scholarly journals Biomechanical Influence of Cartilage Homeostasis in Health and Disease

Arthritis ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
D. L. Bader ◽  
D. M. Salter ◽  
T. T. Chowdhury
Keyword(s):  
Mechanical Loading ◽  
Cell Function ◽  
Cartilage Damage ◽  
Compressive Loading ◽  
3D Models ◽  
Mechanical Stimulus ◽  
Experimental Models ◽  
Ageing Population ◽  
Mechanical Stimuli

There is an urgent demand for long term solutions to improve osteoarthritis treatments in the ageing population. There are drugs that control the pain but none that stop the progression of the disease in a safe and efficient way. Increased intervention efforts, augmented by early diagnosis and integrated biophysical therapies are therefore needed. Unfortunately, progress has been hampered due to the wide variety of experimental models which examine the effect of mechanical stimuli and inflammatory mediators on signal transduction pathways. Our understanding of the early mechanopathophysiology is poor, particularly the way in which mechanical stimuli influences cell function and regulates matrix synthesis. This makes it difficult to identify reliable targets and design new therapies. In addition, the effect of mechanical loading on matrix turnover is dependent on the nature of the mechanical stimulus. Accumulating evidence suggests that moderate mechanical loading helps to maintain cartilage integrity with a low turnover of matrix constituents. In contrast, nonphysiological mechanical signals are associated with increased cartilage damage and degenerative changes. This review will discuss the pathways regulated by compressive loading regimes and inflammatory signals in animal and in vitro 3D models. Identification of the chondroprotective pathways will reveal novel targets for osteoarthritis treatments.

scholarly journals Experimental Models of Hepatocellular Carcinoma—A Preclinical Perspective

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3651
Author(s):  
Alexandru Blidisel ◽  
Iasmina Marcovici ◽  
Dorina Coricovac ◽  
Florin Hut ◽  
Cristina Adriana Dehelean ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Prediction Models ◽  
3D Models ◽  
Experimental Models ◽  
Health Concern ◽  
Liver Carcinoma ◽  
Tumor Type

Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.

scholarly journals Mechanical loading of tissue engineered skeletal muscle prevents dexamethasone induced myotube atrophy

2020 ◽  
Author(s):  
Kathryn W. Aguilar-Agon ◽  
Andrew J. Capel ◽  
Jacob W. Fleming ◽  
Darren J. Player ◽  
Neil R. W. Martin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mechanical Loading ◽  
Muscle Atrophy ◽  
Mechanical Load ◽  
3D Models ◽  
Skeletal Muscle Atrophy ◽  
Treatment Modalities ◽  
Murine Cell Line

Abstract Skeletal muscle atrophy as a consequence of acute and chronic illness, immobilisation, muscular dystrophies and aging, leads to severe muscle weakness, inactivity and increased mortality. Mechanical loading is thought to be the primary driver for skeletal muscle hypertrophy, however the extent to which mechanical loading can offset muscle catabolism has not been thoroughly explored. In vitro 3D-models of skeletal muscle provide a controllable, high throughput environment and mitigating many of the ethical and methodological constraints present during in vivo experimentation. This work aimed to determine if mechanical loading would offset dexamethasone (DEX) induced skeletal muscle atrophy, in muscle engineered using the C2C12 murine cell line. Mechanical loading successfully offset myotube atrophy and functional degeneration associated with DEX regardless of whether the loading occurred before or after 24 h of DEX treatment. Furthermore, mechanical load prevented increases in MuRF-1 and MAFbx mRNA expression, critical regulators of muscle atrophy. Overall, we demonstrate the application of tissue engineered muscle to study skeletal muscle health and disease, offering great potential for future use to better understand treatment modalities for skeletal muscle atrophy.

