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Sox9 Potentiates BMP2-Induced Chondrogenic Differentiation and Inhibits BMP2-Induced Osteogenic Differentiation  [PDF]
Junyi Liao, Ning Hu, Nian Zhou, Liangbo Lin, Chen Zhao, Shixiong Yi, Tingxu Fan, Wei Bao, Xi Liang, Hong Chen, Wei Xu, Cheng Chen, Qiang Cheng, Yongming Zeng, Weike Si, Zhong Yang, Wei Huang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089025
Abstract: Bone morphogenetic protein 2 (BMP2) is one of the key chondrogenic growth factors involved in the cartilage regeneration. However, it also exhibits osteogenic abilities and triggers endochondral ossification. Effective chondrogenesis and inhibition of BMP2-induced osteogenesis and endochondral ossification can be achieved by directing the mesenchymal stem cells (MSCs) towards chondrocyte lineage with chodrogenic factors, such as Sox9. Here we investigated the effects of Sox9 on BMP2-induced chondrogenic and osteogenic differentiation of MSCs. We found exogenous overexpression of Sox9 enhanced the BMP2-induced chondrogenic differentiation of MSCs in vitro. Also, it inhibited early and late osteogenic differentiation of MSCs in vitro. Subcutaneous stem cell implantation demonstrated Sox9 potentiated BMP2-induced cartilage formation and inhibited endochondral ossification. Mouse limb cultures indicated that BMP2 and Sox9 acted synergistically to stimulate chondrocytes proliferation, and Sox9 inhibited BMP2-induced chondrocytes hypertrophy and ossification. This study strongly suggests that Sox9 potentiates BMP2-induced MSCs chondrogenic differentiation and cartilage formation, and inhibits BMP2-induced MSCs osteogenic differentiation and endochondral ossification. Thus, exogenous overexpression of Sox9 in BMP2-induced mesenchymal stem cells differentiation may be a new strategy for cartilage tissue engineering.
Single Bout Short Duration Fluid Shear Stress Induces Osteogenic Differentiation of MC3T3-E1 Cells via Integrin β1 and BMP2 Signaling Cross-Talk  [PDF]
Zhihui Mai, Zhuli Peng, Sihan Wu, Jinglan Zhang, Lin Chen, Huangyou Liang, Ding Bai, Guangmei Yan, Hong Ai
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061600
Abstract: Fluid shear stress plays an important role in bone osteogenic differentiation. It is traditionally believed that pulsed and continuous stress load is more favorable for fracture recovery and bone homeostasis. However, according to our clinical practice, we notice that one single stress load is also sufficient to trigger osteogenic differentiation. In the present study, we subject osteoblast MC3T3-E1 cells to single bout short duration fluid shear stress by using a parallel plate flow system. The results show that 1 hour of fluid shear stress at 12 dyn/cm2 promotes terminal osteogenic differentiation, including rearrangement of F-actin stress fiber, up-regulation of osteogenic genes expression, elevation of alkaline phosphatase activity, secretion of type I collagen and osteoid nodule formation. Moreover, collaboration of BMP2 and integrin β1 pathways plays a significant role in such differentiation processes. Our findings provide further experimental evidence to support the notion that single bout short duration fluid shear stress can promote osteogenic differentiation.
The Osteogenic Study of Tissue Engineering Bone with BMP2 and BMP7 Gene-Modified Rat Adipose-Derived Stem Cell
Wang Qing,Chen Guang-Xing,Guo Lin,Yang Liu
Journal of Biomedicine and Biotechnology , 2012, DOI: 10.1155/2012/410879
Abstract: To evaluate the feasibility and advantages of constructing a novel tissue engineering bone, using -tricalcium phosphate (-TCP) and rat adipose-derived stem cells (ADSCs), modified with BMP2 and BMP7 by lentivirus. In the present study, ADSCs transfected with Lv-BMP2 and Lv-BMP7, alone or together, were seeded on -TCP scaffold and cultured in vitro. Based on the results of DNA assay, alkaline phosphatase (ALP) activity, alizarin red staining and osteogenic marker genes expression analysis, the BMP2 and BMP7 genes cotransfection group exhibited a higher degree of osteogenic differentiation in vitro. To investigate the in vivo osteogenesis of the tissue engineering bone, the ADSCs/-TCP constructs were implanted in rat femurs defects for 6 weeks and studied histomorphology and radiography. The results showed that BMP2 and BMP7 genes cotransfection group dramatically enhanced the efficiency of new bone formation than BMP2 group and BMP7 group in vivo. These results demonstrated that it was advantageous to construct tissue engineering bone using ADSCs cotransfected with BMP2 and BMP7 on -TCP, providing a potential way for treating bone defects.
