice and the genome wide approach of ERalphabinding site, estrogen and SERMs can, at least in part, protect the bone mass by inducing the expression of Fas ligand and controling the life span of osteoclasts. More precise molecular mechanisms of the effect of SERM, especially in tissue/cell type specificity, may help to investigate new SERM, which is more specific and effective to treat post-menopausal osteoporosis.

Androgen is well established to exert anabolic action for skeletal tissues beyond sex difference. However, the target cells/genes remain to be identified. Recently, we have generated a mouse line selectively ablated androgen receptor gene in osteoclasts, and found osteoporotic phenotype in male mutants, indicating that anabolic androgen action is attributed to its repressive action for bone resorption.

Estrogen is quite well known to exert osteoprotective action, and indeed post-menopausal women in estrogen deficiency suffer osteoporotic defects in bone. The molecular basis of such estrogen action had been uncovered, since ER alpha KO mice failed to recapture the osteoporotic phenotype induced by estrogen deficiency in the same mouse strain. Recently, we have selectively disrupted ER alpha gene in mature osteoclasts, and this female mice were found to display a typical osteoporotic bone phenotype. In this review, I briefly overview this aspect.

Androgen is well established to exert anabolic action on skeletal system among mammalians. Since androgen is effective to induce increases in bone mass and muscle content, a tissue-specific androgen analogue is expected to benefit elder peoples. However, the molecular basis and target factors underlining its anabolic action are barely known. In this review, the bone phenotypes of ARKO mice generated by us are described.

Bone mass and strength is mediated by appropriate weight bearing, and it is clear that bone tissue senses and adopts mechanical stresses. However, the precise molecular mechanisms in mechanotransduction remain elusive. Recently, several studies clarified that estrogen receptor alpha (ERalpha) plays important role in mechanotransduction. For example, the lifespan of osteocytes is prolonged by mechanical loading through ERalpha action, which is produced by the plentiful expression of ERalpha in osteocytes. Although these recent findings clearly show the important role of ERalpha in mechanotransduction, the intracellular function of ERalpha is still largely unknown. In this point of view, it will be a great interest to elucidate how ERs functionally associate with regulators involved with mechanotransductions in bone cells.

Adipocytes and osteoblasts are derived from mesenchymal stem cells, and some adipocyte differentiation regulators suppress osteoblast differentiation. PPAR-gammaplays a pivotal role for adipocyte differentiation and glucose tolerance. PPAR-gammais a member of nuclear receptor super family and regulates mRNA expression level of target genes by binding to fatty acid derivatives and thiazolidinediones. Recently, it was found that PPAR-gammainhibits osteoblast differentiation and regulates bone metabolism. In this report, we show recent studies about the extracellular signals regulating the transactivation function of PPAR-gamma.

The multiple physiological effects of steroid hormones are mediated by the cognate nuclear receptors through transcriptional regulation of target gene expression. Recently, post-transcriptional modifications of steroid receptors and cross-talk between steroid hormone signaling with other signaling pathways have been found to play a pivotal role in cell- and gene-specific transcriptional regulation. This is a brief overview on the role of interaction with different transcriptional factors and specific post-translational modifications (phosphorylation, acetylation and ubiquitination) of nuclear receptors in defining the physiological outcome of steroid hormone action.

Steroid hormone receptors are ligand-dependent transcriptional factors and regulate cell differentiation, proliferation, and homeostasis. Recently, many target genes of steroid hormone receptors were identified by genome-wide analysis and associated cofactors were also identified by proteomics analysis. From these findings, the molecular mechanism of ligand-dependent transactivation function of steroid hormone receptors have been elucidated. However, tissue specific regulation and extracellular signal-dependent regulation of steroid hormone receptor function are still under investigation.