Effects of Mechanical Stress on the In Vitro Degradation of Porous Composite Scaffold for Bone Tissue Engineering

2007 ◽  
Vol 342-343 ◽  
pp. 273-276 ◽  
Author(s):  
Yun Qing Kang ◽  
Guang Fu Yin ◽  
Lin Luo ◽  
Ke Feng Wang ◽  
Yu Zhang
Keyword(s):  
Tissue Engineering ◽  
Simulated Body Fluid ◽  
Bone Tissue Engineering ◽  
Mechanical Stress ◽  
Mechanical Loading ◽  
Body Fluid ◽  
Compressive Loading ◽  
Porous Scaffolds ◽  
In Vitro Degradation

In bone tissue engineering, porous scaffolds served as the temporary matrix are often subjected to mechanical stress when implanted in the body. Based on this fact, the goal of this study was to examine the effects of mechanical loading on the in vitro degradation characteristics and kinetics of porous scaffolds in a custom-designed loading system. Porous Poly(L-lactic acid)/β-Tricalcium Phosphate (PLLA/β-TCP) composite scaffolds fabricated by using solution casting/compression molding/particulate leaching technique (SCP) were subjected to degradation in simulated body fluid (SBF) at 37°C for up to 6 weeks under the conditions: with and without static compressive loading, respectively. The results indicated that the increase of the porosity and decrease of the compressive strength under static compressive loading were slower than that of non-loading case, and so did the mass loss rate. It might be due to that the loading retarded the penetration, absorption and transfer of simulated body fluid. These data provide an important step towards understanding mechanical loading factors contributing to degradation.

scholarly journals IL-1β Damages Fibrocartilage and Upregulates MMP-13 Expression in Fibrochondrocytes in the Condyle of the Temporomandibular Joint

2019 ◽  
Vol 20 (9) ◽  
pp. 2260 ◽  
Author(s):  
Hessam Tabeian ◽  
Beatriz F. Betti ◽  
Cinthya dos Santos Cirqueira ◽  
Teun J. de Vries ◽  
Frank Lobbezoo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Temporomandibular Joint ◽  
Mechanical Loading ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Mechanical Stimuli ◽  
Condylar Cartilage ◽  
Catabolic Enzymes ◽  
Mechanical Tensile ◽  
And Function

The temporomandibular joint (TMJ), which differs anatomically and biochemically from hyaline cartilage-covered joints, is an under-recognized joint in arthritic disease, even though TMJ damage can have deleterious effects on physical appearance, pain and function. Here, we analyzed the effect of IL-1β, a cytokine highly expressed in arthritic joints, on TMJ fibrocartilage-derived cells, and we investigated the modulatory effect of mechanical loading on IL-1β-induced expression of catabolic enzymes. TMJ cartilage degradation was analyzed in 8–11-week-old mice deficient for IL-1 receptor antagonist (IL-1RA−/−) and wild-type controls. Cells were isolated from the juvenile porcine condyle, fossa, and disc, grown in agarose gels, and subjected to IL-1β (0.1–10 ng/mL) for 6 or 24 h. Expression of catabolic enzymes (ADAMTS and MMPs) was quantified by RT-qPCR and immunohistochemistry. Porcine condylar cells were stimulated with IL-1β for 12 h with IL-1β, followed by 8 h of 6% dynamic mechanical (tensile) strain, and gene expression of MMPs was quantified. Early signs of condylar cartilage damage were apparent in IL-1RA−/− mice. In porcine cells, IL-1β strongly increased expression of the aggrecanases ADAMTS4 and ADAMTS5 by fibrochondrocytes from the fossa (13-fold and 7-fold) and enhanced the number of MMP-13 protein-expressing condylar cells (8-fold). Mechanical loading significantly lowered (3-fold) IL-1β-induced MMP-13 gene expression by condylar fibrochondrocytes. IL-1β induces TMJ condylar cartilage damage, possibly by enhancing MMP-13 production. Mechanical loading reduces IL-1β-induced MMP-13 gene expression, suggesting that mechanical stimuli may prevent cartilage damage of the TMJ in arthritic patients.

scholarly journals Optimizing Mechanical Stretching Protocols for Hypertrophic and Anti-apoptotic Responses in H9c2 Cardiomyocytes

2020 ◽  
Author(s):  
Evangelos Zevolis ◽  
Anastassios Philippou ◽  
Athanasios Moustogiannis ◽  
Antonis Chatzigeorgiou ◽  
Michael Koutsilieris
Keyword(s):  
Mechanical Loading ◽  
Low Frequency ◽  
Signaling Proteins ◽  
Mechanical Stimuli ◽  
Elastic Membranes ◽  
H9c2 Cardiomyocytes ◽  
H9c2 Cardiomyoblasts ◽  
Mechanical Stretching ◽  
Strain Frequency

