Platelet-released supernatants increase migration and proliferation, and decrease osteogenic differentiation of bone marrow-derived mesenchymal progenitor cells under<i>in vitro</i>conditions

Gruber, Reinhard; Karreth, Florian A.; Kandler, Barbara; Fuerst, Gabor; Rot, Antal; Fischer, Michael B.; Watzek, Georg

doi:10.1080/09537100310001643999

Cited by 167 publications

(169 citation statements)

References 36 publications

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“…Platelet-derived growth factor (PDGF) is a potent MSC mitogen that plays an important role in OB proliferation and differentiation, with the addition of PDGF to osteogenic MSC cultures strongly inhibiting OB differentiation and function in vitro. (11)(12)(13)(14) Two signaling pathways that are strongly activated in response to PDGF are the class I phosphatidylinositol-3-kinase/Akt (PI3K) and mammalian target of rapamycin (mTOR) pathways. (15,16) Class I PI3Ks are heterodimeric complexes composed of a catalytic p110 subunit (a, b, d, g) and a regulatory p85, p55, p50, or p101 subunit.…”

Section: Introductionmentioning

confidence: 99%

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

Martin¹,

Fitter²,

Bong³

et al. 2010

Journal of Bone and Mineral Research

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Osteoblasts are bone-forming cells derived from mesenchymal stromal cells (MSCs) that reside within the bone marrow. In response to a variety of factors, MSCs proliferate and differentiate into mature, functional osteoblasts. Several studies have shown previously that suppression of the PI3K and mTOR signaling pathways in these cells strongly promotes osteogenic differentiation, which suggests that inhibitors of these pathways may be useful as anabolic bone agents. In this study we examined the effect of BEZ235, a newly developed dual PI3K and mTOR inhibitor currently in phase I-II clinical trials for advanced solid tumors, on osteogenic differentiation and function using primary MSC cultures. Under osteoinductive conditions, BEZ235 strongly promotes osteogenic differentiation, as evidenced by an increase in mineralized matrix production, an upregulation of genes involved in osteogenesis, including bone morphogenetic proteins (BMP2, -4, and -6) and transforming growth factor b1 (TGF-b1) superfamily members (TGFB1, TGFB2, and INHBE), and increased activation of SMAD signaling molecules. In addition, BEZ235 enhances de novo bone formation in calvarial organotypic cultures. Using pharmacologic inhibitors to delineate mechanism, our studies reveal that suppression of mTOR and, to a much lesser extent PI3K p110a, mediates the osteogenic effects of BEZ235. As confirmation, shRNA-mediated knockdown of mTOR enhances osteogenic differentiation and function in SAOS-2 osteoblast-like cells. Taken together, our findings suggest that BEZ235 may be useful in treating PI3K/mTOR-dependent tumors associated with bone loss, such as the hematologic malignancy multiple myeloma. ß

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Section: Introductionmentioning

confidence: 99%

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

Martin¹,

Fitter²,

Bong³

et al. 2010

Journal of Bone and Mineral Research

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“…6,7 Among these cells are mesenchymal progenitors that can be attracted by signaling molecules released from activated platelets. 8,9 The functional role of platelets during the early stages of bone regeneration is not, however, entirely clear. Platelets may support the immigration of mesenchymal progenitors by increasing their capacity to digest the fibrin-rich matrix.…”

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confidence: 99%

Activated platelets increase fibrinolysis of mesenchymal progenitor cells

Agis

Kandler

Fischer

et al. 2008

Journal Orthopaedic Research

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Bone regeneration is initiated by the formation of a blood clot. Activated platelets within this fibrin-rich matrix release signaling molecules that can attract mesenchymal progenitor cells. To gain insight into the cellular mechanism by which activated platelets can support the immigration of mesenchymal progenitors, we have tested the hypothesis that platelet-released signaling molecules increase the capacity of bone marrow stromal cells (BMSC) to activate plasminogen. We report herein that platelet-released supernatants (PRS) elevate total urokinase-type plasminogen activator (uPA) and total plasminogen activator inhibitor-1 (PAI-1) levels in BMSC, as assessed by immunoassay. Quantitative polymerase chain reaction showed an upregulation of uPA, uPA receptor, and PAI-1. Zymography and kinetic analysis based on casein hydrolysis revealed enhanced activity of cell-associated uPA upon exposure of BMSC to PRS. Inhibiting c-Jun Nterminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K) signaling reduced uPA production and decreased plasminogen activation. Corresponding Western blot analysis showed increased phosphorylation of JNK and AKT in BMSC treated with PRS. These results suggest that activated platelets can enhance the plasminogen activation capacity of mesenchymal progenitors through the stimulation of uPA production, requiring JNK and PI3K/AKT signaling. By this mechanism platelets may contribute to the organization of the blood clot during bone regeneration. ß

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“…In vitro studies showed that PRP activates proliferation and migration of osteoprogenitor cells (Gruber et al, 2003(Gruber et al, , 2004 but decreases osteogenic differentiation of BMSC (Gruber et al, 2004). This suggests that the osteogenic effect of PRP mainly relies on proliferation and migration, rather than on induction of differentiation.…”

Section: The Underlying Effect Of Platelet-derived Products: Knowledgmentioning

confidence: 99%

State of the art and future perspectives of articular cartilage regeneration: a focus on adipose-derived stem cells and platelet-derived products

Hildner

Albrecht

Gabriel

et al. 2011

J Tissue Eng Regen Med

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Trauma, malposition and age-related degeneration of articular cartilage often result in severe lesions that do not heal spontaneously. Many efforts over the last centuries have been undertaken to support cartilage healing, with approaches ranging from symptomatic treatment to structural cartilage regeneration. Microfracture and matrix-associated autologous chondrocyte transplantation (MACT) can be regarded as one of the most effective techniques available today to treat traumatic cartilage defects. Research is focused on the development of new biomaterials, which are intended to provide optimized physical and biochemical conditions for cell proliferation and cartilage synthesis. New attempts have also been undertaken to replace chondrocytes with cells that are more easily available and cause less donor site morbidity, e.g. adipose derived stem cells (ASC). The number of in vitro studies on adult stem cells has rapidly increased during the last decade, indicating that many variables have yet to be optimized to direct stem cells towards the desired lineage. The present review gives an overview of the difficulties of cartilage repair and current cartilage repair techniques. Moreover, it reviews new fields of cartilage tissue engineering, including stem cells, co-cultures and platelet-rich plasma (PRP).

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Platelet-released supernatants increase migration and proliferation, and decrease osteogenic differentiation of bone marrow-derived mesenchymal progenitor cells underin vitroconditions

Cited by 167 publications

References 36 publications

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

Activated platelets increase fibrinolysis of mesenchymal progenitor cells

State of the art and future perspectives of articular cartilage regeneration: a focus on adipose-derived stem cells and platelet-derived products

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