• Title/Summary/Keyword: Bone homeostasis

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Epigenomic Alteration in Replicative Senescent-mesenchymal Stem Cells (중간엽줄기세포의 노화에 따른 후생유전학적 변화)

  • Oh, Youn Seo;Cho, Goang-Won
    • Journal of Life Science
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    • v.25 no.6
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    • pp.724-731
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    • 2015
  • Mesenchymal stem cells (MSCs) are characterized by their multipotency capacity, which allows them to differentiate into diverse cell types (bone, cartilage, fat, tendon, and neuron-like cells) and secrete a variety of trophic factors (ANG, FGF-2, HGF, IGF-1, PIGF, SDF-1α, TGF-β, and VEGF). MSCs can be easily isolated from human bone-marrow, fat, and umbilical-cord tissues. These features indicate that MSCs might be of use in stem-cell therapy. However, MSCs undergo cellular senescence during long-term expansion, and this is accompanied by functional declines in stem-cell potency. In the human body, because of their senescence and declines in their microenvironmental niches stem cells fail to maintain tissue homeostasis, and as a result, senescent cells accumulate in tissues. This can lead to age-related diseases, including degenerative disorders and cancers. Recent studies suggest that the number of histone modifications to stem cells’ genomes and aberrant alterations to their DNA methylation increase as stem cells progress into senescence. These epigenetic alterations have been partly reversed with treatments in which DNA methyltransferase (DNMT) inhibitors or histone deacetylase (HDAC) inhibitors are introduced into replicative senescent-MSCs. This review focuses on epigenetic alteration in replicative senescent-MSCs and explains how epigenetic modifications are widely associated with stem-cell senescences such as differentiation, proliferation, migration, calcium signaling, and apoptosis.

The estrogen-related receptor γ modulator, GSK5182, inhibits osteoclast differentiation and accelerates osteoclast apoptosis

  • Kim, Hyun-Ju;Yoon, Hye-Jin;Lee, Dong-Kyo;Jin, Xian;Che, Xiangguo;Choi, Je-Yong
    • BMB Reports
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    • v.54 no.5
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    • pp.266-271
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    • 2021
  • Estrogen-related receptor γ (ERRγ), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERRγ has become an attractive target for treating diverse metabolic disorders. We recently reported that ERRγ acts as a negative regulator of osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand (RANKL). In the present study, we explored the effects of an ERRγ-specific modulator, GSK5182, on ERRγ-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERRγ protein levels much as does GSK4716, which is an ERRγ agonist. GSK5182 inhibited osteoclast generation from bone-marrow-derived macrophages without affecting cytotoxicity. GSK5182 also attenuated RANKL-mediated expression of cFos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), pivotal transcription factors for osteoclastogenesis. Arrested osteoclast differentiation was associated with reduced RANK expression, but not with the M-CSF receptor, c-Fms. GSK5182 strongly blocked the phosphorylation of IκBα, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-κB promoter activity in a dose-dependent manner. In addition to osteoclastogenesis, GSK5182 accelerated osteoclast apoptosis by caspase-3 activation. Together, these results suggest that GSK5182, a synthetic ERRγ modulator, may have potential in treating disorders related to bone resorption.

VEGF-RELATED AUTOCRINE GROWTH IN PERIOSTEAL-DERIVED CELLS (골막기원세포에서 발현되는 혈관내피세포성장인자 관련 자가성장)

  • Park, Bong-Wook;Lee, Seong-Gyun;Hah, Young-Sool;Kim, Deok-Ryong;Cho, Yeong-Cheol;Sung, Iel-Yong;Kim, Uk-Kyu;Kim, Jong-Ryoul;Byun, June-Ho
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.35 no.5
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    • pp.294-298
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    • 2009
  • Purpose: The development of a microvascularization is important for the homeostasis of normal bone. Vascular endothelial growth factor (VEGF) is one of the most important factors in vessel formation. The purpose of this study was to examine VEGF-related autocrine growth in periosteal-derived cells. Materials and methods: Periosteal-derived cells were obtained from mandibular periosteums and introduced into the cell culture. After passage 3, the periosteal-derived cells were further cultured for 21 days in an osteogenic inductive culture medium containing dexamethasone, ascorbic acid, and $\beta$-glycerophosphate. Results: The expression of four VEGF isoforms and VEGFRs was observed in periosteal-derived cells. Treatment with cultures with VEGFR-1 and VEGFR-2 Kinase Inhibitor inhibited osteoblastic differentiation and alkaline phosphatase (ALP) activity of periosteal-derived cells. In addition, exogenous VEGF treatment increased calcium content in the periosteal-derived cells. Conclusion: These results suggest that VEGF might act as an autocrine growth molecule during osteoblastic differentiation of cultured human periosteal-derived cells.

Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

  • Atoum, Manar Fayiz;Tchoporyan, Melya Nizar
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.17
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    • pp.7337-7341
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    • 2014
  • Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form $1,25(OH)_2D$ to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study wass to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and Methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by paired t-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancer patients (8.34 ng/ml) compared to the healthy control group (21.02ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT ($8.91{\pm}4.31$) and Tt ($9.15{\pm}5.25$) genotypes compared to control ($21.3{\pm}8.31$) and ($19.3{\pm}7.68$); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.

Association of the A-G Polymorphism in Porcine Adiponectin Gene with Fat Deposition and Carcass Traits

  • Dai, L.H.;Xiong, Y.Z.;Deng, C.Y.;Jiang, S.W.;Zuo, B.;Zheng, R.;Li, F.E.;Lei, M.G.
    • Asian-Australasian Journal of Animal Sciences
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    • v.19 no.6
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    • pp.779-783
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    • 2006
  • The adiponectin gene is known to be involved in the regulation of energy homeostasis involving food intake, carbohydrate and lipid metabolism. Human adiponectin gene polymorphisms have been recently reported to be associated with obesity, insulin sensitivity and the risk of type 2 diabetes. The present study was carried out to investigate the porcine adiponectin gene as a candidate gene for fat deposition and carcass traits. A mutation of A178G of the porcine adiponectin gene that resulted in substitution of the amino acid Isoleucine to Valine was identified. AcyI PCR-RFLP was used to detect the polymorphism of the genotypes in five different pig populations (Large White, Landrace, Duroc, Chinese breeds Meishan and Qingping). The A allele frequency was significantly higher among subjects from Chinsese lard type breeds, while the G allele was the only one present in those from Western lean type breeds. To determine if there was an association of the polymorphism with phenotypic variation, the mutation was tested in 267 pigs of the "Large $White{\times}Meishan$" F2 resource population. The results of association analyses showed significant associations of the genotypes with fat deposition and carcass traits. Allele G was significantly associated with increase in loin eye height, loin eye area and lean meat percentage and bone percentage, and decrease in fat mean percentage, ratio of lean to fat, shoulder fat thickness, 6-7 rib fat thickness, thorax-waist fat thickness and buttock fat thickness. The substitution of A178G (Ile60Val) happened to be located at amino acid 60 in the collagenous domain of porcine adiponectin which might affect the association into higher-order structures, and accordingly affect the posttranslational modifications and optimal biological activity of the multimeric forms. The identified functional polymorphism provides new evidence of adiponectin as an important candidate gene affecting fat deposition and carcass traits in pigs.

Blood Vessel Regeneration using Human Umbilical Cord-derived Endothelial Progenitor Cells in Cyclophosphamide-treated Immune-deficient Mice

