A high-throughput model of post-traumatic osteoarthritis using engineered cartilage tissue analogs

Mohanraj, Bhavana; Meloni, Gregory R.; Mauck, Robert L.; Dodge, George R.

doi:10.1016/j.joca.2014.06.032

Cited by 21 publications

(30 citation statements)

References 44 publications

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“…Previous studies showed that in vitro tissue-engineered cartilage models can be used to study a range of cartilage signaling pathways, including mechanical trauma signaling pathways 11 and cytokine signaling pathways that involve tumor necrosis factor alpha (TNF-α) and…”

Section: Discussionmentioning

confidence: 99%

“…11 Studying the TGF-β signaling pathway in a tissue-engineered cartilage model could help rapidly determine the effectors of TGF-β's anabolic pathway and therefore may accelerate identification of potentially druggable targets for promoting cartilage formation. For example, in vitro tissue-engineered cartilage models have been used to study cytokine signaling pathways 9,10 and mechanical trauma signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

“…For example, in vitro tissue-engineered cartilage models have been used to study cytokine signaling pathways 9,10 and mechanical trauma signaling pathways. 11 Studying the TGF-β signaling pathway in a tissue-engineered cartilage model could help rapidly determine the effectors of TGF-β's anabolic pathway and therefore may accelerate identification of potentially druggable targets for promoting cartilage formation. Such a model could also eventually be used to screen for molecules capable of regenerating or repairing cartilage.…”

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confidence: 99%

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Scaffoldless tissue‐engineered cartilage for studying transforming growth factor beta‐mediated cartilage formation

Chavez

Serra

2019

Biotechnology Progress

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Reduced transforming growth factor beta (TGF-β) signaling is associated with osteoarthritis (OA). TGF-β is thought to act as a chondroprotective agent and provide anabolic cues to cartilage, thus acting as an OA suppressor in young, healthy cartilage.A potential approach for treating OA is to identify the factors that act downstream of TGF-β's anabolic pathway and target those factors to promote cartilage regeneration or repair. The aims of the present study were to (a) develop a scaffoldless tissueengineered cartilage model with reduced TGF-β signaling and disrupted cartilage formation and (b) validate the system for identifying the downstream effectors of TGF-β that promote cartilage formation. Sox9 was used to validate the model because Sox9 is known to promote cartilage formation and TGF-β regulates Sox9 activity. Primary bovine articular chondrocytes were grown in Transwell supports to form cartilage tissues. An Alk5/TGF-β type I receptor inhibitor, SB431542, was used to attenuate TGF-β signaling, and an adenovirus encoding FLAG-Sox9 was used to drive the expression of Sox9 in the in vitro-generated cartilage. SB431542-treated tissues exhibited reduced cartilage formation including reduced thicknesses and reduced proteoglycan staining compared with control tissue. Expression of FLAG-Sox9 in SB431542-treated cartilage allowed the formation of cartilage despite antagonism of the TGF-β receptor. In summary, we developed a three-dimensional in vitro cartilage model with attenuated TGF-β signaling. Sox9 was used to validate the model for identification of anabolic agents that counteract loss of TGF-β signaling. This model has the potential to identify additional anabolic factors that could be used to repair or regenerate damaged cartilage. K E Y W O R D Sanabolic, cartilage, osteoarthritis, scaffoldless tissue engineering, Sox9, TGF-β

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Scaffoldless tissue‐engineered cartilage for studying transforming growth factor beta‐mediated cartilage formation

Chavez

Serra

2019

Biotechnology Progress

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“…However, an adverse biomechanical environment caused by cartilage lesions and focally elevated contact stresses undermine the function of cartilage. Such detrimental environment formed after a traumatic impact may ultimately lead to a loss of mechanical integrity of the tissue and development of post-traumatic osteoarthritis (PTOA) (Heijink et al 2012;Mohanraj et al 2014;Lieberthal et al 2015). Despite extensive research, various mechanisms behind the development of PTOA are not fully understood Heijink et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Maximum shear strain-based algorithm can predict proteoglycan loss in damaged articular cartilage

