An Osteopontin-Integrin Interaction Plays a Critical Role in Directing Adipogenesis and Osteogenesis by Mesenchymal Stem Cells

Chen, Qing; Shou, Peishun; Zhang, Liying; Xu, Chengfu; Zheng, Changwen; Han, Yanyan; Li, Wenzhao; Huang, Yin; Zhang, Xiaoren; Shao, Changshun; Roberts, Arthur I.; Rabson, Arnold B.; Ren, Guangwen; Zhang, Yanyun; Wang, Ying; Denhardt, David T.; Shi, Yufang

doi:10.1002/stem.1567

Cited by 191 publications

(168 citation statements)

References 66 publications

(87 reference statements)

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“…Cytoskeletal rearrangements may also affect osteoblast differentiation through enhanced integrin signaling. FA complexes and integrins are known to directly interact with extracellular matrix proteins, including SPP1 and IBSP, which play a critical role in osteoblast survival and differentiation (11,30,34,35). An increased number of FAs is proposed to increase adhesion to the extracellular matrix (35,36), which may also contribute to osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

Brum

Peppel

Leije

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. In this study, we have identified pathways that stimulate differentiation of bone forming osteoblasts from human mesenchymal stromal cells (hMSCs). Gene expression profiling was performed in hMSCs differentiated toward osteoblasts (at 6 h). Significantly regulated genes were analyzed in silico, and the Connectivity Map (CMap) was used to identify candidate bone stimulatory compounds. The signature of parbendazole matches the expression changes observed for osteogenic hMSCs. Parbendazole stimulates osteoblast differentiation as indicated by increased alkaline phosphatase activity, mineralization, and up-regulation of bone marker genes (alkaline phosphatase/ALPL, osteopontin/SPP1, and bone sialoprotein II/IBSP) in a subset of the hMSC population resistant to the apoptotic effects of parbendazole. These osteogenic effects are independent of glucocorticoids because parbendazole does not up-regulate glucocorticoid receptor (GR) target genes and is not inhibited by the GR antagonist mifepristone. Parbendazole causes profound cytoskeletal changes including degradation of microtubules and increased focal adhesions. Stabilization of microtubules by pretreatment with Taxol inhibits osteoblast differentiation. Parbendazole up-regulates bone morphogenetic protein 2 (BMP-2) gene expression and activity. Cotreatment with the BMP-2 antagonist DMH1 limits, but does not block, parbendazole-induced mineralization. Using the CMap we have identified a previously unidentified lineage-specific, bone anabolic compound, parbendazole, which induces osteogenic differentiation through a combination of cytoskeletal changes and increased BMP-2 activity.Connectivity Map | osteoblast | mesenchymal stem cell | cytoskeleton | osteoporosis

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Section: Discussionmentioning

confidence: 99%

Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

Brum

Peppel

Leije

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Various reports have demonstrated that under defined conditions in vitro , MSCs can differentiate into adipocytes depending on the presence of some particular cytokines (e.g, IFN-γ, TNF-α, TGF-β, and BMPs) and the extracellular matrix [10,11]. It's also documented that the microRNAs (miRNAs) exert essential regulatory functions in adipocyte development [12].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway

Song

Chen

et al. 2015

Cell Physiol Biochem

160

111

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Background: The Notch signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. This study was designed to determine the role of Notch signaling in adipogenic differentiation of human bone marrow derived MSCs (BM-MSCs). Methods: The Notch signaling was inhibited by the γ-secretase inhibitor N-[N-(3,5-difluor- ophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT). The markers involving adipogenic differentiation of MSCs, the relative pathway PTEN-PI3K/Akt/mTOR and autophagy activation were then analyzed. Furthermore, the autophagy inhibitor chloroquine (CQ) and 3-methyladenine (3-MA) were used to study the role of autophagy in the DAPT-induced the adipogenic differentiation of MSCs. Results: We first confirmed the down -regulation of Notch gene expression during MSCs adipocyte differentiation, and showed that the inhibition of Notch signaling significantly enhanced adipogenic differentiation of MSCs. Furthermore, Notch inhibitor DAPT induced early autophagy by acting on PTEN-PI3K/Akt/mTOR pathway. The autophagy inhibitor CQ and 3-MA dramatically abolished the effects of DAPT-induced autophagy and adipogenic differentiation of MSCs. Conclusion: Our results indicate that inhibition of Notch signaling could promote MSCs adipogenesis mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway. Notch signaling could be a novel target for regulating the adipogenic differentiation of MSCs.

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“…Our further observation of Osthole-induced MSCs on day 7 indicates a clear reduction in mRNA expression of osteoblast-specific genes, such as transcription factors RUNX2 (one of the key factors to trigger the osteogenic differentiation cascade [25] and Osterix (a downstream protein of Runx2 and required for the differentiation of MSCs into osteoblasts [26]), Type I collagen (the main component of bone matrix and its degradation always results in bone loss [27,28]), osteocalcin [29], and OPN [30], coinciding completely with our previous results of both ALP activities and calcified nodules.…”

Section: The Influence Of Osthole Removal On Osteoblast Differentiationmentioning

confidence: 64%

An Inhibitory Role of Osthole in Rat MSCs Osteogenic Differentiation and Proliferation via Wnt/β-Catenin and Erk1/2-MAPK Pathways

Chen

Dai

et al. 2016

Cell Physiol Biochem

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Background/Aims: Bone marrow-derived mesenchymal stem cells (MSCs) are responsible for new bone formation during adulthood. Accumulating evidences showed that Osthole promotes the osteogenic differentiation in primary osteoblasts. The aim of this study was to investigate whether Osthole exhibits a potential to stimulate the osteogenic differentiation of MSCs and the underlying mechanism. Methods: MSCs were treated with a gradient concentration of Osthole (6.25 µM, 12.5 µM, and 25 µM). Cell proliferation was assessed by western blotting with the proliferating cell nuclear antigen (PCNA) and Cyclin D1 antibodies, fluorescence activated cell sorting (FACS), and cell counting kit 8 (CCK8). MSCs were cultured in osteogenesis-induced medium for one or two weeks. The osteogenic differentiation of MSCs was estimated by Alkaline Phosphatase (ALP) staining, Alizarin red staining, Calcium influx, and quantitative PCR (qPCR). The underlying mechanism of Osthole-induced osteogenesis was further evaluated by western blotting with antibodies in Wnt/β-catenin, PI3K/Akt, BMPs/smad1/5/8, and MAPK signaling pathways. Results: Osthole inhibited proliferation of rat MSCs in a dose-dependent manner. Osthole suppressed osteogenic differentiation of rat MSCs by down-regulating the activities of Wnt/β-catenin and Erk1/2-MAPK signaling. Conclusions: Osthole inhibits the proliferation and osteogenic differentiation of rat MSCs, which might be mediated through blocking the Wnt/β-catenin and Erk1/2-MAPK signaling pathways.

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An Osteopontin-Integrin Interaction Plays a Critical Role in Directing Adipogenesis and Osteogenesis by Mesenchymal Stem Cells

Cited by 191 publications

References 66 publications

Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway

An Inhibitory Role of Osthole in Rat MSCs Osteogenic Differentiation and Proliferation via Wnt/β-Catenin and Erk1/2-MAPK Pathways

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