  • Kwon, Soon-Keun;Ko, Yu-Jin;Cho, Tae-Jun;Park, Eu-Gene;Kang, Byung-Chul;Lee, Gene;Cho, Jae-Jin
    • International Journal of Oral Biology
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    • v.36 no.3
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    • pp.117-122
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    • 2011
  • Endothelial cells are a vital constituent of most mammalian organs and are required to maintain the integrity of these tissues. These cells also play a major role in angiogenesis, inflammatory reactions, and in the regulation of thrombosis. Angiogenesis facilitates pulp formation and produces the vessels which are essential for the maintenance of tooth homeostasis. These vessels can also be used in bone and tissue regeneration, and in surgical procedures to place implants or to remove cancerous tissue. Furthermore, endothelial cell regeneration is the most critical component of the tooth generation process. The aim of the present study was to stimulate endothelial regeneration at a site of acute cyclophosphamide (CP)-induced endothelial injury by treatment with human umbilical cord-derived endothelial/mesenchymal stem cells (hEPCs). We randomly assigned 16 to 20-week-old female NOD/SCID mice into three separate groups, a hEPC ($1{\times}10^5$ cells) transplanted, 300mg/kg CP treated and saline (control) group. The mice were sacrificed on days 5 and 10 and blood was collected via the abdominal aorta for analysis. The alanine transaminase (ALT), aspartate aminotransferase (AST), serum alkaline phosphatase (s-ALP), and albumin (ALB) levels were then evaluated. Tissue sections from the livers and kidneys were stained with hematoxylin and eosin (HE) for microscopic analysis and were subjected to immunohistochemistry to evaluate any changes in the endothelial layer. CP treatment caused a weight reduction after one day. The kidney/body weight ratio increased in the hEPC treated animals compared with the CP only group at 10 days. Moreover, hEPC treatment resulted in reduced s-ALP, AST, ALT levels compared with the CP only group at 10 days. The CP only animals further showed endothelial injuries at five days which were recovered by hEPC treatment at 10 days. The number of CD31-positive cells was increased by hEPC treatment at both 5 and 10 days. In conclusion, the CP-induced disruption of endothelial cells is recovered by hEPC treatment, indicating that hEPC transplantation has potential benefits in the treatment of endothelial damage.

Expression of UNC-50 DNA in periodontal tissue of rats after application of intermittent orthodontic force (간헐적 교정력 적용 후 백서 치주인대에서 UNC-50 유전자의 발현)

  • Park, Mi-Kyoung;Lim, Sung-Hoon;Kim, Kwang-Won;Park, Joo-Cheol
    • The korean journal of orthodontics
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    • v.36 no.4
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    • pp.242-250
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    • 2006
  • Objective: Periodontal ligament fibroblasts have an ectomesenchymal origin and are thought to play a crucial role for not only homeostasis of periodontal tissues but also bone remodeling, wound healing and regeneration of tissues. Recently, it has been reported that UNC-50 is not expressed in gingival fibroblasts but in PDL fibroblasts. The purpose of this study was to examine the expression of UNC-50 and osteocalcin in the periodontium after application of intermittent force. Methods: Twelve rats had 40 grams of mesially-directed force applied at the upper molar for 1 hour/day. Four rats were sacrificed at 1, 3 and 5 days. Immunohistochemical localization of UNC-50 and osteocalcin antibody was carried out. The results showed apposition of new cellular cementum and a slight increase in periodontal space at the tension side. Results: Strong UNC-50 expression was observed in the differentiating cementoblasts close to PDL fibroblasts in the tension side whereas it was barely expressed at the compression side. Expression was strong at day 3, and decreased at day 5. Osteocalcin immunoreactivity expression was strong in differentiating cementoblasts at the tension side. Conclusion: It can be suggested that UNC-50 is related to the differentiation of cementoblasts, and may be responsible for the molecular event in PDL cells under mechanical stress.

Comparison between the method of the measurement 25 Vitamin D3 (25 Vitamin D3 측정에 있어서 화학발광미세입자 측정법과 화학발광면역 측정법 간의 비교 및 고찰)

