Intracellular collagen in the nonpregnant and IUD‐containing rat uterus

Dyer, Robert F.; Peppler, R. D.

doi:10.1002/ar.1091870209

Cited by 35 publications

(17 citation statements)

References 14 publications

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“…In the extracellular matrix, collagen fibers are cleaved and denatured by matrix MMPs (MMP1, MMP13, and MMP14) and further degraded by the gelatinases (MMP2, MMP9) (33)(34)(35). The intracellular pathway of collagen degradation involves phagocytosis and lysosomal degradation of collagen by cathepsins (6,36,37). MMP cleavage and fragmentation of collagen prior to internalization are also important for this pathway (34), with one group reporting that a much lower rate of internalization can occur despite MMP inhibition (8).…”

Section: Discussionmentioning

confidence: 99%

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages

Atabai¹,

Jamé²,

Azhar³

et al. 2009

J. Clin. Invest.

197

195

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Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8 -/-mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8 +/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8 -/-macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 containing at least one discoidin domain. These data demonstrate a critical role for Mfge8 in decreasing the severity of murine tissue fibrosis by facilitating the removal of accumulated collagen.

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Section: Discussionmentioning

confidence: 99%

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages

Atabai¹,

Jamé²,

Azhar³

et al. 2009

J. Clin. Invest.

197

195

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“…Intracellular collagen degradation was recognized as a pathway for the turnover of this abundant extracellular matrix component more than three decades ago (7,9,15). However, due to the lack of means to manipulate the cellular uptake of collagen in experimental animals, limited information with respect to both the role of this pathway in physiological and pathological processes and its mechanistic relationship to other collagen turnover pathways is available.…”

Section: Discussionmentioning

confidence: 99%

Complementary Roles of Intracellular and Pericellular Collagen Degradation Pathways In Vivo

Wagenaar-Miller¹,

Engelholm

Gavard³

et al. 2007

Molecular and Cellular Biology

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Collagen degradation is essential for cell migration, proliferation, and differentiation. Two key turnover pathways have been described for collagen: intracellular cathepsin-mediated degradation and pericellular collagenase-mediated degradation. However, the functional relationship between these two pathways is unclear and even controversial. Here we show that intracellular and pericellular collagen turnover pathways have complementary roles in vivo. Individual deficits in intracellular collagen degradation (urokinase plasminogen activator receptor-associated protein/Endo180 ablation) or pericellular collagen degradation (membrane type 1-matrix metalloproteinase ablation) were compatible with development and survival. Their combined deficits, however, synergized to cause postnatal death by severely impairing bone formation. Interestingly, this was mechanistically linked to the proliferative failure and poor survival of cartilage-and bone-forming cells within their collagen-rich microenvironment. These findings have important implications for the use of pharmacological inhibitors of collagenase activity to prevent connective tissue destruction in a variety of diseases.The collagens are the most abundant extracellular matrix components in the body and can constitute as much as 90% of the extracellular matrix of a tissue. They consist of three polypeptide chains, each with a single long, uninterrupted section of Gly-X-Y amino acid repeats that are intertwined to produce a superhelix that buries the peptide bonds within the interior of the helix. The fibrillar collagens spontaneously selfassociate to form fibrils that range in diameter from 10 to 300 nm, while basement membrane collagens form complicated sheets with both triple-helical and globular motifs (26,39).Extensive turnover of collagen takes place during a variety of physiological and pathological tissue-remodeling processes, including development, tissue repair, degenerative connective tissue diseases, and cancer. In this context, collagen turnover serves at least five different functions. It facilitates the physical expansion of a tissue (normal or aberrant), liberates latent growth factors embedded within the extracellular matrix, enables vascular development, subverts the proliferative restrictions imposed on cells by the extracellular matrix, and directly regulates cellular differentiation (5, 22, 30). Inhibition of extracellular matrix degradation, therefore, has long been recognized as an attractive target for therapeutic intervention in a variety of human diseases (1, 6).Three molecular pathways are known for the turnover of collagen in physiological and pathological tissue-remodeling processes. The best-studied pathway involves a group of secreted or membrane-associated matrix metalloproteinases, the collagenases, that directly cleave collagens within the pericellular or extracellular environment (4, 44). A second, cathepsin K-mediated pathway is specific for osteoclast-mediated bone resorption and takes place in the acidic microenvironment that is ...

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“…Because of the observation that fibroblasts of most connective tissues contain phagocytosed fibrillar collagen in their lysosomal apparatus (Dyer and Peppier, 1977;Svoboda et al, 1981;Asuwa, 1988), and the presence of collagenolytic enzymes in fibroblast lysosomes (Mort et al, 1981;Wang, 1982), an intracellular route of collagen resorption was advanced. This pathway has been proposed as of major importance to the physiological turnover of extracellular collagen (Ten Cate and Deporter, 1975;Everts et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Participation of intracellular cysteine proteinases, in particular cathepsin B, in degradation of collagen in periosteal tissue explants

et al. 1998

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Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. AbstractThe involvement of cysteine proteinases in the degradation of soft connective tissue collagen was studied in cultured periosteal explants. Using cysteine proteinase inhibitors that were active intracellularly or extracellularly (Ep453 and Ep475, respectively), it was shown that over-all collagen degradation, as measured by the release of hydroxyproline, decreased significantly on inhibition of the intracellular pool of cysteine proteinases by Ep453. This inhibitor also induced an accumulation of intracellular fibrillar collagen in fibroblasts, indicating a decreased degradation of phagocytosed collagen. The extracellular inhibitor, Ep475, had minor or no effects.Histochemical analysis using a substrate for the cysteine proteinases cathepsins B and L revealed a high level of enzyme activity, which was completely blocked in explants preincubated with a selective intracellular inhibitor of cathepsin B, Ca074-Me. Moreover, the cathepsin B inhibitor strongly affected collagen degradation, decreasing the release of hydroxyproline and increasing the accumulation of phagocytosed collagen. These effects were comparable or slightly stronger than those found with the general intracellular inhibitor (Ep453). Taken together, these data strongly suggest that intracellular cysteine proteinases, in particular cathepsin B, play an important role in the digestion of soft connective tissue collagen.

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Intracellular collagen in the nonpregnant and IUD‐containing rat uterus

Cited by 35 publications

References 14 publications

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages

Complementary Roles of Intracellular and Pericellular Collagen Degradation Pathways In Vivo

Participation of intracellular cysteine proteinases, in particular cathepsin B, in degradation of collagen in periosteal tissue explants

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