Unresolved intramuscular inflammation, not diminished skeletal muscle regenerative capacity, is at the root of rheumatoid cachexia: insights from a rat CIA model

Ollewagen, Tracey; Powrie, Yigael S. L.; Myburgh, Kathryn H.; Smith, Carine

doi:10.14814/phy2.15119

Cited by 2 publications

(4 citation statements)

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“…The reduction in TGF- β observed in this study may thus also have resulted in an increase in Id2, contributing to inhibition of differentiation. This is in agreement with a previous rodent collagen-induced arthritis study by our group, where increased Id2 was indeed observed [ 24 ]. This provides additional insight into the occurrence of rheumatoid cachexia despite an increase in myogenic regulatory factors, including myogenin, as reported by our group and others [ 50 ].…”

Section: Discussionsupporting

confidence: 94%

“…These effects were likely the result of various growth factors and cytokines present in the serum stimulating the proliferation of myoblasts and fibroblasts. This aligns with the data observed in the rodent CIA model where increased cellular presence was observed; however, the ratio between the cells did not differ [ 24 ]. While distinguishing between the cells in single culture was possible due to the low desmin/high fibronectin expression in fibroblasts and low fibronectin/high desmin expression in myoblasts, coculture presents some challenges in this regard.…”

Section: Discussionsupporting

confidence: 91%

“…However, this relationship appears to be dysregulated in the RATNR group, where a negative correlation is observed. This relative failure to upregulate IL-10 in response to IL-6 is in line with our earlier suggestion of a failure of RA macrophages to switch to the anti-inflammatory M2c phenotype, which is responsible for IL-10 release [ 3 ] as well as our recent study in CIA rats, which demonstrated decreased IL-10 concentration in muscle to be a robust marker for rheumatoid cachexia in this model [ 24 ]. This aspect should be elucidated further in longitudinal studies in human RA patients, to fully evaluate the potential of IL-10 as a biomarker of disease progression and risk of muscle cachexia in particular.…”

Section: Discussionsupporting

confidence: 90%

“…Primary M1-polarised macrophages were detached with Accutase® (A6964, Sigma-Aldrich). Cells were plated on ECL-precoated plates in the patient serum-containing media in the ratio of 40 000 macrophages:10 000 myoblasts:5 000 fibroblasts as determined with intramuscular cell staining in a rodent collagen-induced arthritis model [ 24 ]. (The number of macrophages was modified to twice the number present in RA rodents, to correct for known lack of proliferation capacity of the terminally differentiated macrophages over the course of the culture protocol.)…”

Section: Methodsmentioning

confidence: 99%

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Therapeutic Benefit in Rheumatoid Cachexia Illustrated Using a Novel Primary Human Triple Cell Coculture Model

Ollewagen

Tarr

Myburgh

et al. 2022

International Journal of Inflammation

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Background. The loss of muscle mass in rheumatoid arthritis (RA), termed rheumatoid cachexia, is predicted to result from the complex interactions between different cell types involved in the maintenance of skeletal muscle mass, namely, myoblasts, fibroblasts, and macrophages. The complexity within the muscle is further highlighted by the incidence of nonresponsiveness to current RA treatment strategies. Method. This study aimed at determining differences in the cellular responses in a novel human primary cell triple coculture model exposed to serum collected from nonarthritic controls (NC), RA treatment naïve (RATN), and RA treatment-nonresponding (RATNR) patients. Bone morphogenetic protein-7 (BMP-7) was investigated as a treatment option. Results. Plasma analysis indicated that samples were indeed representative of healthy and RA patients—notably, the RATNR patients additionally exhibited dysregulated IL-6/IL-10 correlations. Coculture exposure to serum from RATNR patients demonstrated increased cellular growth ( p < 0.001 ), while both hepatocyte growth factor ( p < 0.01 ) and follistatin ( p < 0.001 ) were reduced when compared to NC. Furthermore, decreased concentration of markers of extracellular matrix formation, transforming growth factor-β (TGF-β; p < 0.05 ) and fibronectin ( p < 0.001 ), but increased collagen IV ( p < 0.01 ) was observed following RATNR serum exposure. Under healthy conditions, BMP-7 exhibited potentially beneficial results in reducing fibrosis-generating TGF-β ( p < 0.05 ) and fibronectin ( p < 0.05 ). BMP-7 further exhibited protective potential in the RA groups through reversing the aberrant tendencies observed especially in the RATNR serum-exposed group. Conclusion. Exposure of the triple coculture to RATN and RATNR serum resulted in dysregulated myoblast proliferation and growth, and ECM impairment, which was reversed by BMP-7 treatment.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic Benefit in Rheumatoid Cachexia Illustrated Using a Novel Primary Human Triple Cell Coculture Model

Ollewagen

Tarr

Myburgh

et al. 2022

International Journal of Inflammation

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The potential of zebrafish as drug discovery research tool in immune-mediated inflammatory disease

Smith

2024

Inflammopharmacol

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Immune-mediated inflammatory disease (IMID) prevalence is estimated at 3–7% for Westernised populations, with annual incidence reported at almost 1 in 100 people globally. More recently, drug discovery approaches have been evolving towards more targeted therapies with an improved long-term safety profile, while the requirement for individualisation of medicine in complex conditions such as IMIDs, is acknowledged. However, existing preclinical models—such as cellular and in vivo mammalian models—are not ideal for modern drug discovery model requirements, such as real-time in vivo visualisation of drug effects, logistically feasible safety assessment over the course of a lifetime, or dynamic assessment of physiological changes during disease development. Zebrafish share high homology with humans in terms of proteins and disease-causing genes, with high conservation of physiological processes at organ, tissue, cellular and molecular level. These and other unique attributes, such as high fecundity, relative transparency and ease of genetic manipulation, positions zebrafish as the next major role player in IMID drug discovery. This review provides a brief overview of the suitability of this organism as model for human inflammatory disease and summarises the range of approaches used in zebrafish-based drug discovery research. Strengths and limitations of zebrafish as model organism, as well as important considerations in research study design, are discussed. Finally, under-utilised avenues for investigation in the IMID context are highlighted.

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Unresolved intramuscular inflammation, not diminished skeletal muscle regenerative capacity, is at the root of rheumatoid cachexia: insights from a rat CIA model

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 2 publications

References 54 publications

Therapeutic Benefit in Rheumatoid Cachexia Illustrated Using a Novel Primary Human Triple Cell Coculture Model

Therapeutic Benefit in Rheumatoid Cachexia Illustrated Using a Novel Primary Human Triple Cell Coculture Model

The potential of zebrafish as drug discovery research tool in immune-mediated inflammatory disease

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