Skeletal (stromal) stem cells: An update on intracellular signaling pathways controlling osteoblast differentiation

Abdallah, Basem M.; Jafari, Abbas; Zaher, Walid; Qiu, Weimin; Kassem, Moustapha

doi:10.1016/j.bone.2014.07.028

Cited by 91 publications

(71 citation statements)

References 159 publications

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“…33 β -Catenin and ERK1/2 are two of the most important osteoblast anabolic signaling pathways. 34, 35 The inhibition of β -catenin or ERK1/2 prevents osteoblast differentiation from mesenchymal progenitors, suggesting that these two signaling pathways have critical roles in osteoblast differentiation. 14, 36 In our study, we found that both the β -catenin and ERK pathways are significantly activated accompanied by osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

miR-203 inhibits the traumatic heterotopic ossification by targeting Runx2

Liu

et al. 2016

Cell Death Dis

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Emerging evidence has indicated that dysregulated microRNAs (miRNAs) have an important role in bone formation. However, the pathophysiological role of miRNAs in traumatic heterotopic ossification (HO) remains to be elucidated. Using gene expression profile analyses and subsequent confirmation with real-time PCR assays, we identified the decreased expression of miRNA-203 (miR-203) and increased expression of Runx2 as responses to the development of traumatic HO. We found that miR-203 expression was markedly higher in primary and recurrent HO tissues than in normal bones. The upregulation of miR-203 significantly decreased the level of Runx2 expression, whereas miR-203 downregulation increased Runx2 expression. Mutation of the putative miR-203-binding sites in Runx2 mRNA abolished miR-203-mediated repression of Runx2 3'-untranslated region luciferase reporter activity, indicating that Runx2 is an important target of miR-203 in osteoblasts. We also found that miR-203 is negatively correlated with osteoblast differentiation. Furthermore, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-203 and decreased by agomir-203. We showed that miR-203 suppresses osteoblast activity by inhibiting the β-catenin and extracellular signal-regulated kinase pathways. Moreover, using a tenotomy mouse HO model, we found an inhibitory role of miR-203 in regulating HO in vivo; pretreatment with antagomiR-203 increased the development of HO. These data suggest that miR-203 has a crucial role in suppressing HO by directly targeting Runx2 and that the therapeutic overexpression of miR-203 may be a potential strategy for treating traumatic HO.

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Section: Discussionmentioning

confidence: 99%

miR-203 inhibits the traumatic heterotopic ossification by targeting Runx2

Liu

et al. 2016

Cell Death Dis

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“…1, 2, 3, 4, 5 This approach has led to the identification of several factors that control osteoblast or adipocyte differentiation of hMSC. 3 Using transcriptomic profiling of differentiating hMSC, we identified transgelin ( TAGLN ) as a highly upregulated gene in hMSC during osteoblast and adipocyte differentiation.…”

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confidence: 99%

Transgelin is a TGFβ-inducible gene that regulates osteoblastic and adipogenic differentiation of human skeletal stem cells through actin cytoskeleston organization

et al. 2016

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Regenerative medicine is a novel approach for treating conditions in which enhanced bone regeneration is required. We identified transgelin (TAGLN), a transforming growth factor beta (TGFβ)-inducible gene, as an upregulated gene during in vitro osteoblastic and adipocytic differentiation of human bone marrow-derived stromal (skeletal) stem cells (hMSC). siRNA-mediated gene silencing of TAGLN impaired lineage differentiation into osteoblasts and adipocytes but enhanced cell proliferation. Additional functional studies revealed that TAGLN deficiency impaired hMSC cell motility and in vitro transwell cell migration. On the other hand, TAGLN overexpression reduced hMSC cell proliferation, but enhanced cell migration, osteoblastic and adipocytic differentiation, and in vivo bone formation. In addition, deficiency or overexpression of TAGLN in hMSC was associated with significant changes in cellular and nuclear morphology and cytoplasmic organelle composition as demonstrated by high content imaging and transmission electron microscopy that revealed pronounced alterations in the distribution of the actin filament and changes in cytoskeletal organization. Molecular signature of TAGLN-deficient hMSC showed that several genes and genetic pathways associated with cell differentiation, including regulation of actin cytoskeleton and focal adhesion pathways, were downregulated. Our data demonstrate that TAGLN has a role in generating committed progenitor cells from undifferentiated hMSC by regulating cytoskeleton organization. Targeting TAGLN is a plausible approach to enrich for committed hMSC cells needed for regenerative medicine application.

