S100A4 a classical DAMP as a therapeutic target in fibrosis

O'Reilly, Steven

doi:10.1016/j.matbio.2024.01.002

Cited by 4 publications

(3 citation statements)

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“…Tendon injuries typically heal in a fibrotic manner, characterized by excessive and disorganized deposition of extracellular matrix 28 . Both Myofibroblasts (αSMA+ cells) and S100A4+ cells are highly active in fibrosis 29 . While S100A4 serves as a marker for tenocytes in intact tendons and granulation tissue, it is also critical driver of fibrosis and fibrotic tendon healing 30 .…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone treatment influences tendon healing through altered resolution and a direct effect on tendon cells

Dietrich-Zagonel,

Alim,

Beckman

et al. 2024

Sci Rep

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Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone treatment influences tendon healing through altered resolution and a direct effect on tendon cells

Dietrich-Zagonel,

Alim,

Beckman

et al. 2024

Sci Rep

View full text Add to dashboard Cite

show abstract

“…These interactions in turn trigger multiple downstream pathways involved in inflammation and fibrosis. Several publications provide experimental evidence that extracellular S100A4 is intimately involved in various types of organ fibrosis (( 10 ) and references therein). Released S100A4 could trigger neighboring fibroblasts to differentiate into myofibroblasts and stimulate neighboring cells to produce and secrete more S100A4 in a feed-forward manner.…”

mentioning

confidence: 99%

“…Both extra- and intracellular S100A4 seem to be key players in fibrotic disorders and both are potentially attractive targets for therapeutic intervention. Neutralizing antibodies against extracellular S100A4 are in clinical trials ( 10 ), and S100A4-specific small molecule inhibitors are also under development. Finally, it should be taken into account when trying to unravel the role of S100 proteins in physiological processes and as a target for therapeutic purposes, that other family members are also expressed in fibroblasts, and since S100 possesses some functional redundancy ( 7 ), their possible contribution to myofibroblast transdifferentiation needs to be explored.…”

mentioning

confidence: 99%