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Lncrna GAS5 Overexpression Alleviates the Development Of European Review for Medical and Pharmacological Sciences 2019; 23: 7757-7765 LncRNA GAS5 overexpression alleviates the development of osteoporosis through promoting osteogenic differentiation of MSCs via targeting microRNA-498 to regulate RUNX2 J. FENG1, J.-X. WANG2, C.-H. LI3 1Health Management Centre, Weifang People’s Hospital, Weifang, China 2Department of Orthopedics, Rizhao People’s Hospital, Rizhao, China 3Laboratory Medicine, Ju County Hospital of Traditional Chinese Medicine, Rizhao, China Abstract. – OBJECTIVE: The aim of this Introduction study was to elucidate whether long non-coding RNA (lncRNA) GAS5 could target microRNA-498 Osteoporosis refers to a systemic bone dis- to regulate RUNX2, thus alleviating the develop- ease caused by the decrease in bone mass and ment of osteoporosis. PATIENTS AND METHODS: Human multipo- degradation of bone microstructure. This may tential mesenchymal stem cells (hMSCs) were eventually result in increased bone fragility and isolated from bone marrow of osteoporosis reduced strength1. The main symptoms of oste- patients or healthy controls. Quantitative Re- oporosis include severe pain, multiple fractures, al-time polymerase chain reaction (qRT-PCR) and difficulty breathing caused by thoracic cav- was performed to detect the expression levels 2 of GAS5, microRNA-498 and RUNX2 in hMSCs ity reduction . Osteoporosis patients are prone of osteoporosis patients and controls, respec- to suffer from bone fracture, especially in the tively. Meanwhile, the protein level of RUNX2 in elderly population. Therefore, effective preven- hMSCs was detected by Western blot. Further- tion and treatment of osteoporosis are of great more, alkaline phosphatase (ALP) activity assay significance. Human multi-potential mesenchy- and ALP staining were performed to evaluate mal stem cells (hMSCs) are progenitor cells with the degree of osteogenic differentiation under the control of GAS5, microRNA-498 and RUNX2. multiple differentiation potentials. Previous stud- RESULTS: MicroRNA-498 was highly ex- ies have demonstrated that hMSCs exert a crucial pressed in hMSCs derived from osteoporosis role in the maintenance and repair of various patients, whereas GAS5 and RUNX2 were low- connective tissues, including bone and adipose ly expressed. GAS5 overexpression significant- tissues, cartilages and muscle tissues3. Numerous ly increased ALP activity and promoted osteo- advantages of hMSCs have been found, such genic differentiation of hMSCs derived from os- teoporosis patients. Meanwhile, GAS5 signifi- as easy isolation and cell culture, high accept- cantly promoted osteogenic differentiation by ability and plasticity. Therefore, they have been mediating microRNA-498 expression to up-reg- widely applied in stem cell transplantation for ulate RUNX2. Co-overexpression of GAS5 and various diseases. In this study, hMSCs isolated microRNA-498 could remarkably reverse the in- from osteoporosis patients and healthy controls crease of RUNX2 expression. Besides, RUNX2 overexpression markedly elevated ALP activity. were selected for a series of in vitro experiments. CONCLUSIONS: LncRNA GAS5 is lowly ex- Long non-coding RNA (LncRNA) is a class of pressed in patients with osteoporosis. Overex- ncRNA transcripts transcribed from RNA poly- pression of GAS5 promotes osteogenic differ- merase 2 with about 200-100 000 nt in length. entiation of hMSCs through regulating microR- LncRNA barely has protein-coding function; NA-498 to up-regulate RUNX2 expression, thus however, it is able to interact with small inter- alleviating the development of osteoporosis. fering RNA (siRNA), miRNA and Piwi protein4. Key Words: Current studies5,6 have proved that lncRNAs exert Osteoporosis, LncRNA GAS5, MicroRNA-498, epigenetic, transcriptional and post-transcription- RUNX2. al regulations on gene expressions. Meanwhile, Corresponding Author: Caihua Li, BM; e-mail: [email protected] 7757 J. Feng, J.-X. Wang, C.-H. Li they are involved in various regulatory process- respectively. Meanwhile, their functions in osteo- es, including X chromosome silencing, genomic genic differentiation were further elucidated. Our imprinting, chromatin modification and nuclear results might provide a theoretical basis for the transport. The major functions of lncRNAs can prevention and treatment of osteoporosis. be summarized as follows: (1) interference with downstream gene transcription by inhibition of RNA polymerase 2 recruitment, (2) regulation of Patients and Methods chromatin remodeling and histone modification, (3) interference with mRNA cleavage by forma- Isolation and Culture of hMSCs tion of heterozygous duplexes with sense tran- Bone marrow samples were first collected scripts, (4) production of endogenous interfering from