Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling

Abstract

Collagens of most connective tissues are subject to continuous remodelling and turnover, a phenomenon which occurs under both physiological and pathological conditions. Degradation of these proteins involves participation of a variety of proteolytic enzymes including members of the following proteinase classes: matrix metalloproteinases (e.g. collagenase, gelatinase and stromelysin), cysteine proteinases (e.g. cathepsin B and L) and serine proteinases (e.g. plasmin and plasminogen activator). Convincing evidence is available indicating a pivotal role for matrix metalloproteinases, in particular collagenase, in the degradation of collagen under conditions of rapid remodelling, e.g. inflammation and involution of the uterus. Under steady state conditions, such as during turnover of soft connective tissues, involvement of collagenase has yet to be demonstrated. Under these circumstances collagen degradation is likely to take place particularly within the lysosomal apparatus after phagocytosis of the fibrils. We propose that this process involves the following steps: (i) recognition of the fibril by membrane-bound receptors (integrins?), (ii) segregation of the fibril, (iii) partial digestion of the fibril and/or its surrounding non-collagenous proteins by matrix metalloproteinases (possibly gelatinase), and finally (iv) lysosomal digestion by cysteine proteinases, such as cathepsin B and/or L. Modulation of this pathway is carried out under the influence of growth factors and cytokines, including transforming growth factor beta and interleukin 1 alpha.

Cell–Matrix Entanglement and Mechanical Anchorage of Fibroblasts in Three-dimensional Collagen Matrices

“…Fibroblasts in tissues are phagocytic cells (McGaw and Ten Cate, 1983;Everts et al, 1996Everts et al, , 2003, and in culture they have been shown to ingest both fibronectin and collagen-coated latex particles (Grinnell and Geiger, 1986; McCulloch and Knowles, 1993). In the present study, we found that phagocytosis of fibronectin-coated beads by fibroblasts on collagen matrices was reduced compared with cells on collagencoated coverslips.…”

“…Similar morphological features have been described for cells in tissues (Breathnach, 1978;Doljanski, 2004;Goldsmith et al, 2004;Langevin et al, 2005). In part, differences in morphology between cells in twodimensional (2D) versus 3D culture may result from the symmetric adhesive interactions in 3D matrices versus the forced asymmetry of 2D surfaces (Beningo et al, 2004).In tissues, fibroblasts are phagocytic cells (McGaw and Ten Cate, 1983;Everts et al, 1996Everts et al, , 2003, and in culture they have been shown to ingest both fibronectin (FN) and collagen-coated latex particles (Grinnell and Geiger, 1986;McCulloch and Knowles, 1993). Cell adhesion and spreading on 2D surfaces was reported to constrain phagocytic activity (Arora et al, 2003).…”

“…Fibroblasts in tissues are phagocytic cells (McGaw and Ten Cate, 1983;Everts et al, 1996Everts et al, , 2003, and in culture they have been shown to ingest both fibronectin and collagen-coated latex particles (Grinnell and Geiger, 1986; McCulloch and Effect of EDTA and integrin ␣2␤1 blocking antibody on cell adhesion to collagen matrices. Cells were attached to collagen matrices for the time periods shown in medium containing 10 g/ml anti-integrin ␣2␤1 blocking antibody or 10 mM EDTA as indicated.…”

“…In tissues, fibroblasts are phagocytic cells (McGaw and Ten Cate, 1983;Everts et al, 1996Everts et al, , 2003, and in culture they have been shown to ingest both fibronectin (FN) and collagen-coated latex particles (Grinnell and Geiger, 1986;McCulloch and Knowles, 1993). Cell adhesion and spreading on 2D surfaces was reported to constrain phagocytic activity (Arora et al, 2003).…”

Mechanisms of Lung Fibrosis Resolution

“…18,23,24 Extracellular Pathways of ECM Degradation Matrix degradation likely occurs through a multistep process that involves extracellular protease-mediated cleavage, recognition of fibrils by membrane-bound receptors, and cellular uptake with intracellular lysosomal degradation of cleaved matrix fragments. 24,25 Several enzymatic families are known to degrade matrix in the lung through the extracellular pathway, including matrix metalloproteinases (MMPs), cysteine proteinases (cathepsins B and L), and serine proteinases (plasmin and plasminogen activator). The foremost proteolytic enzymes involved in extracellular cleavage are the MMPs.…”