Matricellular Hevin Regulates Decorin Production and Collagen Assembly

Sullivan, Millicent M.; Barker, Thomas H.; Funk, Sarah E.; Karchin, Ari; Seo, Neung Seon; Höök, Magnus; Sanders, Joan E.; Starcher, Barry; Wight, Thomas N.; Puolakkainen, Pauli; Sage, E. Helene

doi:10.1074/jbc.m510507200

Cited by 61 publications

(64 citation statements)

References 46 publications

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“…and turnover of the ECM (35,54). The gene expression levels by clinical scarring grade were broadly consistent with the levels by IVCM connective tissue grade, and the expression levels by clinical inflammation were consistent with the IVCM inflammatory infiltrate correlation.…”

Section: Figsupporting

confidence: 63%

Innate Immune Responses and Modified Extracellular Matrix Regulation Characterize Bacterial Infection and Cellular/Connective Tissue Changes in Scarring Trachoma

Weiss

Ramadhani

et al. 2012

Infect Immun

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Trachoma is the most common infectious cause of blindness and a major public health problem in many developing countries. It is caused by recurrent ocular infection with Chlamydia trachomatis in childhood, with conjunctival scarring seen later in life. The pathogenesis of trachomatous scarring, however, is poorly understood, and this study was carried out to investigate the immunofibrogenic correlates of trachomatous conjunctival scarring. A case-control study of 363 cases with conjunctival scarring and 363 control participants was conducted. Investigations included in vivo confocal microscopy (IVCM) assessment, quantitative real-time PCR gene expression, C. trachomatis detection, and nonchlamydial bacterial culture. Trachomatous scarring was found to be strongly associated with a proinflammatory, innate immune response with increased expression of psoriasin, interleukin-1␤, tumor necrosis factor alpha, defensin-␤4A, chemokine ligand 5, and serum amyloid A1. There was also differential expression of various modifiers of the extracellular matrix, including metalloproteinases 7, 9, 10, and 12, tissue inhibitor of matrix metalloproteinase 1, and secreted protein acidic cystein-rich-like 1. The expression of many of these genes was also significantly associated with the presence of nonchlamydial bacterial infection. These infections had a marked effect on conjunctival immune processes, including an increased inflammatory infiltrate and edema seen with IVCM. This study supports the possibility that the immunofibrogenic response in scarring trachoma is partly stimulated by nonchlamydial bacterial infection, which is characterized by the expression of innate factors.

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Section: Figsupporting

confidence: 63%

Innate Immune Responses and Modified Extracellular Matrix Regulation Characterize Bacterial Infection and Cellular/Connective Tissue Changes in Scarring Trachoma

Weiss

Ramadhani

et al. 2012

Infect Immun

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“…S1B). Decorin also inhibits cell spreading (24), and CAR-decorin was more potent in this regard than decorin ( Fig. 2A, 72 h).…”

Section: Activities Of Decorin and Car Peptide Are Retained In The Fumentioning

confidence: 99%

“…The dose for decorins was 40 μg per injection in 150 μL PBS was selected on the basis of previous decorin-treatment studies (8,24,25), except that the dose was doubled on days 4-6 to coincide with the expected peak of TGF-β expression in the wounds (5). The dose for CAR-HSA was 65 μg per injection.…”

Section: Methodsmentioning

confidence: 99%

Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice

Järvinen

Ruoslahti

2010

Proc. Natl. Acad. Sci. U.S.A.

179

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Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-β activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-β1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem.

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“…On the other hand, Hevin, which shares the critical amino acids for 4 J. C. Marini, unpublished observations. the collagen binding in the homologous EC domain with SPARC, was shown to enhance the collagen fibril formation (62), and these proteins have opposite effects on the collagen assembly. The data obtained in this study suggest that SPARC may regulate the initiation of collagen fibril formation.…”

Section: (Dark Blue Triangles) Cb8 (Green Inverted Triangles) and Cmentioning

confidence: 99%

Mapping of SPARC/BM-40/Osteonectin-binding Sites on Fibrillar Collagens

Giudici

Raynal

Wiedemann

et al. 2008

Journal of Biological Chemistry

100

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The 33-kDa matrix protein SPARC (BM-40, osteonectin) binds several collagen types with moderate affinity. The collagen-binding site resides in helix ␣A of the extracellular calciumbinding domain of SPARC and is partially masked by helix ␣C. Previously, we found that the removal of helix ␣C caused a 10-fold increase in the affinity of SPARC for collagen, and we identified amino acids crucial for binding by site-directed mutagenesis. In this study, we used rotary shadowing, CNBr peptides, and synthetic peptides to map binding sites of SPARC onto collagens I, II, and III. Rotary shadowing and electron microscopy of SPARC-collagen complexes identified a major binding site ϳ180 nm from the C terminus of collagen. SPARC binding was also detected with lower frequency near the matrix metalloproteinase cleavage site. These data fit well with our analysis of SPARC binding to CNBr peptides, denaturation of which abolished binding, indicating triple-helical conformation of collagen to be essential. SPARC binding was substantially decreased in two of seven ␣2(I) mutant procollagen I samples and after N-acetylation of Lys/Hyl side chains in wild-type collagen. Synthetic peptides of collagen III were used to locate the binding sites, and we found SPARC binding activity in a synthetic triple-helical peptide containing the sequence GPOG-PSGPRGQOGVMGFOGPKGNDGAO (where O indicates 4-hydroxyproline), with affinity for SPARC comparable with that of procollagen III. This sequence is conserved among ␣ chains of collagens I, II, III, and V. In vitro collagen fibrillogenesis was delayed in the presence of SPARC, suggesting that SPARC might modulate collagen fibril assembly in vivo.Collagens are major components of the extracellular matrix, comprising ϳ30% of the protein mass of vertebrates. At least 28 collagens have been identified so far (1-3) encoded by 46 separate genes. The defining feature of collagens is a triple-helical domain assembled from three polypeptide strands, called ␣-chains, which each consist of repeating Gly-X-Y sequences, where X is often proline and Y is often hydroxyproline. This primary structure facilitates left-handed poly-proline II helical conformation in each ␣-chain, and three ␣-chains form a righthanded triple helix stabilized by interchain hydrogen bonds (4). To form this structure, Gly is required as every third residue. Its lack of side chains allows contact between ␣-chains, whereas the side chains of residues X and Y are exposed on the surface of the triple helix where they can interact with various molecules. Collagens are major structural proteins, endowing mechanical strength upon the extracellular matrix and also regulating cell behavior through the binding of cell surface receptors and other proteins, such as discoidin domain receptors, a subset of the integrins ␣1␤1, ␣2␤1, ␣10␤1, and ␣11␤1, NG2 proteoglycan, and many matrix molecules (5-7). Nearly 50 different ligands have been shown to interact with collagen, and the binding sites for half of these have been mapped onto collagen I (8). The bind...

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Matricellular Hevin Regulates Decorin Production and Collagen Assembly

Cited by 61 publications

References 46 publications

Innate Immune Responses and Modified Extracellular Matrix Regulation Characterize Bacterial Infection and Cellular/Connective Tissue Changes in Scarring Trachoma

Innate Immune Responses and Modified Extracellular Matrix Regulation Characterize Bacterial Infection and Cellular/Connective Tissue Changes in Scarring Trachoma

Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice

Mapping of SPARC/BM-40/Osteonectin-binding Sites on Fibrillar Collagens

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