TGFβ3 and loading increases osteocyte survival in human cancellous bone cultured ex vivo

Simpson, Angharad E.; Stoddart, Martin J.; Davies, Catrin; Jähn, Katharina; Furlong, Pamela I.; Gasser, Jürg A.; Jones, David B.; Noble, Brendon; Richards, R. Geoff

doi:10.1002/cbf.1529

Cited by 17 publications

(14 citation statements)

References 23 publications

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“…Specifically, transcription of Growth Differentiation Factors (GDF) 3 and 10 and TGFβ 3 were all upregulated 6-8 fold as a result of CD47 exposure. Due to its role in scar tissue reduction and extracellular matrix remodeling [27,36,37], we chose to further investigate the effects of immobilized CD47 exposure upon TGFβ 3 protein expression and potential downstream signaling. TGFβ 3 has been shown to inhibit fibrosis by increasing expression of matrix metalloproteinase (MMP) [26,38,39].…”

Section: Discussionmentioning

confidence: 99%

Intracellular signaling mechanisms associated with CD47 modified surfaces

et al. 2013

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We have previously established that recombinant CD47 can ameliorate the inflammatory response to synthetic polymeric surfaces. Here, we begin to profile, at the transcriptional, translational and cell signaling level, the inflammatory cell response when blood interacts with CD47 modified polyvinyl chloride (PVC) (CD47-PVC). We used qPCR arrays to compare transcriptional changes between human whole blood exposed to CD47-PVC or PVC. Transcription of IL1F5, IL1F10, IL17F, CCL3, CCL8, CCL28, CXCL12, and CXCL13 was upregulated in blood exposed to PVC, compared to CD47-PVC. The increase in CCL3 and CCL8 transcription correlated with an increase in the chemokines' presence in the plasma. Exposure of blood to CD47-PVC resulted in an increase, compared to PVC, in transcription of CCL2, CCL4, CCL20, CXCL1, TGFβ3, GDF3, GDF10, CD40LG, and TNFSF10. CD47-PVC exposure resulted in an increase of the following matrix metalloproteinase related genes: MMP1, MMP7, MMP13, and MMP16. Phosflow cytometry, and assays examining transcription factor binding, cell attachment, and genome wide chromatin association indicated that members of the JAK-STAT signaling pathway, particularly JAK2 and STAT5, mediate inflammatory cell interactions with CD47-PVC. Our data demonstrate that differential molecular responses to CD47 involve downregulation of cytokines, upregulation of MMPs, and JAK/STAT signaling mechanisms.

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Section: Discussionmentioning

confidence: 99%

Intracellular signaling mechanisms associated with CD47 modified surfaces

et al. 2013

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“…9,16,83 Enhanced loading within the physiologic range is anti-apoptotic for osteocytes. 16,84 The anti-apoptotic effects of physiologic mechanical stimulation are mediated by an integrin–MapK pathway that involves the β 1 , α 2 and α 5 integrin subunits, activation of several integrin-associated kinases (Fak, Src), and activation/translocation of Erk to the nucleus. 47 Interestingly, mechanically induced Erk activation is modulated by the estrogen receptor, in a nonligand (i.e., even in the absence of estrogen analogs) dependent manner.…”

