Osteocalcin is the most abundant non-collagenous protein produced in bone. It has traditionally been regarded as a marker of bone turnover and is thought to act in the bone matrix to regulate mineralization. However, emerging knowledge regarding osteocalcin has expanded to include functions in energy metabolism, fertilization, and regulation of cognition. Fully carboxylated osteocalcin binds to hydroxyapatite, thereby modulating bone turnover, whereas undercarboxylated osteocalcin in the circulation binds to osteocalcin-sensing receptors and acts as a hormone that affects multiple physiological aspects. In this review, we summarize the current knowledge regarding the hormonal actions of osteocalcin in various organs and potential cellular downstream signaling pathway that may be involved.

In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression.Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells. Survival gene DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), was found to be overexpressed in various cancer types. The potential of DX2 inhibitors as an anti-cancer drug arises from its unique ability to interact with various oncoproteins, such as KRAS and HSP70. Meanwhile, AIMP2 has been reported as a multifunctional cell death-inducing gene, and survival gene DX2 directly and indirectly inhibits AIMP2-induced cell death. DX2 plays multifaceted survival roles in degenerating neurons via various signaling pathways, including PARP 1, TRAF2, and p53 pathways. It is noteworthy that genes that were previously classified as oncogenes, such as AKT and XBP1, are now being considered as curative transgenes for targeting neurodegenerative diseases. A strategic direction for clinical application of survival genes in neurodegenerative disease and in cancer is justified.

In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression.Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells. Survival gene DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), was found to be overexpressed in various cancer types. The potential of DX2 inhibitors as an anti-cancer drug arises from its unique ability to interact with various oncoproteins, such as KRAS and HSP70. Meanwhile, AIMP2 has been reported as a multifunctional cell death-inducing gene, and survival gene DX2 directly and indirectly inhibits AIMP2-induced cell death. DX2 plays multifaceted survival roles in degenerating neurons via various signaling pathways, including PARP 1, TRAF2, and p53 pathways. It is noteworthy that genes that were previously classified as oncogenes, such as AKT and XBP1, are now being considered as curative transgenes for targeting neurodegenerative diseases. A strategic direction for clinical application of survival genes in neurodegenerative disease and in cancer is justified.

In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression.Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells. Survival gene DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), was found to be overexpressed in various cancer types. The potential of DX2 inhibitors as an anti-cancer drug arises from its unique ability to interact with various oncoproteins, such as KRAS and HSP70. Meanwhile, AIMP2 has been reported as a multifunctional cell death-inducing gene, and survival gene DX2 directly and indirectly inhibits AIMP2-induced cell death. DX2 plays multifaceted survival roles in degenerating neurons via various signaling pathways, including PARP 1, TRAF2, and p53 pathways. It is noteworthy that genes that were previously classified as oncogenes, such as AKT and XBP1, are now being considered as curative transgenes for targeting neurodegenerative diseases. A strategic direction for clinical application of survival genes in neurodegenerative disease and in cancer is justified.

Tumor necrosis factor alpha (TNFalpha) is a multifunctional inflammatory cytokine that regulates various cellular and biological processes. Increased levels of TNFalpha have been implicated in a number of human diseases including diabetes and arthritis. Sympathetic nervous system stimulation via the beta2-adrenergic receptor (beta2AR) in osteoblasts suppresses osteogenic activity. We previously reported that TNFalpha up-regulates beta2AR expression in murine osteoblastic cells and that this modulation is associated with TNFalpha inhibition of osteoblast differentiation. In our present study, we explored whether TNFalpha induces beta2AR expression in human osteoblasts and then identified the downstream signaling pathway. Our results indicated that beta2AR expression was increased in Saos-2 and C2C12 cells by TNFalpha treatment, and that this increase was blocked by the inhibition of NF-kappaB activation. Chromatin immunoprecipitation and luciferase reporter assay results indicated that NF-kappaB directly binds to its cognate elements on the beta2AR promoter and thereby stimulates beta2AR expression. These findings suggest that the activation of TNFalpha signaling in osteoblastic cells leads to an upregulation of beta2AR and also that TNFalpha induces beta2AR expression in an NF-kappaB-dependent manner.
Arthritis ; Biological Processes ; Chromatin Immunoprecipitation ; Durapatite ; Humans ; Luciferases ; NF-kappa B ; Osteoblasts ; Receptors, Adrenergic ; Sympathetic Nervous System ; Tumor Necrosis Factor-alpha ; Up-Regulation

Receptor activator of nuclear factor-κB ligand (RANKL) is an osteoblast/stromal cell-derived essential factor for osteoclastogenesis. During endochondral bone formation, hypertrophic chondrocytes calcify cartilage matrix that is subsequently resorbed by osteoclasts in order to be replaced by new bone. Hypoxia-induced upregulation of RANKL expression has been previously demonstrated in an in vitro system using osteoblasts; however, the involved mechanism remains unclear in chondrocytes. In the present study, we investigated whether hypoxia regulates RANKL expression in ATDC5 cells, a murine chondrogenic cell line, and hypoxia-inducible factor-1α (HIF-1α) mediates hypoxia-induced RANKL expression by transactivating the RANKL promoter. The expression levels of RANKL mRNA and protein, as well as HIF-1α protein, were significantly increased in ATDC5 cells under hypoxic condition. Constitutively active HIF-1α alone significantly increased the levels of RANKL expression under normoxic conditions, whereas dominant negative HIF-1α reduced hypoxia-induced RANKL expression. HIF-1α increased RANKL promoter reporter activity in a HIF-1α binding element-dependent manner in ATDC5 cells. Hypoxia-induced RANKL levels were much higher in differentiated ATDC5 cells, as compared to proliferating ATDC5 cells. These results suggested that under hypoxic conditions, HIF-1α mediates induction of RANKL expression in chondrocytes; in addition, hypoxia plays a role in osteoclastogenesis during endochondral bone formation, at least in part, through the induction of RANKL expression in hypertrophic chondrocytes.
Anoxia* ; Cartilage ; Cell Line ; Chondrocytes* ; Osteoblasts ; Osteoclasts ; Osteogenesis ; RANK Ligand ; RNA, Messenger ; Up-Regulation