Abstract Background: Cardiomyocytes are sensitive to mechanical loading, possessing the ability to respond to mechanical stimuli by reprogramming their gene expression. In this study, signaling as well as expression responses of myogenic, anabolic, inflammatory, atrophy and pro-apoptotic genes to different mechanical stretching protocols were examined in differentiated cardiomyocytes.Methods: H9C2 cardiomyoblasts were cultured on elastic membranes up to their 5th day of differentiation (myotubes) and then subjected to three different stretching protocols by altering their strain, frequency and duration characteristics, using an in vitro cell tension system. cells were harvested and lysed 24 hours after the completion of each stretching protocol and Real Time-PCR was used to monitor changes in mRNA expression of myogenic regulatory factors (MyoD, Myogenin, MRF4), the IGF-1 isoforms (IGF-1Ea, IGF-1Eb), as well as atrophy (Atrogin-1), pro-apoptotic (FoxO, Fuca), and inflammatory (IL-6) factors in response to the different mechanical loading conditions. The activation of Akt and Erk 1/2 signaling proteins following the various stretching protocols was also evaluated by Western blot analysis.Results: We documented that the low strain (2.7% elongation), low frequency (0.25 Hz) and intermediate duration (12 hrs) stretching protocol was overall the most effective in inducing beneficial responses in differentiated cardiomyoblasts as it increased the expression of IGF-1 isoforms and phosphorylation of Akt and Erk1/2 (p<0.05), while it provoked the downregulation of all the other factors examined (p<0.05-0.001). Conclusion: These findings demonstrated that a low strain, low frequency of intermediate duration stretching protocol is the most effective in inducing a hypertrophic and anti-apoptotic response in H9C2 cardiomyotubes, in vitro.

scholarly journals Temperature Evolution Following Joint Loading Promotes Chondrogenesis by Synergistic Cues via Calcium Signaling

2021 ◽  
Author(s):  
Naser Nasrollahzadeh ◽  
Peyman Karami ◽  
Jian Wang ◽  
Lida Bagheri ◽  
Yanheng Guo ◽  
...  
Keyword(s):  
Mechanical Loading ◽  
Mechanical Energy ◽  
Synergetic Effect ◽  
Temperature Evolution ◽  
Tissue Temperature ◽  
Effect Of Temperature ◽  
Mechanical Stimuli ◽  
Self Heating

During loading of viscoelastic tissues, part of the mechanical energy is transformed into heat that can locally increase the tissue temperature, a phenomenon known as self-heating. In the framework of mechanobiology, it has been accepted that cells react and adapt to mechanical stimuli. However, the cellular effect of temperature increase as a by-product of loading has been widely neglected. In this work, we focused on cartilage self-heating to present a thermo-mechanobiological paradigm, and demonstrate how the synergy of a biomimetic temperature evolution and mechanical loading could influence cell behavior. We thereby developed a customized in vitro system allowing to recapitulate pertinent in vivo physical cues and determined the cells chondrogenic response to thermal and/or mechanical stimuli. Cellular mechanisms of action and potential signaling pathways of thermo-mechanotransduction process were also investigated. We found that co-existence of thermo-mechanical cues had a superior effect on chondrogenic gene expression compared to either signal alone. Specifically, a synergetic effect was observed for upregulation of Sox9 by application of the physiological thermo-mechanical stimulus. Multimodal TRPV4 channels were identified as key mediators of thermo-mechanotransduction process, which becomes ineffective without external calcium sources. We also observed that the isolated temperature evolution, as a by-product of loading, is a contributing factor to the cells response and this could be considered as important as the conventional mechanical loading. Providing an optimal thermo-mechanical environment by synergy of heat and loading portrays new opportunity for development of novel treatments for cartilage regeneration and can furthermore signal key elements for emerging cell-based therapies.

scholarly journals In Vivo and In Vitro Mechanical Loading of Mouse Achilles Tendons and Tenocytes—A Pilot Study

