bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-219a-5p Regulates Rorβ During Osteoblast Differentiation and in Age-related Bone Loss
Authors: Aquino-Martinez Ruben , Farr Joshua N , Weivoda Megan M , Negley Brittany A , Onken Jennifer L , Thicke Brianne S , Fulcer McKenzie M , Fraser Daniel G , van Wijnen Andre J , Khosla Sundeep , Monroe David G 
Published: October 2018

ABSTRACT

Developing novel approaches to treat skeletal disorders requires an understanding of how critical molecular factors regulate osteoblast differentiation and bone remodeling. We have reported that (1) retinoic acid receptor-related orphan receptor beta (Rorβ) is upregulated in bone samples isolated from aged mice and humans in vivo; (2) Rorβ expression is inhibited during osteoblastic differentiation in vitro; and (3) genetic deletion of Rorβ in mice results in preservation of bone mass during aging. These data establish that Rorβ inhibits osteogenesis and that strict control of Rorβ expression is essential for bone homeostasis. Because microRNAs (miRNAs) are known to play important roles in the regulation of gene expression in bone, we explored whether a predicted subset of nine miRNAs regulates Rorβ expression during both osteoblast differentiation and aging. Mouse osteoblastic cells were differentiated in vitro and assayed for Rorβ and miRNA expression. As Rorβ levels declined with differentiation, the expression of many of these miRNAs, including miR-219a-5p, was increased. We further demonstrated that miR-219a-5p was decreased in bone samples from old (24-month) mice, as compared with young (6-month) mice, concomitant with increased Rorβ expression. Importantly, we also found that miR-219a-5p expression was decreased in aged human bone biopsies compared with young controls, demonstrating that this phenomenon also occurs in aging bone in humans. Inhibition of miR-219a-5p in mouse calvarial osteoblasts led to increased Rorβ expression and decreased alkaline phosphatase expression and activity, whereas a miR-219a-5p mimic decreased Rorβ expression and increased osteogenic activity. Finally, we demonstrated that miR-219a-5p physically interacts with Rorβ mRNA in osteoblasts, defining Rorβ as a true molecular target of miR-219a-5p. Overall, our findings demonstrate that miR-219a-5p is involved in the regulation of Rorβ in both mouse and human bone. © 2018 American Society for Bone and Mineral Research.
A Novel Rhein Derivative Modulates Bone Formation and Resorption and Ameliorates Estrogen-Dependent Bone Loss
Authors: Jiang Min , Wang Tianqi , Yan Xueming , Liu Zhuochao , Yan Yufei , Yang Kai , Qi Jin , Zhou Hanbing , Qian Niandong , Zhou Qi , Chen Bo , Xu Xing , Xi Xiaobing , Yang Chunhao , Deng Lianfu 
Published: October 2018

ABSTRACT

Osteoporosis, an osteolytic disease that affects millions of people worldwide, features a bone remodeling imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Identifying dual target-directed agents that inhibit excessive bone resorption and increase bone formation is considered an efficient strategy for developing new osteoporosis treatments. Rhein, a natural anthraquinone, can be isolated from various Asian herbal medicines. Rhein and its derivatives have been reported to have various beneficial pharmacological effects, especially their bone-targeting ability and anti-osteoclastogenesis activity. Moreover, hydrogen sulfide (H2S) was reported to prevent ovariectomy- (OVX-) induced bone loss by enhancing bone formation, and sulfur replacement therapy has been considered a novel and plausible therapeutic option. Based on this information, we synthesized a rhein-derived thioamide (RT) and investigated its effects on bone resorption and bone formation in vitro and in vivo. It has been found that the RT-inhibited receptor activator of the nuclear factor-κB (NF-κB) ligand- (RANKL-) induced osteoclastogenesis and bone resorption in a dose-dependent manner. The expression of osteoclast marker genes was also suppressed by RT treatment. Furthermore, exploration of signal transduction pathways indicated that RT markedly blocked RANKL-induced osteoclastogenesis by attenuating MAPK pathways. However, RT treatment in an osteoblastic cell line, MC3TE-E1, indicated that RT led to an increase in the deposition of minerals and the expression of osteoblast marker genes, as demonstrated by Alizarin Red staining and alkaline phosphatase activity. Importantly, an OVX mouse model showed that RT could attenuate the bone loss in estrogen deficiency-induced osteoporosis in vivo with a smart H2S-releasing property and that there was a considerable improvement in the biomechanical properties of bone. Accordingly, our current work highlights the dual regulation of bone remodeling by the rhein-derived molecule RT. This may be a highly promising approach for a new type of anti-osteoporosis agent. © 2018 American Society for Bone and Mineral Research.
Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies
Authors: Baird Denis A , Evans Daniel S , Kamanu Frederick K , Gregory Jennifer S , Saunders Fiona R , Giuraniuc Claudiu V , Barr Rebecca J , Aspden Richard M , Jenkins Deborah , Kiel Douglas P , Orwoll Eric S , Cummings Steven R , Lane Nancy E , Mullin Benjamin H , Williams Frances MK , Richards J Brent , Wilson Scott G , Spector Tim D , Faber Benjamin G , Lawlor Deborah A , Grundberg Elin , Ohlsson Claes , Pettersson-Kymmer Ulrika , Capellini Terence D , Richard Daniel , Beck Thomas J , Evans David M , Paternoster Lavinia , Karasik David , Tobias Jonathan H 
Published: October 2018

