Discerning the spatio-temporal disease patterns of surgically induced OA mouse models

Haase, Tobias; Sunkara, Vikram; Kohl, Benjamin; Meier, Carola; Bußmann, Patricia; Becker, Jéssica; Jagielski, M; Kleist, Max von; Ertel, Wolfgang

doi:10.1371/journal.pone.0213734

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…In addition, the Supplementary video in this article shows the in silico model's feasibility as a prediction tool for further in vitro experiments. The observed fast decline in the cell number accompanied by a slower Col-2 degradation is in accordance with a previously published study indicating a high chondrocyte death before matrix changes occur [39]. In comparison to the model described by Kar Thus, the simplified model in our study here displays the same features but at the same time involves a smaller number of parameters and uncertainties.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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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“…Cartilage can also be excised surgically through induction of an osteochondral defect. These defects may progress at different rates depending on the operative site (Haase et al, 2019), and so makes for difficulty in determining the optimal timing of EV treatment. In contrast, DMM models may progress to display cartilage loss at time points later than direct osteochondral injury and therefore may not benefit from EV treatment in the acute post-injury phase.…”

Section: Discussionmentioning

confidence: 99%

The Treatment of Cartilage Damage Using Human Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review of in vivo Studies

Romain

Mak

et al. 2020

Front. Bioeng. Biotechnol.

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Damage to joints through injury or disease can result in cartilage loss, which if left untreated can lead to inflammation and ultimately osteoarthritis. There is currently no cure for osteoarthritis and management focusses on symptom control. End-stage osteoarthritis can be debilitating and ultimately requires joint replacement in order to maintain function. Therefore, there is growing interest in innovative therapies for cartilage repair. In this systematic literature review, we sought to explore the in vivo evidence for the use of human Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs) for treating cartilage damage. We conducted a systematic literature review in accordance with the PRISMA protocol on the evidence for the treatment of cartilage damage using human MSC-EVs. Studies examining in vivo models of cartilage damage were included. A risk of bias analysis of the studies was conducted using the SYRCLE tool. Ten case-control studies were identified in our review, including a total of 159 murine subjects. MSC-EVs were harvested from a variety of human tissues. Five studies induced osteoarthritis, including cartilage loss through surgical joint destabilization, two studies directly created osteochondral lesions and three studies used collagenase to cause cartilage loss. All studies in this review reported reduced cartilage loss following treatment with MSC-EVs, and without significant complications. We conclude that transplantation of MSC-derived EVs into damaged cartilage can effectively reduce cartilage loss in murine models of cartilage injury. Additional randomized studies in animal models that recapitulates human osteoarthritis will be necessary in order to establish findings that inform clinical safety in humans.

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“…Haase et al have recently compared two surgically induced PTOA models in C57BL/6 mice, specifically DMM and transection of the medial collateral ligament (MCL-MM) [20]. Mice that underwent MCL-MM demonstrated rapid and pronounced degradation of the collagen matrix component, with cartilage lesions being identified as early as 6-weeks post-surgery.…”

Section: Models Of Oa and Cartilage Damagementioning

confidence: 99%

“…Moreover, previous studies have reported that the rate of progression and severity of cartilage degeneration and OA-related changes in the joint differ among commonly used trauma-induced models [19,20], such as destabilization of the medial meniscus (DMM) and anterior cruciate ligament transection (ACLT). In that sense, one might question whether the inability to protect against OA is driven by an overwhelmed endogenous repair response or the complete lack of any regenerative potential in the tissue.…”

Section: Introductionmentioning

confidence: 99%

Understanding cartilage protection in OA and injury: a spectrum of possibilities

Masson

Krawetz

2020

BMC Musculoskelet Disord

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Background: Osteoarthritis (OA) is a prevalent musculoskeletal disease resulting in progressive degeneration of the hyaline articular cartilage within synovial joints. Current repair treatments for OA often result in poor quality tissue that is functionally ineffective compared to the hyaline cartilage and demonstrates increased failure rates posttreatment. Complicating efforts to improve clinical outcomes, animal models used in pre-clinical research show significant heterogeneity in their regenerative and degenerative responses associated with their species, age, genetic/epigenetic traits, and context of cartilage injury or disease. These can lead to variable outcomes when testing and validating novel therapeutic approaches for OA. Furthermore, it remains unclear whether protection against OA among different model systems is driven by inhibition of cartilage degeneration, enhancement of cartilage regeneration, or any combination thereof. Main text: Understanding the mechanistic basis underlying this context-dependent duality is essential for the rational design of targeted cartilage repair and OA therapies. Here, we discuss some of the critical variables related to the cross-species paradigm of degenerative and regenerative abilities found in pre-clinical animal models, to highlight that a gradient of regenerative competence within cartilage may exist across species and even in the greater human population, and likely influences clinical outcomes. Conclusions: A more complete understanding of the endogenous regenerative potential of cartilage in a species specific context may facilitate the development of effective therapeutic approaches for cartilage injury and/or OA.

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Discerning the spatio-temporal disease patterns of surgically induced OA mouse models

Cited by 16 publications

References 38 publications

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

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

The Treatment of Cartilage Damage Using Human Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review of in vivo Studies

Understanding cartilage protection in OA and injury: a spectrum of possibilities

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