  • Kim, dae-won;Lee, jung-hee;Jung, an-na;Seo, so-yoen
    • The Korean Journal of Nuclear Medicine Technology
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    • v.19 no.2
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    • pp.112-114
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    • 2015
  • Purpose Vitamin D to Anti- Rickets both steroid compounds showing activity, By acting on bone tissue secretary and the key to maintain serum Ca homeostasis. The blood level of vitamin D is the largest in D3 that the concentration of the metabolite is reflected in the holding state of vitamin D in vivo. Sunlight to change the 7-dehydrocholesterol in the skin and through the skin to D3, In the liver in combination with the D2 and D3 D4 changes. The Radioimmunoassay(RIA) method is measuring the D 3, the sensitivity can be measured also difficult trace substance to measure the normal test because it is very sensitive, but recently, a check is possible, for the Total D3 in Chemimicroparticle immunoassay(CMIA) or Chemiluminescent immunoassay(CLIA) measuring using microparticle RIA and CMIA(Architect i2000SR) / use the CLIA(DXI-800) method to compare and evaluate the correlation between the tests in the same test items. Materials and Methods Commissioned from January 2014 to March 2015 patients were enrolled in a total of 273 people. 29 out of 273 people conducted by RIA were compared with CMIA, 244 patients were compared with CLIA. Using reagents and equipment were used RIA(Diasource), CMIA(Architect i2000SR, Abbott Diagnostics) / CLIA( Unicel DXi-800, Beckman coulter). Results Correlation of the RIA and CLIA was a R2 = 0.1844 (y = 0.7303x + 3.9005), and the correlation of RIA CMIA is R2 = 0.2762 (y = 0.8862x + 4.56) respectively. (According to statistics, during the same period RIA is Deficiency 4.31%, Insufficiency 90.53%, Sufficiency 5.16%, was Excess 0%, CLIA / CMIA is Deficiency 17.02%, Insufficiency 75.91%, Sufficiency 7.03%, indicating the distribution of 0.03 % Excess) Conclusion Serum vitamin D and parathyroid hormone that show an inverse relationship, the level above which are not parathyroid hormone and vitamin D reduced the increase. The density is different for each study, at most 20 is reported to be the maximum between 30 ng / ml. In Korea it requires a proposed standard of vitamin D deficiency, reference to the WHO lack the case more than 10ng/ml, 20ng/ml and defined by the lack of, if not more than, the IOM, but looking at 12ng/ml or less to the normal to lack, at least 20ng/ml, the reference do not match the deficit under 20ng/ml, 21-29ng/ml relative lack between, was also defined as a sufficient condition for more than 30ng/ml. Although not statistically is between RIA and CLIA two ways to vitamin D levels change according to season match, when seasonally seen in summer as commonly known (April to September), winter (October to March) relative to the increase measured than it was found. Finally, the study on the correlation between the two methods have been expected to result in a consistent and apply the same view high reference value on the graph is difficult. However, there may be differences between the test equipment and methods, and could be especially the case of RIA method using an organic solvent is difficult to compare different methods and correlated view similar trend in vitamin D deficiency and quarterly aspect ratio.

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Analysis of Global Gene Expression Profile of Human Adipose Tissue Derived Mesenchymal Stem Cell Cultured with Cancer Cells (암세포주와 공동 배양된 인간 지방 조직 유래 중간엽 줄기 세포의 유전자 발현 분석)

  • Kim, Jong-Myung;Yu, Ji-Min;Bae, Yong-Chan;Jung, Jin-Sup
    • Journal of Life Science
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    • v.21 no.5
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    • pp.631-646
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    • 2011
  • Mesenchymal stem cells (MSC) are multipotent and can be isolated from diverse human tissues including bone marrow, fat, placenta, dental pulp, synovium, tonsil, and the thymus. They function as regulators of tissue homeostasis. Because of their various advantages such as plasticity, easy isolation and manipulation, chemotaxis to cancer, and immune regulatory function, MSCs have been considered to be a potent cell source for regenerative medicine, cancer treatment and other cell based therapy such as GVHD. However, relating to its supportive feature for surrounding cell and tissue, it has been frequently reported that MSCs accelerate tumor growth by modulating cancer microenvironment through promoting angiogenesis, secreting growth factors, and suppressing anti-tumorigenic immune reaction. Thus, clinical application of MSCs has been limited. To understand the underlying mechanism which modulates MSCs to function as tumor supportive cells, we co-cultured human adipose tissue derived mesenchymal stem cells (ASC) with cancer cell lines H460 and U87MG. Then, expression data of ASCs co-cultured with cancer cells and cultured alone were obtained via microarray. Comparative expression analysis was carried out using DAVID (Database for Annotation, Visualization and Integrated Discovery) and PANTHER (Protein ANalysis THrough Evolutionary Relationships) in divers aspects including biological process, molecular function, cellular component, protein class, disease, tissue expression, and signal pathway. We found that cancer cells alter the expression profile of MSCs to cancer associated fibroblast like cells by modulating its energy metabolism, stemness, cell structure components, and paracrine effect in a variety of levels. These findings will improve the clinical efficacy and safety of MSCs based cell therapy.