Section: Mechanical Control Of Bone Resorptionmentioning

confidence: 99%

Mechanical Signaling for Bone Modeling and Remodeling

Robling

Turner

2009

Crit Rev Eukar Gene Expr

313

235

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Proper development of the skeleton in utero and during growth requires mechanical stimulation. Loading results in adaptive changes in bone that strengthen bone structure. Bone’s adaptive response is regulated by the ability of resident bone cells to perceive and translate mechanical energy into a cascade of structural and biochemical changes within the cells — a process known as mechanotransduction. Mechanotransduction pathways are among the most anabolic in bone, and consequently, there is great interest in elucidating how mechanical loading produces its observed effects, including increased bone formation, reduced bone loss, changes in bone cell differentiation and lifespan, among others. A molecular understanding of these processes is developing, and with it comes a profound new insight into the biology of bone. In this article, we review the nature of the physical stimulus to which bone cells mount an adaptive response, including the identity of the sensor cells, their attributes and physical environment, and putative mechanoreceptors they express. Particular attention is allotted to the focal adhesion and Wnt signaling, in light of their emerging role in bone mechanotransduction. The cellular mechanisms for increased bone loss during disuse, and reduced bone loss during loading are considered. Finally, we summarize the published data on bone cell accommodation, whereby bone cells stop responding to mechanical signaling events. Collectively, these data highlight the complex yet finely orchestrated process of mechanically regulated bone homeostasis.

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“…Ex vivo cultured bone models have been employed for the study of bone cell biology and the interactions of cells with each other and with the surrounding bone ECM. Nevertheless, the limited nutrient and oxygen supply to the central portion of the explanted bone cultured under static conditions leads to cell necrosis, constituting a big limitation of ex vivo models (Simpson et al, 2009). The introduction of bioreactors allowed an increase in cell viability and the development of long-term ex vivo cultured models, demonstrating the importance of mechanical stress on osteoblast behavior (David et al, 2008; Simpson et al, 2009).…”

Section: Bone In Vitro Modelsmentioning

confidence: 99%

“…Nevertheless, the limited nutrient and oxygen supply to the central portion of the explanted bone cultured under static conditions leads to cell necrosis, constituting a big limitation of ex vivo models (Simpson et al, 2009). The introduction of bioreactors allowed an increase in cell viability and the development of long-term ex vivo cultured models, demonstrating the importance of mechanical stress on osteoblast behavior (David et al, 2008; Simpson et al, 2009). However, the use of explants of human bone tissue cultured ex vivo has shown a large variability due to the different sex, age, health conditions, and life style of the donor patients (Simpson et al, 2009).…”

Section: Bone In Vitro Modelsmentioning

confidence: 99%

Tissue Engineering Approaches in the Design of Healthy and Pathological In Vitro Tissue Models

Caddeo

Boffito

Sartori

2017

Front. Bioeng. Biotechnol.

224

172

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In the tissue engineering (TE) paradigm, engineering and life sciences tools are combined to develop bioartificial substitutes for organs and tissues, which can in turn be applied in regenerative medicine, pharmaceutical, diagnostic, and basic research to elucidate fundamental aspects of cell functions in vivo or to identify mechanisms involved in aging processes and disease onset and progression. The complex three-dimensional (3D) microenvironment in which cells are organized in vivo allows the interaction between different cell types and between cells and the extracellular matrix, the composition of which varies as a function of the tissue, the degree of maturation, and health conditions. In this context, 3D in vitro models can more realistically reproduce a tissue or organ than two-dimensional (2D) models. Moreover, they can overcome the limitations of animal models and reduce the need for in vivo tests, according to the “3Rs” guiding principles for a more ethical research. The design of 3D engineered tissue models is currently in its development stage, showing high potential in overcoming the limitations of already available models. However, many issues are still opened, concerning the identification of the optimal scaffold-forming materials, cell source and biofabrication technology, and the best cell culture conditions (biochemical and physical cues) to finely replicate the native tissue and the surrounding environment. In the near future, 3D tissue-engineered models are expected to become useful tools in the preliminary testing and screening of drugs and therapies and in the investigation of the molecular mechanisms underpinning disease onset and progression. In this review, the application of TE principles to the design of in vitro 3D models will be surveyed, with a focus on the strengths and weaknesses of this emerging approach. In addition, a brief overview on the development of in vitro models of healthy and pathological bone, heart, pancreas, and liver will be presented.

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TGFβ₃ and loading increases osteocyte survival in human cancellous bone cultured ex vivo

Cited by 17 publications

References 23 publications

Intracellular signaling mechanisms associated with CD47 modified surfaces

Intracellular signaling mechanisms associated with CD47 modified surfaces

Mechanical Signaling for Bone Modeling and Remodeling

Tissue Engineering Approaches in the Design of Healthy and Pathological In Vitro Tissue Models

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