ABSTRACT

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p &lt; 5 × 10−9, adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 &gt; 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
Preventing and Repairing Myeloma Bone Disease by Combining Conventional Antiresorptive Treatment With a Bone Anabolic Agent in Murine Models
Authors: Paton-Hough Julia , Tazzyman Simon , Evans Holly , Lath Darren , Down Jenny M , Green Alanna C , Snowden John A , Chantry Andrew D , Lawson Michelle A 
Published: October 2018

ABSTRACT

Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current antiresorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard of care antiresorptive zoledronic acid (Zol) with a bone anabolic (anti-TGFβ/1D11) would be more effective at treating myeloma-induced bone disease than Zol therapy alone. JJN3 myeloma-bearing mice (n = 8/group) treated with combined Zol and 1D11 resulted in a 48% increase (p ≤ 0.001) in trabecular bone volume (BV/TV) compared with Zol alone and a 65% increase (p ≤ 0.0001) compared with 1D11 alone. Our most significant finding was the substantial repair of U266-induced osteolytic bone lesions with combination therapy (n = 8/group), which resulted in a significant reduction in lesion area compared with vehicle (p ≤ 0.01) or Zol alone (p ≤ 0.01). These results demonstrate that combined antiresorptive and bone anabolic therapy is significantly more effective at preventing myeloma-induced bone disease than Zol alone. Furthermore, we demonstrate that combined therapy is able to repair established myelomatous bone lesions. This is a highly translational strategy that could significantly improve bone outcomes and quality of life for patients with myeloma. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Silencing of FOXO6 inhibits the proliferation, invasion, and glycolysis in colorectal cancer cells
Authors: Li Quanying , Tang Hongna , Hu Fangfang , Qin Changjiang 
Published: October 2018

AbstractForkhead box class O6 (FOXO6) is an important member of FOXO family, which has been demonstrated to be implicated in tumor development. However, the role of FOXO6 in colorectal cancer (CRC) is still unclear. The study aimed to investigate the potential roles of FOXO6 in the development of CRC. Our results showed that FOXO6 was overexpressed in CRC tissues and cell lines. FOXO6 knockdown inhibited cell proliferation, as well as repressed the migration and invasion of CRC cells. Additionally, we found that FOXO6 knockdown altered cellular metabolism by inhibiting glycolysis and promoting mitochondrial respiration. Furthermore, FOXO6 knockdown inhibited the activation of PI3K/Akt/mTOR pathway in CRC cells. The results herein indicated that FOXO6 knockdown inhibited cell proliferation, migration, invasion, and glycolysis in CRC cells. PI3K/Akt/mTOR pathway was involved in the effects of FOXO6 on CRC cells. These findings suggested that FOXO6 might be a potential target for the CRC therapy.
Protein translation associated to PERK arm is a new target for regulation of metainflammation: A connection with hepatocyte cholesterol
Authors: Galindo‐Hernández Octavio , Córdova‐Guerrero Iván , Díaz‐Rubio Laura Janeth , Pulido‐Capiz Ángel , Díaz‐Villanueva José Fernando , Castañeda‐Sánchez César Yahel , Serafín‐Higuera Nicolás , García‐González Víctor 
Published: October 2018

