Jeong Joong Kim

Oleanolic acid acetate inhibits osteoclast differentiation by downregulating PLCγ2–Ca2 +-NFATc1 signaling, and suppresses bone loss in mice

Owing to their potential pharmacological activities in human disease, natural plant-derived compounds have recently become the focus of increased research interest. In this study, we first isolated oleanolic acid acetate (OAA), a triterpenoid compound, from Vigna angularis (azuki bean) to discover anti-bone resorptive agents. Many studies have identified and described the various medicinal effects of V. angularis extract. However, the pharmacological effect of OAA-derived V. angularis extract, particularly the effect on osteoclastogenesis, is not known. Therefore, we investigated the effect and mechanism of OAA in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. OAA inhibited RANKL-induced osteoclast differentiation in bone marrow macrophages (BMMs) without any evidence of cytotoxicity. Interestingly, OAA significantly inhibited Btk phosphorylation, phospholipase Cγ2 (PLCγ2) phosphorylation, calcium ion (Ca(2+)) oscillation, and nuclear factor of activated T cell c1 (NFATc1) expression in RANKL-stimulated BMMs, but did not affect RANKL-induced mitogen-activated protein kinase. OAA also inhibited the bone-resorbing activity of mature osteoclasts. Furthermore, mice treated with OAA demonstrated marked attenuation of lipopolysaccharide-induced bone erosion based on micro-computed tomography and histologic analysis of femurs. Taken together, the results suggested that OAA inhibited RANKL-mediated osteoclastogenesis via PLCγ2-Ca(2+)-NFATc1 signaling in vitro and suppressed inflammatory bone loss in vivo.

Glutaredoxin2 isoform b (Glrx2b) promotes RANKL-induced osteoclastogenesis through activation of the p38-MAPK signaling pathway

Receptor activator of NF-κB ligand (RANKL) triggers the differentiation of bone marrow-derived monocyte/macrophage precursor cells (BMMs) of hematopoietic origin into osteoclasts through the activation of mitogen-activated protein (MAP) kinases and transcription factors. Recently, reactive oxygen species (ROS) and antioxidant enzymes were shown to be closely associated with RANKL-mediated osteoclast differentiation. Although glutaredoxin2 (Glrx2) plays a role in cellular redox homeostasis, its role in RANKL-mediated osteoclastogenesis is unclear. We found that Glrx2 isoform b (Glrx2b) expression is induced during RANKLmediated osteoclastogenesis. Over-expression of Glrx2b strongly enhanced RANKL- mediated osteoclastogenesis. In addition, Glrx2b-transduced BMMs enhanced the expression of key transcription factors c-Fos and NFATc1, but pre-treatment with SB203580, a p38-specific inhibitor, completely blocked this enhancement. Conversely, down-regulation of Glrx2b decreased RANKL- mediated osteoclastogenesis and the expression of c-Fos and NFATc1 proteins. Also, Glrx2b down-regulation attenuated the RANKL-induced activation of p38. Taken together, these results suggest that Glrx2b enhances RANKL-induced osteoclastogenesis via p38 activation.

Human chorionic gonadotropin induces nitric oxide synthesis by murine microglia

This study investigated the effects of human chorionic gonadotropin (hCG) on the synthesis of nitric oxide (NO) in murine neonatal microglial cells. When hCG was used in combination with interferon-gamma (IFN-gamma), there was a marked cooperative induction of NO synthesis in a dose-dependent manner. This increase in NO synthesis was reflected as an increased amount of iNOS protein. The increase of NO synthesis by IFN-gamma-plus-hCG was associated with the increase of tumor necrosis factor-alpha (TNF-alpha) secretion and hCG-induced NO production was decreased by the treatment with anti-murine TNF-alpha neutralizing antibody. This study provides evidence that hCG activates expression of iNOS protein in murine microglial cells accompanied by NO accumulation via pathway dependent on L-arginine in the culture medium, and further offers that TNF-alpha acts on the NO synthesis from IFN-gamma-primed murine microglial cells.

Costunolide inhibits osteoclast differentiation by suppressing c-Fos transcriptional activity.

Costunolide, a sesquiterpene lactone, exhibits anti‐inflammatory and anti‐oxidant properties and mediates apoptosis. However, its effects and mechanism of action in osteoclasts remain unknown. Herein, we found that costunolide significantly inhibited RANKL‐induced BMM differentiation into osteoclasts in a dose‐dependent manner without affecting cytotoxicity. Costunolide did not regulate the early signaling pathways of RANKL, including the mitogen‐activated protein kinase and NF‐κB pathways. However, costunolide suppressed nuclear factor of activated T‐cells, cytoplasmic 1 (NFATc1) expression via inhibition of c‐Fos transcriptional activity without affecting RANKL‐induced c‐Fos expression. The inhibitory effects of costunolide were rescued by overexpression of constitutively active (CA)‐NFATc1. Taken together, our results suggest that costunolide inhibited RANKL‐induced osteoclast differentiation by suppressing RANKL‐mediated c‐Fos transcriptional activity. Copyright

Prenatal detection of de novo inversion of chromosome 9 with duplicated heterochromatic region and postnatal follow-up

We report the first de novo case of a heterochromatic duplication on the long arm of the chromosome 9, which then was pericentrically inverted at p11q13. This condition was detected prenatally and carry to term. We then performed the follow up for over 1 year. So far, there seems to be no phenotypical abnormalities.