The matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis

Abstract

Fibrosis is a pervasive disease in which the excessive deposition of extracellular matrix (ECM) compromises tissue function. Although the underlying mechanisms are mostly unknown, matrix stiffness is increasingly appreciated as a contributor to fibrosis rather than merely a manifestation of the disease. Here we show that the loss of Fibulin-5, an elastic fibre component, not only decreases tissue stiffness, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis. These results suggest that Fibulin-5 may be a therapeutic target to short-circuit this profibrotic feedback loop.

Influence of the extracellular matrix on cell-intrinsic circadian clocks

“…During pregnancy and lactation, epithelial spherical alveoli develop towards the ends of ducts, which synthesise milk and secrete it into the ductal network. Surrounding the ducts and alveoli is stromal tissue, comprising ECM components as well as fibroblasts, adipocytes, immune cells and endothelial cells (Muschler and Streuli, 2010). These latter cells contribute both to epithelial function in development and lactation, and they provide the architectural structure of breast tissue (Sternlicht et al, 2006).…”

“…laminin, collagen, perlecan and fibronectin), as well as other cells (e.g. through cadherins, and gap and tight junctions), have critical roles in tissue function (Muschler and Streuli, 2010). Moreover, abnormal functioning of the matrix underpins many of the pathologies associated with advanced age.…”

“…Importantly, the biomechanical and biochemical properties of tissues alter during ageing, which can impact on cell and tissue functions (Sherratt, 2009). For instance, increased tissue stiffness contributes to the pathogenesis of diseases, such as fibrosis and malignancy (Boyd et al, 2014;Fiorino et al, 2018;Handorf et al, 2015;Nakasaki et al, 2015). It is therefore important to know whether a cell type that normally lives in a biomechanically soft environment changes its clock properties when the ECM becomes stiffer, or vice versa.…”

Combined magnetic resonance elastography and collagen molecular magnetic resonance imaging accurately stage liver fibrosis in a rat model

“…MRE has been most widely applied to assess liver fibrosis and has been reported to be most reliable at detecting advanced fibrosis and cirrhosis . Portal hypertension, inflammation, and collagen crosslinking are some of the commonly acknowledged factors contributing to this late‐stage liver stiffening …”

“…(8) Portal hypertension, inflammation, and collagen crosslinking are some of the commonly acknowledged factors contributing to this late-stage liver stiffening. (9)(10)(11) Molecular imaging also holds great promise for the noninvasive detection of organ fibrosis. A peptidebased type 1 collagen-specific magnetic resonance (MR) probe, termed EP-3533, was demonstrated to detect and stage disease in animal models of cardiac, pulmonary, and hepatic fibrosis.…”