Adhesion to Vitronectin and Collagen I Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells
Roman M. Salasznyk,William A. Williams,Adele Boskey,Anna Batorsky,George E. Plopper
Journal of Biomedicine and Biotechnology , 2004, DOI: 10.1155/s1110724304306017
Abstract: The mechanisms controlling human mesenchymal stem cells (hMSC) differentiation are not entirely understood. We hypothesized that the contact with extracellular matrix (ECM) proteins normally found in bone marrow would promote osteogenic differentiation of hMSC in vitro. To test this hypothesis, we cultured hMSC on purified ECM proteins in the presence or absence of soluble osteogenic supplements, and assayed for the presence of well-established differentiation markers (production of mineralized matrix, osteopontin, osteocalcin, collagen I, and alkaline phosphatase expression) over a 16-day time course. We found that hMSC adhere to ECM proteins with varying affinity (fibronectin > collagen I ≥ collagen IV ≥ vitronectin > laminin-1) and through distinct integrin receptors. Importantly, the greatest osteogenic differentiation occurred in cells plated on vitronectin and collagen I and almost no differentiation took place on fibronectin or uncoated plates. We conclude that the contact with vitronectin and collagen I promotes the osteogenic differentiation of hMSC, and that ECM contact alone may be sufficient to induce differentiation in these cells.
Adhesion to Vitronectin and Collagen I Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells  [cached]
Salasznyk Roman M.,Williams William A.,Boskey Adele,Batorsky Anna
Journal of Biomedicine and Biotechnology , 2004,
Abstract: The mechanisms controlling human mesenchymal stem cells (hMSC) differentiation are not entirely understood. We hypothesized that the contact with extracellular matrix (ECM) proteins normally found in bone marrow would promote osteogenic differentiation of hMSC in vitro. To test this hypothesis, we cultured hMSC on purified ECM proteins in the presence or absence of soluble osteogenic supplements, and assayed for the presence of well-established differentiation markers (production of mineralized matrix, osteopontin, osteocalcin, collagen I, and alkaline phosphatase expression) over a 16-day time course. We found that hMSC adhere to ECM proteins with varying affinity (fibronectin > collagen I ≥ collagen IV ≥ vitronectin > laminin-1) and through distinct integrin receptors. Importantly, the greatest osteogenic differentiation occurred in cells plated on vitronectin and collagen I and almost no differentiation took place on fibronectin or uncoated plates. We conclude that the contact with vitronectin and collagen I promotes the osteogenic differentiation of hMSC, and that ECM contact alone may be sufficient to induce differentiation in these cells.
Suppression of bone morphogenetic protein inhibitors promotes osteogenic differentiation: therapeutic implications
Manolis Heliotis, Eleftherios Tsiridis
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2467
Abstract: Bone morphogenetic proteins (BMPs), a distinct transforming growth factor (TGF)-β subgroup that is also involved in organogenesis, have been shown to be expressed during various stages of bone healing process. Mesenchymal stem cells (MSCs) that are capable of differentiation toward the osteogenic lineage are recruited from local deposits or the circulation to initiate callous formation. Kwong and coworkers [1], in their recent report, presented the expression of BMP-2 and its inhibitor chordin in human MSCs undergoing differentiation in an osteogenic medium. Temporal and spatial expression of BMPs, has attracted research interest because a number of its members, namely BMP-2, -7, -9 and -14, can induce de novo bone formation [2].BMPs bind to two different type I and type II serine/threonine kinase receptors. BMP heteromeric receptor complexes activate intracellular proteins known as Smads (small 'mothers against' decapentaplegic), including regulating R-Smads (Smad1, Smad5 and Smad8), common co-Smad (Smad4), and inhibitory I-Smads (Smad6 and Smad7), which translocate to the nucleus activating specific target genes [3].BMP inhibitors regulate local negative feedback mechanisms. Some act extracellularly, preventing BMP binding to receptors, whereas others act intracellularly, inhibiting Smad downstream activation.The most studied BMP inhibitor, noggin, reduces the activity of both osteoblasts and osteoclasts, leading to osteopenia and nonhealing fractures. In contrast, noggin knockout leads to irregularly thickened long bones and is lethal shortly after birth [4]. Chordin has a similar action to noggin. It antagonizes BMP-2, -4 and -7 by preventing them from activating BMP receptors, augmented by the co-factor twisted gastrulation (Tsg) [5]. This causes a decrease in osteogenic differentiation and a reduction in BMP-2 and BMP-4 expression [1,5]. Gremlin, another extracellular inhibitor of BMP-2, -4 and -7 engineered in transgenic mice, suppresses osteoblasts with cons