The calciotropic hormone 1alpha, 25-dihydroxyvitamin D(3) [1alpha, 25 (OH)(2)D(3)] regulates many biological actions such as calcium homeostasis, cell differentiation and proliferations. Most of the biological actions of 1alpha, 25 (OH)(2)D(3) are thought to be mediated by the vitamin D receptor (VDR) , which is a member of a nuclear receptor superfamily acting as a ligand-inducible transcription factor. VDR deficient mice (conventional-VDRKO mice) appear the typical phenotype of vitamin D dependent type II rickets. However, no defect in conventional-VDRKO mice was observed in osteoblast specific-conditional VDRKO mice. Here, we introduce VDR function in bone involving such difference phenotype in these mice.

Selective estrogen receptor modulator (SERM) is designated as synthetic ligands for estrogen receptors (ERs), exhibiting tissue-specific agonisitic/antagonisitic activities. Among SERM, raloxifen is a most clinically successful as an anti-oseteoporotic agent. Such tissue-specific actions of SERM are presumed to mediate through unusual structure alteration of liganded ERs coupled with co-regulator recruitments.

Female sex steroid hormone, estrogen, exerts a wide variety of biological actions including lipid metabolism and bone remodeling. Moreover, estrogen is known to be involved in many pathological states like osteoporosis, tumor incidence and tumor development of female reproductive organs. Most of such estrogen actions are believed to mediate transcriptional controls of a particular set of target genes by its nuclear receptor, estrogen receptor (ER). The products of the genes regulated by ER are responsible for the overt estrogen actions in the many estrogen target tissues. Reflecting the estrogen actions, two ER subtypes (alpha, beta) express in the bone and the other target tissues. ER is a hormone-dependent transcriptional factor and hormone binding is known to alter the structure of ER protein, following dissociation/recruitment of multiple co-regulator complexes. Synthetic ER ligands, SERM, are believed to cause the ligand type-specific alteration in ER structure. This SERM-induced structural alteration acquires the tissue-specific function of liganded ER, as SERM acts as an agonist for bone remodeling.

PPAR(alpha, beta/delta, gamma) are ligand-dependent nuclear receptors and regulate homeostasis, cell proliferation/differentiation and associate with hypolipidemia, atherosclerosis, diabetes, and obesity. Through heterodimerization with retinoid X receptors (RXRs), PPARs bind the same consensus response element, formed by a direct repeat of two AGGTCA hexamers separated by one base. Recently, many PPAR direct and indirect target genes have been reported. Here, we summarize the PPAR direct/indirect target genes, and their functions related to lipid metabolism, adipocyte differentiation.

Typical abnormalities of hereditary rickets type II patients were observed in the mice deficient of VDR with growth retardation, impaired bone formation and alopecia. Except alopecia, all of the abnormalities were rescued by dietary supplement of high minerals. Genetic mutations in the critical vitamin D biosynthesis enzyme in humans and mice also suffer rachtic phenotypes except alopecia. The function of VDR in skin will be discussed.

PPARgamma is a ligand-dependent nuclear receptor and regulates adipogenesis and associates with diabetes, obesity. Recently, relationship between PPARgamma and bone metabolism was investigated. Here, we report the molecular mechanism of PPARgamma transcriptional activity and the suppression of PPARgamma activity by cytokines in bone marrow-derived mesenchymal stem cells.

Although the physiological significance of estrogen receptor function on skeletal tissues has been established, that of androgen receptor (AR) function has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene targeting technique caused bone loss in males, but not in females, which indicated that AR function is indispensable for male-type bone formation and remodeling.

SERM like tamoxifene and raloxifene is a synthetic ligand for estrogen receptor (ER), and exert tissue-specific actions in many target tissues as an agonist/antagonist thorough modifying the ER function. ER is a member of the nuclear steroid/thyroid hormone, fat-soluble vitamin receptor gene superfamily and acts as a ligand-inducible factor. The ligand-dependent transactivation of ER requires direct interactions of co-regulators through its C-terminal helix-12. Ligand binding to ER causes structural alteration with the helix 12 shifting, but such structural alterations appear distinct among the ligand types. Tissue-specific actions of SERM are speculated to exert through ligand-type-specific alterations in structure with consequent recruitments of regulators.