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“…For example, BMSCs from osteoporotic women have a low growth rate and exhibit enhanced adipocyte differentiation that proceeds at the expense of osteogenesis, leading to low bone mass and a high marrow fat mass [8-10]. Many factors have been identified as key determinants in the process of osteogenic differentiation by BMSCs, and many studies have demonstrated that a change in the expression and/or activity of these factors is associated with bone formation or bone loss [11-13]. Therefore, understanding the cellular and molecular factors that influence BMSC fate may provide us with potential therapeutic targets for several diseases associated with bone loss and high marrow adiposity.…”

Section: Introductionmentioning

confidence: 99%

“…Several signaling pathways have been shown to participate in the regulation of osteogenesis [13]. The Wnt/beta-catenin signaling pathway is an essential pathway for BMSC commitment to osteogenic differentiation [33-35].…”

Section: Introductionmentioning

confidence: 99%

Connexin 43 Modulates Osteogenic Differentiation of Bone Marrow Stromal Cells Through GSK-3beta/Beta-Catenin Signaling Pathways

Lin

Zheng

Chang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Bone marrow stromal cells (BMSCs) are multipotent precursors that give rise to osteoblasts, and contribute directly to bone formation. Connexin 43 (Cx43) is the most ubiquitous gap junction protein expressed in bone cell types, and plays crucial roles in regulating intercellular signal transmission for bone development, differentiation and pathology. However, the precise role and mechanism of Cx43 in BMSCs are less known. Here, we investigate the function of Cx43 in osteogenic differentiation of BMSCs in vitro. Methods: BMSCs were isolated by whole bone marrow adherent culture. Knock down of Cx43 was performed by using lentiviral transduction of Cx43 shRNA. BMSCs were induced to differentiate by culturing in a-MEM, 10% FBS, 50 µM ascorbic acid, 10 mM beta-glycerophosphate, and 100 nM dexamethasone. Alkaline phosphatase (ALP) activity and alizarin red S staining were used to evaluate osteogenic differentiation in calcium nodules. Target mRNAs and proteins were analyzed by using real-time quantitative PCR (qPCR) and western blotting. Results: Cx43 expression markedly increased during osteogenic differentiation. Osteogenic differentiation was suppressed following lentiviral-mediated knockdown of Cx43 expression, as judged by decreased levels of Runt-related transcription factor 2 (Runx2), bone sialoprotein (BSP), osteocalcin (Bglap), Osterix (Osx), alkaline phosphatase (ALP) activity and the number of calcium nodules in response to osteogenic differentiation stimuli. Knock down of Cx43 reduced the level of phosphorylation of GSK-3beta at Ser9 (p-GSK-3beta), resulting in decreased beta-catenin expression and activation. Furthermore, treatment of Cx43-knockdown cells with lithium chloride (LiCl), a GSK-3beta inhibitor, reduced osteogenic differentiation and decreased GSK-3beta levels, as well as partially rescued levels of both total and activated beta-catenin. Conclusion: These findings indicate that Cx43 positively modulates osteogenic differentiation of BMSCs by up-regulating GSK-3beta/beta-catenin signaling pathways, suggesting a potential role for Cx43 in determining bone mass and bone mineral density by modulating osteogenesis.

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Skeletal (stromal) stem cells: An update on intracellular signaling pathways controlling osteoblast differentiation

Cited by 91 publications

References 159 publications

miR-203 inhibits the traumatic heterotopic ossification by targeting Runx2

miR-203 inhibits the traumatic heterotopic ossification by targeting Runx2

Transgelin is a TGFβ-inducible gene that regulates osteoblastic and adipogenic differentiation of human skeletal stem cells through actin cytoskeleston organization

Connexin 43 Modulates Osteogenic Differentiation of Bone Marrow Stromal Cells Through GSK-3beta/Beta-Catenin Signaling Pathways

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