2020 ◽  
Vol 21 (4) ◽  
pp. 1313
Author(s):  
Viviane Fleischhacker ◽  
Franka Klatte-Schulz ◽  
Susann Minkwitz ◽  
Aysha Schmock ◽  
Maximilian Rummler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pilot Study ◽  
Mechanical Loading ◽  
Cell Shape ◽  
Compressive Loading ◽  
Collagen Type I ◽  
Type I ◽  
The Impact

Mechanical force is a key factor for the maintenance, adaptation, and function of tendons. Investigating the impact of mechanical loading in tenocytes and tendons might provide important information on in vivo tendon mechanobiology. Therefore, the study aimed at understanding if an in vitro loading set up of tenocytes leads to similar regulations of cell shape and gene expression, as loading of the Achilles tendon in an in vivo mouse model. In vivo: The left tibiae of mice (n = 12) were subject to axial cyclic compressive loading for 3 weeks, and the Achilles tendons were harvested. The right tibiae served as the internal non-loaded control. In vitro: tenocytes were isolated from mice Achilles tendons and were loaded for 4 h or 5 days (n = 6 per group) based on the in vivo protocol. Histology showed significant differences in the cell shape between in vivo and in vitro loading. On the molecular level, quantitative real-time PCR revealed significant differences in the gene expression of collagen type I and III and of the matrix metalloproteinases (MMP). Tendon-associated markers showed a similar expression profile. This study showed that the gene expression of tendon markers was similar, whereas significant changes in the expression of extracellular matrix (ECM) related genes were detected between in vivo and in vitro loading. This first pilot study is important for understanding to which extent in vitro stimulation set-ups of tenocytes can mimic in vivo characteristics.

scholarly journals Early Weight-Bearing Improves Cartilage Repair in an in vitro Model of Microfracture: Comparison of Two Mechanical Loading Regimens on Simulated Microfracture Based onFibrin Gel Scaffolds Encapsulating Bone Marrow Mesenchymal Stem Cells

2019 ◽  
Vol 7 (7_suppl5) ◽  
pp. 2325967119S0029 ◽  
Author(s):  
Tomoya Iseki ◽  
Benjamin B. Rothrauff ◽  
Shinsuke Kihara ◽  
Shinichi Yoshiya ◽  
Freddie H. Fu ◽  
...  
Keyword(s):  
Mechanical Loading ◽  
In Vitro Model ◽  
Weight Bearing ◽  
Compressive Loading ◽  
Shear Loading ◽  
Fibrin Gel ◽  
Early Weight Bearing ◽  
Vitro Model ◽  
Dynamic Compressive Loading

Objectives: Microfracture of focal chondral defects produces fibrocartilage, which inconsistently integrates with the surrounding native tissue and possesses inferior mechanical properties compared to hyaline cartilage. Mechanical loading modulates cartilage during development, but it remains unclear how loads produced in the course of postoperative rehabilitation affect the formation of the new fibrocartilaginous tissue. The purpose of this study was to assess the influence of different mechanical loading regimens simulating weight-bearing or passive motion exercises on an in vitro model of microfracture repair based on fibrin gel scaffolds encapsulating mesenchymal stem cells (MSCs). Methods: Cylindrical cores were made in bovine hyaline cartilage explants and filled with either: (1) cartilage plug returned to original location (positive control), (2) fibrin gel (negative control), or (3) fibrin gel with encapsulated bone marrow-derived MSCs (BM-MSCs) (microfracture mimic). Constructs were then subjected to one of three loading regimens, including (1) no loading (i.e., unloaded) (2) dynamic compressive loading, or (3) rotational shear loading. On days 0, 7, 14, and 21, the integration strength between the outer chondral ring and the central insert was measured with an electroforce mechanical tester. The central core component, mimicking microfracture neotissue, was also analyzed for gene expression by real-time RT-PCR, glycosaminoglycan and dsDNA contents, and tissue morphology by histology. Results: Integration strengths between the outer chondral ring and central neotissue of the cartilage plug and fibrin + BM-MSC groups significantly increased upon exposure to compressive loading, compared to day 0 controls (p= 0.007). Compressive loading upregulated expression of chondrogenesis-associated genes (SOX9, collagen type II, and collagen type II: I, an indicator of more hyaline phenotype) in the neotissue of the fibrin + BM-MSC group, as compared to the unloaded group at day 21 (SOX9, p =0.0032; COL2A1, p <0.0001; COL2A1/COL1A1, p = 0.0308,). Fibrin + BM-MSC constructs exposed to shear loading expressed higher levels of chondrogenic genes as compared to the unloaded condition, but not as high as the compressive loading condition. Furthermore, catabolic markers (MMP3 and ADAMTS 5) were significantly upregulated by shear loading (p = 0.0234 and p< 0.0001, respectively) at day 21, as compared to day 0. Conclusion: Dynamic compressive loading enhanced neotissue chondrogenesis and maturation in a simulated in vitro model of microfracture, with generation of more hyaline-like cartilage and improved integration with the surrounding tissue. Early weight-bearing after microfracture may be beneficial in promoting the formation of more hyaline-like cartilage repair tissue, whereas range of motion exercise by continuous passive motion without weight-bearing might not be as effective, or even negatively affect the formation of the repair tissue during post-surgery rehabilitation.