Glycogen Synthase Kinase 3β Promotes Osteogenic Differentiation of Murine Adipose-Derived Stromal Cells  [PDF]
Jeong-Eun Huh, Ryeojin Ko, Hyun Ju Jung, Soo Young Lee
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054551
Abstract: Although the role of glycogen synthase kinase 3β (GSK3β) in osteogenic differentiation of bone marrow-derived mesenchymal stromal cells (BMSCs) is well-characterized as a negative regulator of β-catenin, its effect on osteogenesis of adipose-derived stromal cells (ADSCs) is poorly understood. Here, we show that GSK3β positively regulates osteogenic differentiation of murine ADSCs. Gain-of-function studies showed that GSK3β promotes in vitro osteogenesis of ADSCs. Regulation of GSK3β activity in ADSCs, either by small interfering RNA (siRNA)-mediated GSK3β silencing or by pharmacological inhibitors, blunted osteogenesis and the expression of osteogenic markers. Importantly, we demonstrated that transgenic mice, engineered to overexpress the constitutively active GSK3β (GSK3β-S9A) mutant, exhibited a marked increase in osteogenesis, whereas expression of the catalytically inactive GSK3β (GSK3β-K85A) in mice inhibits osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by GSK3β was mediated by downregulation of β-catenin. Remarkably, β-catenin silencing enhances osteogenesis and osteoblast marker gene expression such as alkaline phosphatase (ALP) and osterix. Taken together, these findings demonstrate a novel role for GSK3β in the regulation of osteogenic differentiation in ADSCs.
Circular RNA CircHIPK3 Promotes NCI-H1299 and NCI-H2170 Cell Proliferation through miR-379 and its Target IGF1  [PDF]
Fang TIAN, Yun WANG, Zhe XIAO, Xuejun ZHU
- , 2017, DOI: : 10.3779/j.issn.1009-3419.2017.07.04
Abstract: Background and objective It has been proven that the circular RNA, possessing a stable covalently closed continuous loop, is a type of RNA molecule which is expressed widespread in mammals. The circular RNA circHIPK3 is abundantly expressed in hepatocellular carcinoma (HCC) and promotes tumourgenesis. However, a role for circHIPK3 has not been systematically examined in non-small cell lung cancer (NSCLC). In this study, we investigated whether circHIPK3 has an effect on cell proliferation in the NSCLC cell lines NCI-H1299 and NCI-H2170 and the underlying molecular mechanisms. Methods The expression of circHIPK3 was measured by real-time PCR in NSCLC cell lines. Nuclear mass separation experiment was used to detect the location of circHIPK3 in cells. The gain and loss function experiments were used to examine the proliferation of NCI-H1299 and NCI-H2170 cells by Cell Counting Kit-8 (CCK-8) and the colony formation assays. Then, circHIPK3 was cloned into the downstream of the luciferase reporter gene which activity was detected to verify whether miR-379 could bind with circHIPK3 or IGF1 mRNA. The protein level of IGF1 was detected by Western blot and ELISA in circHIPK3 overexpressed/knock-down NCI-H1299 and NCI-H2170 cells. Results CircHIPK3 was generally expressed in six kinds of NSCLC cells lines we detected, and the expression level was highest in H2170 and lowest in H1299. Overexpression of circHIPK3 obviously promoted NCI-H1299 cell proliferation and knock-down of circHIPK3 inhibited NCI-H2170 cell proliferation. In the luciferase assay, miR-379 was observed to sequester circHIPK3 and IGF1 mRNA with potential binding sites. Furthermore, we found that the overexpression of circHIPK3 could increase the expression levels of IGF1 and knock-down reduced it. Moreover, up-regulation of miR-379 rescued the phenotype induced by overexpression of circHIPK3. Conclusion CircHIPK3 could promote cell proliferation by a circHIPK3/miR-379 pathway in NCI-H1299 and NCI-H2170 cells and might be a potential tumor biomarker for NSCLC.