Osteocytes may function as mechanotransducers by regulating local osteoclastogenesis. Reduced availability of oxygen, i.e. hypoxia, could occur during disuse, bone development, and fracture. Receptor activator of nuclear factor-kappaB ligand (RANKL) is an osteoblast/stromal cell derived essential factor for osteoclastogenesis. The hypoxia induced osteoclastogenesis via increased RANKL expression in osteoblasts was demonstrated. Hypoxic regulation of gene expression generally involves activation of the hypoxia-inducible factor (HIF) transcription pathway. In the present study, we investigated whether hypoxia regulates RANKL expression in murine osteocytes and HIF-1alpha mediates hypoxia-induced RANKL expression by transactivating RANKL promoter, to elucidate the role of osteocyte in osteoclastogenesis in the context of hypoxic condition. The expression levels of RANKL mRNA and protein, as well as hypoxia inducible factor-1alpha (HIF-1alpha) protein, were significantly increased in hypoxic condition in MLO-Y4s. Constitutively active HIF-1alpha alone significantly increased the levels of RANKL expression in MLO-Y4s under normoxic conditions, whereas dominant negative HIF-1alpha blocked hypoxia-induced RANKL expression. To further explore to find if HIF-1alpha directly regulates RANKL transcription, a luciferase reporter assay was conducted. Hypoxia significantly increased RANKL promoter activity, whereas mutations of putative HIF-1alpha binding elements in RANKL promoter prevented this hypoxia-induced RANKL promoter activity in MLO-Y4s. These results suggest that HIF-1alpha mediates hypoxia-induced up-regulation of RANKL expression, and that in osteocytes of mechanically unloaded bone, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in osteocytes.
Anoxia* ; Bone Development ; Gene Expression Regulation ; Luciferases ; Osteoblasts ; Osteocytes* ; Oxygen ; RANK Ligand* ; RNA, Messenger ; Up-Regulation

Species that belong to Penicillium section Sclerotiora are commonly found in various terrestrial environments, but only a few have been reported in marine environments. Because the number of Penicillium species reported in marine environments is increasing, we investigated the diversity of Penicillium section Sclerotiora in marine environments in Korea. Based on sequence analyses of β-tubulin and calmodulin loci, 21 strains of section Sclerotiora were identified as P. bilaiae, P. daejeonium, P. exsudans, P. herquei, P. cf. guanacastense, P. mallochii, P. maximae, and P. viticola. Three of them were confirmed as new to Korea: P. exsudans, P. mallochii, and P. maximae. Here, we have provided detailed morphological descriptions of these unrecorded species.
Calmodulin ; Korea ; Penicillium ; Phylogeny ; Sequence Analysis

Some parts of published paper were misprinted.

Tumor necrosis factor alpha (TNFalpha) is a multifunctional cytokine that is elevated in inflammatory diseases such as atherosclerosis, diabetes and rheumatoid arthritis. Recent evidence has suggested that beta2 adrenergic receptor (beta2AR) activation in osteoblasts suppresses osteogenic activity. In the present study, we explored whether TNFalpha modulates betaAR expression in osteoblastic cells and whether this regulation is associated with the inhibition of osteoblast differentiation by TNFalpha. In the experiments, we used C2C12 cells, MC3T3-E1 cells and primary cultured mouse bone marrow stromal cells. Among the three subtypes of betaAR, beta2 and beta3AR were found in our analysis to be upregulated by TNFalpha. Moreover, isoproterenol-induced cAMP production was observed to be significantly enhanced in TNFalpha-primed C2C12 cells, indicating that TNFalpha enhances beta2AR signaling in osteoblasts. TNFalpha was further found in C2C12 cells to suppress bone morphogenetic protein 2-induced alkaline phosphatase (ALP) activity and the expression of osteogenic marker genes including Runx2, ALP and osteocalcin. Propranolol, a beta2AR antagonist, attenuated this TNFalpha suppression of osteogenic differentiation. TNFalpha increased the expression of receptor activator of NF-kappaB ligand (RANKL), an essential osteoclastogenic factor, in C2C12 cells which was again blocked by propranolol. In summary, our data show that TNFalpha increases beta2AR expression in osteoblasts and that a blockade of beta2AR attenuates the suppression of osteogenic differentiation and stimulation of RANKL expression by TNFalpha. These findings imply that a crosstalk between TNFalpha and beta2AR signaling pathways might occur in osteoblasts to modulate their function.
Alkaline Phosphatase ; Animals ; Arthritis, Rheumatoid ; Atherosclerosis ; Bone Morphogenetic Proteins ; Durapatite ; Mesenchymal Stromal Cells ; Mice ; Osteoblasts ; Osteocalcin ; Propranolol ; Receptor Activator of Nuclear Factor-kappa B ; Receptors, Adrenergic ; Tumor Necrosis Factor-alpha