• Journal of Oral Medicine and Pain
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• v.40 no.3
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• pp.110-114
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• 2015

Purpose: Growth and differentiation factor (GDF)-11 is a transforming growth factor-${\beta}$ family member that plays important regulatory roles in development of multiple tissues which include axial skeletal patterning, palatal closure, and tooth formation. Proteins that have been identified as GDF-11 inhibitors include GDF-associated serum protein (GASP)-1 and GASP-2. Recently, we found that mice genetically engineered to lack both Gasp1 and Gdf11 have an increased frequency of cleft palate. The goal of this study was to investigate the roles of GDF-11 and its inhibitors, GASP-1 and GASP-2, during dental and craniofacial development and growth. Methods: Mouse genetic studies were used in this study. Homozygous knockout mice for Gasp1 ($Gasp1^{-/-}$) and Gasp2 ($Gasp2^{-/-}$) were viable and fertile, but Gdf11 homozygous knockout ($Gdf11^{-/-}$) mice died within 24 hours after birth. The effect of either Gasp1 or Gasp2 deletion in $Gdf11^{-/-}$ mice during embryogenesis was evaluated in $Gasp1^{-/-}$;$Gdf11^{-/-}$ and $Gasp2^{-/-}$;$Gdf11^{-/-}$ mouse embryos at 18.5 days post-coitum (E18.5). For the analysis of adult tissues, we used $Gasp1^{-/-}$;$Gdf11^{+/-}$ and $Gasp2^{-/-}$;$Gdf11^{+/-}$ mice to evaluate the potential haploinsufficiency of Gdf11 in $Gasp1^{-/-}$ and $Gasp2^{-/-}$ mice. Results: Although Gasp2 expression decreased after E10.5, Gasp1 expression was readily detected in various ectodermal tissues at E17.5, including hair follicles, epithelium in nasal cavity, retina, and developing tooth buds. Interestingly, $Gasp1^{-/-}$;$Gdf11^{-/-}$ mice had abnormal formation of lower incisors: tooth buds for lower incisors were under-developed or missing. Although $Gdf11^{+/-}$ mice were viable and had mild transformations of the axial skeleton, no specific defects in the craniofacial development have been observed in $Gdf11^{+/-}$ mice. However, loss of Gasp1 in $Gdf11^{+/-}$ mice occasionally resulted in small and abnormally shaped auricles. Conclusions: These findings suggest that both GASP-1 and GDF-11 play important roles in dental and craniofacial development both during embryogenesis and in adult tissues.

• Journal of Oral Medicine and Pain
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• v.45 no.4
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• pp.83-88
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• 2020

Purpose: Growth differentiation factor 11 (GDF11) and myostatin (MSTN) are closely-related transforming growth factor β family members reported to play crucial roles in bone formation. We previously reported that, in contrast to MSTN, GDF11 promotes osteogenesis of vertebrae and limbs. GDF11 has been also reported as an important regulator in tooth development by inducing differentiation of pulp stem cells into odontoblasts for reparative dentin formation. The goal of this study was to investigate the differential roles of GDF11 and MSTN in dental and cranial bone formation. Methods: Micro-computed tomography analysis was performed on cranial bones, including frontal, parietal, and interparietal bones, and lower incisors of wild-type, Gdf11 knockout (Gdf11-/-), and Mstn knockout (Mstn-/-) mice. Tissue volume, thickness, and mineral density were evaluated for both cranial bone and lower incisors. Lower incisor lengths were also measured. Because Gdf11-/- mice die shortly after birth, analysis was performed on newborn (P0) mice. Results: Compared to those of Mstn-/- mice, cranial bone volume, thickness, and mineral density levels were all significantly diminished in Gdf11-/- mice. Tissue mineral density of Gdf11-/- mice were also significantly decreased compared to wild-type mice. Likewise, lower incisor length, tissue volume, thickness, and mineral density levels were all significantly reduced in Gdf11-/- mice compared to Mstn-/- mice. Incisor length was also significantly decreased in Gdf11-/- mice compared to wild-type mice. Mstn-/- mice exhibited mildly increased levels of tissue volume, thickness, and density in cranial bone and lower incisor compared to wild-type mice although statistically not significant. Conclusions: Our findings suggest that GDF11, unlike MSTN, endogenously promotes cranial bone and tooth development.

