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Fibrosis

ECM remodelling by ADAMTS12 in fibrosis

Nature Reviews Nephrology volume 20, page 770 (2024)Cite this article

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Fibrosis results from the continuous deposition of extracellular matrix (ECM) by fibroblasts in response to injurious stimuli; however, the exact roles of fibroblasts in this process are unclear. New findings demonstrate a key role for the protease ADAMTS12 in driving fibrosis through the remodelling of ECM and activation of profibrotic fibroblasts. “On the basis of these observations, we hypothesize that ADAMTS12 serves as an autocrine switch that controls the initiation of fibroblast activation, including [their] detachment and migration from the perivascular niche,” say the researchers.

Using unbiased gene expression analyses, Konrad Hoeft, Lars Koch and colleagues observed upregulated expression of ADAMTS12 in fibroblasts after injury in mouse and human kidneys. Mice with deletion of Adamts12 were protected from kidney and cardiac fibrosis, characterized by the limited upregulation of ECM proteins and restricted expansion of profibrotic mesenchymal cells, indicating a regulatory role in the fibrotic process. In line with these findings, deletion of ADAMTS12 in immortalized PDGFRβ+ human mesenchymal kidney cells attenuated expression of the ECM component gene COL1A1 in response to TGFβ, associated with downregulation of JAK–STAT signalling and of pathways related to cell adhesion, cell migration and locomotion. Live cell imaging over a period of 24 h confirmed that the knockout cells exhibited a blunted migratory response to TGFβ, which was rescued by the expression of active ADAMTS12, along with upregulation of JAK–STAT signalling. Mechanistically, the researchers determined that active ADAMTS12 acts to cleave the fibulin HMCN1 — a component of basement membranes that tethers cells to membranes. Knockdown of HMCN1 in ADAMTS12-overexpressing cells inhibited their migration, which indicates that cleaved HMCN1 peptides (which are produced in the presence of activated ADAMTS12) promote mesenchymal cell migration, activation and perpetuation of fibrosis.

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References

Original article

  • Hoeft, K. et al. ADAMTS12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts. J. Clin. Invest. 134, e170246 (2024)

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  1. Nature Reviews Nephrology http://www.nature.com/nrneph

    Susan J. Allison

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  1. Susan J. Allison
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Correspondence to Susan J. Allison.

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Allison, S.J. ECM remodelling by ADAMTS12 in fibrosis. Nat Rev Nephrol 20, 770 (2024). https://doi.org/10.1038/s41581-024-00905-2

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  • DOI: https://doi.org/10.1038/s41581-024-00905-2

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