AbstractEndoplasmic reticulum stress is a cellular phenomenon that has been associated with metabolic disorders, contributing to the development of obesity, fatty liver disease, and dyslipidemias. Under metabolic overload conditions, in cells with a high protein‐secretory activity, such as hepatocytes and Langerhans β cells, the unfolded protein response (UPR) is critical in to maintain protein homeostasis (proteostasis). UPR integrated by a tripartite signaling system, through activating transcription factor 6, protein kinase R‐like endoplasmic reticulum kinase (PERK), and inositol‐requiring enzyme 1, regulates gene transcription and translation to resolve stress and conserve proteostasis. In the current study, we demonstrated in hepatocytes under metabolic overload by saturated palmitic and stearic fatty acids, through activation of PERK signaling and CCAAT‐enhancer‐binding protein homologous protein (CHOP) transcription factor, an association with the expression of cyclooxygenase 2. More important, isolated exosomes from supernatants of macrophages exposed to lipopolysaccharides can also induce a metainflammation phenomenon, and when treated on hepatocytes, induced a rearrangement in cholesterol metabolism through sterol regulatory element‐binding protein 2 (SREBP2), low‐density lipoprotein receptor (LDLR), apolipoprotein A‐I, and ABCA1. Moreover, we demonstrate the cellular effect of terpene‐derived molecules, such as cryptotanshinone, isolated of plant Salvia brandegeei, regulating metainflammatory conditions through PERK pathway in both hepatocytes and β cells. Our data suggest the presence of a modulatory mechanism on specific protein translation process. This effect could be mediated by eukaryotic initiation factor‐4A, evaluating salubrinal as a control molecule. Likewise, the protective mechanisms of unsaturated fatty acids, such as oleic and palmitoleic acid were confirmed. Therefore, modulation of metainflammation suggests a new target through PERK signaling in cells with a high secretory activity, and possibly the regulation of cholesterol in hepatocytes is promoted via exosomes.
Starvation‐induced autophagy promotes the invasion and migration of human bladder cancer cells via TGF‐β1/Smad3‐mediated epithelial‐mesenchymal transition activation
Authors: Tong Hang , Yin Hubin , Hossain Mohammad Arman , Wang Yiyang , Wu Feixiang , Dong Xiaoyong , Gao Shun , Zhan Kai , He Weiyang 
Published: October 2018

AbstractThe biological characteristics of bladder cancer include enhanced invasion and migration, which are the main causes of death in patients. Starvation is a typical feature of the bladder cancer microenvironment and can induce autophagy. Autophagy has an important relationship with the invasion and migration of tumors. However, the role of autophagy in the invasion and migration of bladder cancer cells remains unclear. Hence, the aim of the current study was to clarify this role and underlying mechanism. In this study, we found that starvation enhanced the epithelial‐mesenchymal transition (EMT)‐mediated invasion and migration of T24 and 5637 cells while inducing autophagy. The inhibition of autophagy with chloroquine (CQ) or 3‐methyladenine (3MA) decreased EMT‐mediated invasion and migration. In addition, the expression of transforming growth factor 1 (TGF‐β1) and phosphorylated Smad3 (p‐Smad3) increased after starvation. The inhibition of autophagy with CQ or 3MA also decreased the expression of TGF‐β1 and p‐Smad3. The inhibitor of TGF‐β receptor sb431542 also inhibited the invasion, migration, and EMT of T24 and 5637 cells during starvation. Furthermore, recombinant TGF‐β1 induced autophagy and inhibition of the TGF‐β/Smad signaling pathway with sb431542 suppressed autophagy. In summary, our results suggested that autophagy promotes the invasion and migration of bladder cancer cells by inducing EMT through the TGF‐β1/Smad3 signaling pathway. Moreover, autophagy and TGF‐β1 can form a positive feedback loop to synergistically promote invasion and migration. Thus, our findings may provide a theoretical basis for the prevention of invasion and migration in bladder cancer.
Status of topoisomerase‐2β protein in all‐trans retinoic acid–treated human neuroblastoma (SK‐N‐SH) cells
Authors: Bhanothu Venkanna , Kondapi Anand Kumar 
Published: October 2018