• BMB Reports
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• v.53 no.4
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• pp.206-211
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• 2020

Vascular smooth muscle cells (VSMCs) are a unique cell type that has unusual plasticity controlled by environmental stimuli. As an abnormal increase of VSMC proliferation is associated with various vascular diseases, tight regulation of VSMC phenotypes is essential for maintaining vascular homeostasis. Hypoxia is one environmental stress that stimulates VSMC proliferation. Emerging evidence has indicated that microRNAs (miRNAs) are critical regulators in the hypoxic responses of VSMCs. Therefore, we previously investigated miRNAs modulated by hypoxia in VSMCs and found that miR-1260b is one of the most upregulated miRNAs under hypoxia. However, the mechanism that underlies the regulation of VSMCs via miR-1260b in response to hypoxia has not been explored. Here we demonstrated that hypoxia-induced miR-1260b promotes VSMC proliferation. We also identified growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, as a novel target of miR-1260b. miR-1260b directly targets the 3'UTR of GDF11. Downregulation of GDF11 inhibited Smad signaling and consequently enhanced the proliferation of VSMCs. Our findings suggest that miR-1260b-mediated GDF11-Smad-dependent signaling is an essential regulatory mechanism in the proliferation of VSMCs, and this axis is modulated by hypoxia to promote abnormal VSMC proliferation. Therefore, our study unveils a novel function of miR-1260b in the pathological proliferation of VSMCs under hypoxia.

• Journal of Genetic Medicine
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• v.11 no.1
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• pp.27-30
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• 2014

Brachydactyly type C is a limb malformation characterized by shortening of the second, third, and fifth middle and/or proximal phalanges, but it has variable phenotypic expressivity. Mutations in the growth differentiation factor-5 (GDF5) gene cause isolated brachydactyly C. Herein, we report a familial case with isolated brachydactyly type C characterized by brachymesophalangy of both second and third digits, with a GDF5 missense mutation, and discuss the phenotypic variability of the condition. Identifying more cases with genetic confirmation will help elucidate the clinical and genetic characteristics of this condition in the Korean population.

• Clinical and Experimental Reproductive Medicine
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• v.38 no.4
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• pp.210-215
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• 2011

Objective: This study was performed to identify whether growth and differentiation factor-9 (GDF-9) and transforming growth factor-${\beta}1$ (TGF-${\beta}1$) expressions would be lower in the follicular fluid (FF) of those over age 35 who underwent IVF than under age 35. Methods: A total of 24 IVF cycles (20 patients) were included in this study. All of patients were stimulated for IVF by the GnRH short protocol and divided into two groups for analysis, according to their age: <35 group (14 cycles, 11 patients) vs. ${\geq}35$ group (10 cycles, 9 patients). The expression levels of GDF-9 and TGF-${\beta}1$ were determined by western blotting and quantitative enzyme-linked immunosorbent assay. Results: The numbers of retrieved oocytes and metaphase II oocytes were significantly lower in the ${\geq}35$ group. Lower expression of GDF-9 and TGF-${\beta}1$ by western blotting in the ${\geq}35$ group were observed as well. The mean GDF-9 and TGF-${\beta}1$ levels by enzyme-linked immunosorbent assay were lower in the ${\geq}35$ group. The values were $6,850.5{\pm}928.4$ ng/L vs. $3,333.3{\pm}1,089.2$ ng/L of GDF-9 ($p$ <0.05) and $3,844.1{\pm}571.1$ ng/L vs. $2,187.7{\pm}754.0$ ng/L of TGF-${\beta}1$ ($p$ <0.05). A negative correlation between GDF-9 and age was observed (r=-0.546, $p$=0.006). Conclusion: GDF-9 and TGF-${\beta}1$ production from stimulated ovaries during IVF appears to decrease with age.

• Tuberculosis and Respiratory Diseases
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• v.77 no.6
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• pp.243-250
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• 2014

Background: Information regarding prognostic value of growth differentiation factor 15 (GDF-15) and heart-type fatty acid-binding protein (H-FABP) in patients with chronic obstructive pulmonary disease (COPD) exacerbation is limited. The aim of this study was to investigate whether serum levels of GDF-15 and H-FABP predict an adverse outcome for COPD exacerbation. Methods: Clinical variables, including serum GDF-15 and H-FABP levels were compared in prospectively enrolled patients with COPD exacerbation that did or did not experience an adverse outcome. An adverse outcome included 30-day mortality and need for endotracheal intubation or inotropic support. Results: Ninety-seven patients were included and allocated into an adverse outcome (n=10) or a control (n=87) group. Frequencies of mental change and $PaCO_2$>37 mm Hg were significantly higher in the adverse outcome group (mental change: 30% vs. 6%, p=0.034 and $PaCO_2$>37 mm Hg: 80% vs. 22%, p<0.001, respectively). Serum GDF-15 elevation (>1,600 pg/mL) was more common in the adverse outcome group (80% vs. 43%, p=0.041). However, serum H-FABP level and frequency of serum H-FABP elevation (>755 pg/mL) did not differ between the two groups. Multivariate analysis showed that an elevated serum GDF-15 and $PaCO_2$>37 mm Hg were significant predictors of an adverse outcome (odds ratio [OR], 25.8; 95% confidence interval [CI], 2.7-243.8; p=0.005 and OR, 11.8; 95% CI, 1.2-115.3; p=0.034, respectively). Conclusion: Elevated serum GDF-15 level and $PaCO_2$>37 mm Hg were found to predict an adverse outcome independently in patients with COPD exacerbation, suggesting the possibility that serum GDF-15 could be used as a prognostic biomarker of COPD exacerbation.

