Research ArticleFibrosis

Thrombospondin-1 promotes matrix homeostasis by interacting with collagen and lysyl oxidase precursors and collagen cross-linking sites

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Science Signaling  29 May 2018:
Vol. 11, Issue 532, eaar2566
DOI: 10.1126/scisignal.aar2566

Thrombospondin-1 controls collagen homeostasis directly

Collagens, components of the extracellular matrix important for tissue architecture and function, undergo a complex series of processing events before and after secretion. Deposition of excessive amounts of collagens and abnormal cross-linking of collagen fibrils are associated with fibrosis. Using knockout mice, primary human dermal fibroblasts, and in vitro binding assays, Rosini et al. found that thrombospondin-1 (TSP1) bound to and inhibited the processing of the precursor form of the collagen cross-linking enzyme lysyl oxidase. TSP1 also bound to collagen molecules intracellularly and at conserved cross-linking sites. Blocking the latter interaction extracellularly stimulated fibroblasts to undergo inappropriate conversion to myofibroblasts. Although the mechanism by which the TSP1-collagen interaction prevents fibroblast-to-myofibroblast conversion is unclear, these findings identify a direct role for TSP1 as a modulator of the collagen matrix.


Fibrillar collagens of the extracellular matrix are critical for tissue structure and physiology; however, excessive or abnormal deposition of collagens is a defining feature of fibrosis. Regulatory mechanisms that act on collagen fibril assembly potentially offer new targets for antifibrotic treatments. Tissue weakening, altered collagen fibril morphologies, or both, are shared phenotypes of mice lacking matricellular thrombospondins. Thrombospondin-1 (TSP1) plays an indirect role in collagen homeostasis through interactions with matrix metalloproteinases and transforming growth factor–β1 (TGF-β1). We found that TSP1 also affects collagen fibril formation directly. Compared to skin from wild-type mice, skin from Thbs1−/− mice had reduced collagen cross-linking and reduced prolysyl oxidase (proLOX) abundance with increased conversion to catalytically active LOX. In vitro, TSP1 bound to both the C-propeptide domain of collagen I and the highly conserved KGHR sequences of the collagen triple-helical domain that participate in cross-linking. TSP1 also bound to proLOX and inhibited proLOX processing by bone morphogenetic protein-1. In human dermal fibroblasts (HDFs), TSP1 and collagen I colocalized in intracellular vesicles and on extracellular collagen fibrils, whereas TSP1 and proLOX colocalized only in intracellular vesicles. Inhibition of LOX-mediated collagen cross-linking did not prevent the extracellular association between collagen and TSP1; however, treatment of HDFs with KGHR-containing, TSP1-binding, triple-helical peptides disrupted the collagen-TSP1 association, perturbed the collagen extracellular matrix, and increased myofibroblastic differentiation in a manner that depended on TGF-β receptor 1. Thus, the extracellular KGHR-dependent interaction of TSP1 with fibrillar collagens contributes to fibroblast homeostasis.

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