scholarly journals Blocking mechanosensitive ion channels eliminates the effects of applied mechanical loading on chick joint morphogenesis

2018 ◽  
Vol 373 (1759) ◽  
pp. 20170317 ◽  
Author(s):  
Cristian Parisi ◽  
Vikesh V. Chandaria ◽  
Niamh C. Nowlan
Keyword(s):  
Ion Channels ◽  
Mechanical Loading ◽  
Calcium Ion ◽  
Prenatal Development ◽  
Mechanical Stimuli ◽  
Voltage Gated ◽  
Calcium Ion Channels ◽  
Fetal Movements ◽  
Voltage Gated Ion Channels

Abnormalities in joint shape are increasingly considered a critical risk factor for developing osteoarthritis in life. It has been shown that mechanical forces during prenatal development, particularly those due to fetal movements, play a fundamental role in joint morphogenesis. However, how mechanical stimuli are sensed or transduced in developing joint tissues is unclear. Stretch-activated and voltage-gated calcium ion channels have been shown to be involved in the mechanoregulation of chondrocytes in vitro . In this study, we analyse, for the first time, how blocking these ion channels influences the effects of mechanical loading on chick joint morphogenesis. Using in vitro culture of embryonic chick hindlimb explants in a mechanostimulation bioreactor, we block stretch-activated and voltage-gated ion channels using, respectively, gadolinium chloride and nifedipine. We find that the administration of high doses of either drug largely removed the effects of mechanical stimulation on growth and shape development in vitro , while neither drug had any effect in static cultures. This study demonstrates that, during joint morphogenesis, mechanical cues are transduced—at least in part—through mechanosensitive calcium ion channels, advancing our understanding of cartilage development and mechanotransduction. This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.

Fluid-Structure Interaction Modelling Predicts That Strain Transfer Through Focal Attachments of Osteoblast Cells are the Primary Mediators of Mechanical Stimulation Under Fluid Flow

2013 ◽  
Author(s):  
T. J. Vaughan ◽  
M. G. Haugh ◽  
L. M. McNamara
Keyword(s):  
Fluid Flow ◽  
Mechanical Stimulation ◽  
Interstitial Fluid ◽  
Bone Cells ◽  
Mechanical Stimulus ◽  
Mechanical Stimuli ◽  
Interstitial Fluid Flow ◽  
Interaction Modelling

Bone continuously adapts its internal structure to accommodate the functional demands of its mechanical environment. It has been proposed that indirect strain-induced flow of interstitial fluid surrounding bone cells may be the primary mediator of mechanical stimuli in-vivo [1]. Due to the practical difficulties in ascertaining whether interstitial fluid flow is indeed the primary mediator of mechanical stimuli in the in vivo environment, much of the evidence supporting this theory has been established through in vitro investigations that have observed cellular activity in response to fluid flow imposed by perfusion chambers [2]. While such in vitro experiments have identified key mechanisms involved in the mechanotransduction process, the exact mechanical stimulus being imparted to cells within a monolayer is unknown [3]. Furthermoreit is not clear whether the mechanical stimulation is comparable between different experimental systems or, more importantly, is representative of physiological loading conditions experienced by bone cells in vivo.

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