• Journal of Life Science
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• v.27 no.12
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• pp.1515-1522
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• 2017

Most people have a desire to live longer. According to ancient Chinese and Korean mythology, Dongfang Shuo (Dongbang Sahk) lived for 18,000 years. According to a WHO report, the average longevity of humans has extended from 50-odd years in the 1960s to 75-85 years in 2016. Parabiosis, the joining to circulatory systems of two animals, was described as early as the 1860s. It provides a powerful experimental model to investigate the effects of one animal on its partner animal in vivo. Research on reverse aging is an immensely popular in parabiosis studies. In this review, the origin of the parabiosis model and important historical findings based on parabiosis models are presented. Surprising and debated discoveries in aging research are also introduced. Using heterochronic parabiosis of connecting circulatory systems of a young mouse and old mouse, various groups claim to have identified a reverse aging factor, growth differentiation factor 11 (GDF11), which was significantly reduced in blood of old mice. Although the potential existence of any one factor or factors that could reverse aging remains to be confirmed, studies have shown that the parabiosis model is powerful enough to detect reverse aging factors.

• Asian-Australasian Journal of Animal Sciences
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• v.26 no.11
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• pp.1545-1552
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• 2013

This study was conducted to investigate the effects of Trichostatin A (TSA) on cumulus expansion during mouse oocyte maturation. TSA treatment inhibited cumulus expansion and significantly reduced the cumulus expansion index (CEI) (p<0.05). To determine the underlying mechanism, the expression levels of several key factors that play crucial roles in cumulus expansion including components of extracellular matrix (ECM) (Has2, Ptgs2, Ptx3, and Tnfaip6) and Growth differentiation factor 9 (GDF9) were measured in control and TSA treated samples by real-time PCR. The effect of TSA on ERK phosphorylation (p-ERK1/2) in cumulus cells and GDF9 protein level in fully grown oocytes (FGOs) were detected by Western blotting. The expression levels of the ECM genes were significantly decreased (p<0.05) by TSA treatment while GDF9 expression did not response to TSA (p>0.05). TSA treatment blocked the activation of ERK1/2 (p<0.05) and had no significant effect on GDF9 protein expression (p>0.05). Collectively, these results suggested that TSA treatment altered ECM gene expression and blocked ERK1/2 activation to inhibit cumulus expansion in the mouse.

• Fisheries and Aquatic Sciences
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• v.12 no.3
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• pp.185-193
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• 2009

A complete cDNA, which encodes for a myostatin-like protein (Es-MSTN), was isolated from the Chinese mitten crab, Eriocheir sinensis. Es-MSTN was composed of 2,397 nucleotides and the open reading frame (ORF) specified a protein containing 468 amino acids. Es-MSTN exhibited 32% amino acid sequence identity and 52% similarity to human myostatin. Multiple sequence alignment analysis indicated that Es-MSTN possessed the conserved proteolytic cleavage site (RXXR) for maturation of the protein and nine cysteine residues for disulfide bridges. Besides the conserved structural features, Es-MSTN also exhibits its unique characters; a longer N-terminal domain which is involved in protein folding and latent form of myostatin and absence of the cleavage site for BMP-1/tolloid family of metalloproteinase to activate mature myostatin. Phylogenetic analysis suggests that Es-MSTN showed the closely related to both vertebrate myostatin and GDF11. Es-MSTN is expressed highly in the claw muscle, leg muscle, thoracic muscle and heart, and moderately in the hindgut suggesting that Es-MSTN may play important roles in the muscle tissues. As homolog of mammalian myostatin and GDF11, Es-MSTN may be involved in development of muscular tissue and further study will help to produce high-quality seafood.

• Fisheries and Aquatic Sciences
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• v.10 no.1
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• pp.16-23
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• 2007

Myostatin (GDF8) is a growth factor that limits muscle tissue growth and development in vertebrates. We isolated a myostatin-like gene (Py-MSTN) from the marine invertebrate, the scallop Patinopecten yessoensis. Py-MSTN was highly expressed in the adductor muscle and in the gill unexpectedly. Amino acid analysis showed that Py-MSTN has 49% amino acid sequence identity and 64% similarity to human myostatin (Hs-MSTN), and 42% identity and 61% similarity to myoglianin, the only invertebrate homolog. These results indicated that Py-MSTN may be functionally similar to the vertebrate MSTN than the invertebrate homolog. Phylogenetic analysis suggested that Py-MSTN is an ancestral form of vertebrate MSTN and GDF11 and does not belong to other $TGF-{\beta}$ family members. Molecular modeling showed that Py-MSTN exhibits a similar tertiary structure to mammalian BMP7, a member of $TGF-{\beta}$ family. In addition, the amino acid residues which contact extracellular domain of the receptor were relavively conserved. Given these results, we propose that Py-MSTN is a functionally active member of the $TGF-{\beta}$ family and is involved In muscle growth and regulation.