AbstractOf the mammalian topoisomerase (Topo)‐2 isozymes (α and β), Topo‐2β protein has been reported to regulate neuronal development and differentiation. However, the status of Topo‐2β in all‐trans retinoic acid (ATRA)‐treated human neuroblastoma (SK‐N‐SH) cells is not understood. More information about the effects of ATRA on SK‐N‐SH cells is needed to reveal the role of ATRA in the regulation of Topo‐2β levels and spontaneous regression of SK‐N‐SH cells to predict the clinical activity. This study was proposed to investigate the status and role of Topo‐2β protein in ATRA‐induced survival and neuronal differentiation of SK‐N‐SH cells. Microscopic, sodium dodecyl sulfate polyacrylamide gel electrophoresis after immunoprecipitations and Western blot analysis were used to study and compare Topo‐2β protein among 10 µM ATRA‐treated SK‐N‐SH cells and controls at different time points. The level of Topo‐2β protein increased in the initial days of treatment but markedly decreased upon induction of differentiation by ATRA in later stages. Upon ATRA treatment, SK‐N‐SH cells stretched, exhibited neurite extensions, and acquired a neuronal phenotype. Both treated and untreated SK‐N‐SH cells were able to migrate, occupy the scratched area, and completely recolonized 24 hours later. These results suggest an indirect role of Topo‐2β protein in regulation of genes involved in cell migration and differentiation of ATRA‐treated SK‐N‐SH cells. This study suggests that Topo‐2β may be part of activation/repression of protein complexes activated by epigenetic modifying agents, differentiating signals, and inducible locus. However, detailed studies are needed to explore the ATRA‐downstream genes leading to Topo‐2β regulation and regulatory proteins of neuronal differentiation.
MicroRNA‐129‐1‐3p regulates cyclic stretch–induced endothelial progenitor cell differentiation by targeting Runx2
Authors: Li Na , Wang Wen‐Bin , Bao Han , Shi Qian , Jiang Zong‐Lai , Qi Ying‐Xin , Han Yue 
Published: October 2018

AbstractEndothelial progenitor cells (EPCs) are vital to the recovery of endothelial function and maintenance of vascular homeostasis. EPCs mobilize to sites of vessel injury and differentiate into mature endothelial cells (ECs). Locally mobilized EPCs are exposed to cyclic stretch caused by blood flow, which is important for EPC differentiation. MicroRNAs (miRNAs) have emerged as key regulators of several cellular processes. However, the role of miRNAs in cyclic stretch–induced EPC differentiation remains unclear. Here, we investigate the effects of microRNA‐129‐1‐3p (miR‐129‐1‐3p) and its novel target Runt‐related transcription factor 2 (Runx2) on EPC differentiation induced by cyclic stretch. Bone marrow‐derived EPCs were exposed to cyclic stretch with a magnitude of 5% (which mimics physiological mechanical stress) at a constant frequency of 1.25 Hz for 24 hours. The results from a miRNA array revealed that cyclic stretch significantly decreased miR‐129‐1‐3p expression. Furthermore, we found that downregulation of miR‐129‐1‐3p during cyclic stretch–induced EPC differentiation toward ECs. Meanwhile, expression of Runx2, a putative target gene of miR‐129‐1‐3p, was increased as a result of cyclic stretch. A 3′UTR reporter assay validated Runx2 as a direct target of miR‐129‐1‐3p. Furthermore, small interfering RNA (siRNA)‐mediated knockdown of Runx2 inhibited EPC differentiation into ECs and attenuated EPC tube formation via modulation of vascular endothelial growth factor (VEGF) secretion from EPCs in vitro. Our findings demonstrated that cyclic stretch suppresses miR‐129‐1‐3p expression, which in turn activates Runx2 and VEGF to promote endothelial differentiation of EPCs and angiogenesis. Therefore, targeting miR‐129‐1‐3p and Runx2 may be a potential therapeutic strategy for treating vessel injury.
Cell‐free microRNA‐148a is associated with renal allograft dysfunction: Implication for biomarker discovery
Authors: Nariman‐Saleh‐Fam Ziba , Bastami Milad , Ardalan Mohammadreza , Sharifi Simin , Hosseinian Khatib Seyed Mahdi , Zununi Vahed Sepideh 
Published: October 2018