Crosstalk between Wnt/β-Catenin and Estrogen Receptor Signaling Synergistically Promotes Osteogenic Differentiation of Mesenchymal Progenitor Cells  [PDF]
Yanhong Gao, Enyi Huang, Hongmei Zhang, Jinhua Wang, Ningning Wu, Xian Chen, Ning Wang, Sheng Wen, Guoxin Nan, Fang Deng, Zhan Liao, Di Wu, Bosi Zhang, Junhui Zhang, Rex C. Haydon, Hue H. Luu, Lewis L. Shi, Tong-Chuan He
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082436
Abstract: Osteogenic differentiation from mesenchymal progenitor cells (MPCs) are initiated and regulated by a cascade of signaling events. Either Wnt/β-catenin or estrogen signaling pathway has been shown to play an important role in regulating skeletal development and maintaining adult tissue homeostasis. Here, we investigate the potential crosstalk and synergy of these two signaling pathways in regulating osteogenic differentiation of MPCs. We find that the activation of estrogen receptor (ER) signaling by estradiol (E2) or exogenously expressed ERα in MPCs synergistically enhances Wnt3A-induced early and late osteogenic markers, as well as matrix mineralization. The E2 or ERα-mediated synergy can be effectively blocked by ERα antagonist tamoxifen. E2 stimulation can enhance endochondral ossification of Wnt3A-transduced mouse fetal limb explants. Furthermore, exogenously expressed ERα significantly enhances the maturity and mineralization of Wnt3A-induced subcutaneous and intramuscular ectopic bone formation. Mechanistically, we demonstrate that E2 does not exert any detectable effect on β-catenin/Tcf reporter activity. However, ERα expression is up-regulated within the first 48h in AdWnt3A-transduced MPCs, whereas ERβ expression is significantly inhibited within 24h. Moreover, the key enzyme for the biosynthesis of estrogens aromatase is modulated by Wnt3A in a biphasic manner, up-regulated at 24h but reduced after 48h. Our results demonstrate that, while ER signaling acts synergistically with Wnt3A in promoting osteogenic differentiation, Wnt3A may crosstalk with ER signaling by up-regulating ERα expression and down-regulating ERβ expression in MPCs. Thus, the signaling crosstalk and synergy between these two pathways should be further explored as a potential therapeutic approach to combating bone and skeletal disorders, such as fracture healing and osteoporosis.
Long Bone Structure and Strength Depend on BMP2 from Osteoblasts and Osteocytes, but Not Vascular Endothelial Cells  [PDF]
Sarah H. McBride, Jennifer A. McKenzie, Bronwyn S. Bedrick, Paige Kuhlmann, Jill D. Pasteris, Vicki Rosen, Matthew J. Silva
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096862
Abstract: The importance of bone morphogenetic protein 2 (BMP2) in the skeleton is well known. BMP2 is expressed in a variety of tissues during development, growth and healing. In this study we sought to better identify the role of tissue-specific BMP2 during post-natal growth and to determine if BMP2 knockout affects the ability of terminally differentiated cells to create high quality bone material. We targeted BMP2 knockout to two differentiated cell types known to express BMP2 during growth and healing, early-stage osteoblasts and their progeny (osterix promoted Cre) and vascular endothelial cells (vascular-endothelial-cadherin promoted Cre). Our objectives were to assess post-natal bone growth, structure and strength. We hypothesized that removal of BMP2 from osteogenic and vascular cells (separately) would result in smaller skeletons with inferior bone material properties. At 12 and 24 weeks of age the osteoblast knockout of BMP2 reduced body weight by 20%, but the vascular knockout had no effect. Analysis of bone in the tibia revealed reductions in cortical and cancellous bone size and volume in the osteoblast knockout, but not in the vascular endothelial knockout. Furthermore, forelimb strength testing revealed a 30% reduction in ultimate force at both 12 and 24 weeks in the osteoblast knockout of BMP2, but no change in the vascular endothelial knockout. Moreover, mechanical strength testing of femurs from osteoblast knockout mice demonstrated an increased Young’s modulus (greater than 35%) but decreased post-yield displacement (greater than 50%) at both 12 and 24 weeks of age. In summary, the osteoblast knockout of BMP2 reduced bone size and altered mechanical properties at the whole-bone and material levels. Osteoblast-derived BMP2 has an important role in post-natal skeletal growth, structure and strength, while vascular endothelial-derived BMP2 does not.
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