Eskelinen

Mononen

Venäläinen

et al. 2019

Biomech Model Mechanobiol

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Post-traumatic osteoarthritis (PTOA) is a common disease, where the mechanical integrity of articular cartilage is compromised. PTOA can be a result of chondral defects formed due to injurious loading. One of the first changes around defects is proteoglycan depletion. Since there are no methods to restore injured cartilage fully back to its healthy state, preventing the onset and progression of the disease is advisable. However, this is problematic if the disease progression cannot be predicted. Thus, we developed an algorithm to predict proteoglycan loss of injured cartilage by decreasing the fixed charge density (FCD) concentration. We tested several mechanisms based on the local strains or stresses in the tissue for the FCD loss. By choosing the degeneration threshold suggested for inducing chondrocyte apoptosis and cartilage matrix damage, the algorithm driven by the maximum shear strain showed the most substantial FCD losses around the lesion. This is consistent with experimental findings in the literature. We also observed that by using coordinate system-independent strain measures and selecting the degeneration threshold in an ad hoc manner, all the resulting FCD distributions would appear qualitatively similar, i.e., the greatest FCD losses are found at the tissue adjacent to the lesion. The proposed strain-based FCD degeneration algorithm shows a great potential for predicting the progression of PTOA via biomechanical stimuli. This could allow identification of high-risk defects with an increased risk of PTOA progression.

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“…[8]. [28]. In addition, there are some comparable approaches which focus on the production of SFCCs [9,11,[29][30][31].…”

Section: Discussionmentioning

confidence: 99%

In vitro and in silico modeling of cellular and matrix-related changes during the early phase of osteoarthritis

Weber

Fischer

Damerau

et al. 2019

Preprint

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Objective: Understanding the pathophysiological processes of osteoarthritis (OA) require adequate model systems. Although different in vitro or in vivo models have been described, further comprehensive approaches are needed to study specific parts of the disease. This study aimed to combine in vitro and in silico modeling to describe cellular and matrix-related changes during the early phase of OA. We developed an in vitro OA model based on scaffoldfree cartilage-like constructs (SFCCs), which was mathematically modeled using a partial differential equation (PDE) system to resemble the processes during the onset of OA.Design: SFCCs were produced from mesenchymal stromal cells and analyzed weekly by histology and qPCR to characterize the cellular and matrix-related composition. To simulate the early phase of OA, SFCCs were treated with interleukin-1β (IL-1β), tumor necrosis factor α (TNFα) and examined after 3 weeks or cultivated another 3 weeks without inflammatory cytokines to validate the regeneration potential. Mathematical modeling was performed in parallel to the in vitro experiments.Results: SFCCs expressed cartilage-specific markers, and after stimulation an increased expression of inflammatory markers, matrix degrading enzymes, a loss of collagen II (Col-2) and a reduced cell density was observed which could be partially reversed by retraction of stimulation. Based on the PDEs, the distribution processes within the SFCCs, including those of IL-1β, Col-2 degradation and cell number reduction was simulated. Conclusions:By combining in vitro and in silico methods, we aimed to develop a valid, efficient alternative approach to examine and predict disease progression and new therapeutic strategies.

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A high-throughput model of post-traumatic osteoarthritis using engineered cartilage tissue analogs

Cited by 21 publications

References 44 publications

Scaffoldless tissue‐engineered cartilage for studying transforming growth factor beta‐mediated cartilage formation

Scaffoldless tissue‐engineered cartilage for studying transforming growth factor beta‐mediated cartilage formation

Maximum shear strain-based algorithm can predict proteoglycan loss in damaged articular cartilage

In vitro and in silico modeling of cellular and matrix-related changes during the early phase of osteoarthritis

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