AbstractBackgroundChronic allograft dysfunction (CAD), the foremost cause of renal graft loss worldwide, is a serious challenge for most of the recipients. As the epigenetic era is emerging, epigenetic biomarkers especially microRNAs (miRNAs) may reflect the current stage of the disease and patient’s therapy response. The current study investigated the potential significance of circulating miRNA‐148a in predicting the renal graft function.Design and MethodsCirculating miRNAs were isolated from 53 plasma samples of recipients with histologically validated interstitial fibrosis and tubular atrophy (IFTA, n = 26), and recipients with stable graft function (SGF,
n = 27), and also healthy individuals (
n = 15). The level of miRNA‐148a was evaluated by the quantitative polymerase chain reaction (qPCR) and correlated with clinical and histological parameters.ResultsSignificantly, miRNA‐148a decreased in IFTA compared with SGF subjects (P < 0.001). MiRNA‐148a levels indicated a significant association with serum creatinine levels (
r = 0.451,
P = 0.021) and glomerular filtration rate (
r = −0.520,
P = 0.006). MiRNA‐148a expression levels could discriminate IFTA cases from SGF individuals with an area under the curve of 0.89 (
P < 0.001), 97% sensitivity, and 72% specificity. A number of predicted targets that might be involved in CAD by miRNA‐148a were predicted.ConclusionPlasma cell‐free miRNA‐148a correlated with renal function and histological grades; therefore, it may be further investigated as a novel noninvasive molecular marker of the progression to IFTA in renal transplant recipients; moreover, the emerging biomarker may become a therapeutic target in the future clinic.
Effects of phospholipase D during cultured osteoblast mineralization and bone formation
Authors: Abdallah Dina , Skafi Najwa , Hamade Eva , Borel Mathieu , Reibel Sophie , Vitale Nicolas , El Jamal Alaeddine , Bougault Carole , Laroche Norbert , Vico Laurence , Badran Bassam , Hussein Nader , Magne David , Buchet Rene , Brizuela Leyre , Mebarek Saida 
Published: October 2018

AbstractMammalian phospholipase D (PLD) mostly hydrolyzes phosphatidylcholine producing phosphatidic acid. PLD activity was previously detected in different osteoblastic cell models, and was increased by several growth factors involved in bone homeostasis. To confirm possible actions of PLD isoforms during mineralization process, we analyzed their effects in osteoblastic cell models and during bone formation. PLD1 expression, along with PLD activity, increased during differentiation of primary osteoblasts and Saos‐2 cells, and peaked at the onset of mineralization. Subsequently, both PLD1 expression and PLD activity decreased, suggesting that PLD1 function is regulated during osteoblast maturation. In contrast, PLD2 expression was not significantly affected during differentiation of osteoblasts. Overexpression of PLD1 in Saos‐2 cells improved their mineralization potential. PLD inhibitor Halopemide or PLD1‐selective inhibitor, led to a decrease in mineralization in both cell types. On the contrary, the selective inhibitor of PLD2, did not affect the mineralization process. Moreover, primary osteoblasts isolated from PLD1 knockout (KO) mice were significantly less efficient in mineralization as compared with those isolated from wild type (WT) or PLD2 KO mice. In contrast, bone formation, as monitored by high‐resolution microcomputed tomography analysis, was not impaired in PLD1 KO nor in PLD2 KO mice, indicating that the lack of PLD1 or that of PLD2 did not affect the bone structure in adult mice. Taken together, our findings indicate that PLD activity, especially which of PLD1 isoform, may enhance the mineralization process in osteoblastic cells. Nonetheless, the lack of PLD1 or PLD2 do not seem to significantly affect bone formation in adult mice.