osteoporosis patients (n=30) and healthy RNA by binding and cleaving gene transcripts, controls (n=30), followed by isolation of hMSCs. (5) regulation of protein function and localization Informed consent was obtained from all par- by binding to specific proteins, (6) formation of ticipants prior to bone marrow collection. This small RNA precursors and (7) inhibition of miR- study was approved by the Ethics Committee of NA function as miRNA sponges7. In recent years, Weifang People’s Hospital. Bone marrow samples the functions of lncRNA in regulating MSCs and were placed on 10-mm plates, and cultured in osteoblasts have been identified, greatly affect- 10 mL of low-glucose Dulbecco’s Modified Ea- ing bone metabolism8. LncRNA-GAS5, origi- gle’s Medium (DMEM, Gibco, Rockville, MD, nally isolated from NIH 3T3 cells9, encodes a USA) supplemented with 10% fetal bovine serum lymphoma-associated chromosomal locus (1q25). (FBS, Gibco, Rockville, MD, USA), 100 U/mL Recent studies have confirmed that it exerts an penicillin, 100 μg/mL streptomycin and 0.5 μg/ important regulatory role in tumorigenesis. Cur- mL of fungizone. All cells were maintained in rently, another study has found that GAS5 is an incubator with 5% CO2 at 37°C. To induce os- associated with the occurrence and development teogenic differentiation, osteogenic inducer was of malignant tumors10. GAS5 participates in the applied until 70-80% of cell density. Osteogenic development of bone diseases as well. Song et differentiation was induced by DMEM (Gibco, al11 have shown that lncRNA GAS5 regulates the Gibco, Rockville, MD, USA) containing 10% pathogenesis of osteoarthritis by inhibiting miR- fetal bovine serum (FBS), 10 mmol/L sodium 21 activity. However, the exact role of lncRNA β-glycerophosphate, 50 μg/mL Vitamin C, 1% GAS5 in osteoporosis, as well as the possible HEPES and 1% penicillin/streptomycin. underlying mechanism remains unclear. MicroR- NAs are classified as non-coding, endogenous Cell Transfection and single-stranded RNAs with 19-25 nucleotides hMSCs were transfected with pcDNA-GAS5 in length. MicroRNAs are highly conserved, and (pcDNA as control), si-GAS5 (si-control as con- can bind to target genes by incompletely pairing. trol), microRNA-498 inhibitor (NC as control) It is estimated that microRNAs account for 1% or microRNA-498 mimics (pre-NC as control) of human genome, regulating 30% of human according to the instructions of Lipofectamine gene expressions12. Multiple microRNAs have 2000 (Invitrogen, Carlsbad, CA, USA). 48 h after been found to be involved in the development of transfection, the expressions of relative genes in osteoporosis, osteosarcoma and osteoarthritis13-16. transfected cells were determined by quantitative Differentially expressed microRNAs have been Real-time polymerase chain reaction (qRT-PCR). verified in hMSCs, including miR-204, miR-30a, miR-17-5p, miR-106a, miR-22, miR-705, miR- QRT-PCR 3077-5p, miR-637 and etc. These microRNAs Total RNA in hMSCs was extracted in strict contribute to maintain the balance between ad- accordance with TRIzol reagent (Invitrogen, ipogenic differentiation and osteogenic differ- Carlsbad, CA, USA). RNA integrity was eval- entiation through regulating the expressions of uated by agarose gel electrophoresis, and RNA RUNX2 and osterix17-23. Hence, it is of extremely concentration and purity were assessed by spec- importance to elucidate the potential roles of trophotometry. Subsequently, 1 μg of total RNA microRNAs in osteoporosis. In this study, we was reverse transcribed into cDNA using a Pri- determined the expression levels of GAS5, mi- mescript RT kit (TaKaRa Bio Inc., Otsu, Shiga, croRNA-498, and RUNX2 in hMSCs derived Japan). QRT-PCR was performed according to from osteoporosis patients and healthy controls, the instructions of SYBR premix Ex TaqII kit 7758 LncRNA GAS5 alleviates development of osteoporosis (TaKaRa, Otsu, Shiga, Japan) on an ABI Prism 15 min and stained with 1% alizarin red stain- 7500 HT Sequence Detection System (Applied ing for 5 min. Finally, calcified nodules were Biosystems, Foster City, CA, USA). Specific observed and captured using an inverted micro- qRT-PCR conditions were as follows: pre-de- scope. naturation at 95°C for 10 minutes, followed by 40 cycles of denaturation at 95°C for 30 s, an- Statistical Analysis nealing at 60°C for 20 s, and extension at 50°C. Statistical Product and Service Solutions Glyceraldehyde 3-phosphate dehydrogenase (SPSS) 18.0 (SPSS Inc., Chicago, IL, USA) was (GAPDH) was utilized as an internal reference. used for all statistical analysis. Data were repre- Primer sequences used in this study were as fol- sented as mean ± SD (Standard Deviation). t-test lows: GAS5, F: 5’-CAAGGACTTCCTCCTCT- was used to compare the differences between TAC-3’, R: 5’-CGGTAGCCATGTGTCTTA-
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