Connective Tissue Formation in Wound Healing - E-thesis

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Figure 3. Steps in the biosynthesis of a collagen fiber and the location in the cell where they occur. RER = rough endoplasmic reticulum (Phillips et al., 1992) (56). 20
Structure and biosynthesis of collagens The characteristic feature of a typical collagen molecule is its long, stiff, triple-stranded helical structure, in which three collagen polypeptide chains, called α-chains, are wound around one another in a ropelike superhelix. Each polypeptide forms a left-handed helix and this results in the formation of a right-handed superhelix. The amino-acid sequences of triple helical domains are characterized by the repetition of triplets Gly-X-Y. Any other amino acid sequence would perturb the triple helical conformation (Fig. 2.). The triple helical conformation is stabilized by the presence of prolyl and hydroxyproly residues in the X and Y positions and by hydrogen bonds between the chains perpendicular to the helix axis (57). To date at least 20 collagen types have been identified and over 30 different collagenous polypeptides, each being a distinct gene product (Table I) (54). Traditionally collagens have been divided into two subgroups, fibril-forming and non-fibril-forming collagens, according to their structural features. The latter group may be further divided in to subfamilies: network-forming collagens, a beaded filamentforming collagen, a collagen which forms anchoring fibrils, FACIT collagens (fibril-associated collagens with interrupted triple helices), collagens with a transmembrane domain, and MULTIPLEXINs (proteins with multiple triple helix domains and interruptions). Collagen biosynthesis involves an unusually large number of post-translational modifications, many of which are unique to collagens and a few other proteins with collagen-like amino acid sequences. This post-translational processing takes place in two stages. Intracellular modifications, together with the synthesis of the α-chains, result in the formation of triple- helical pro-collagen molecules, and extracellular processing converts these molecules into collagens and incorporates the collagen molecules into stable cross-linked fibrils (Fig. 3.) (58) After transcription of the pro-collagen genes and processing of the pre-mRNAs, the proα- chains are synthesized as larger precursors. In addition to the short N-terminal signal peptide, they also have additional amino acids, called propeptides, at both their N-and C-terminal ends (N-P and C-P in Figure 4.A). For post-translational modifications in collagen biosynthesis several specific enzymes are required. Proline and lysine residues in the Y-position are hydroxylated to 4-hydroxyproline and hydroxylysine, respectively, and some of the proline in the X-position are hydroxylated to 3-hydroxyproline. Carbohydrate moieties can be attached to some hydroxylysine and lysine residues by specific transferases. C-terminal propeptides of at least type I and III pro-collagens contain asparagines-linked high-mannose type oligosaccharide side chains. Intra- and interchain disulfide bonds are formed between cysteine residues by protein disulfide isomerase (PDI), which is a subunit of prolyl-4-hydoxylase (59). Pro-collagen 21
Page 1 and 2: Connective Tissue Formation in Woun
Page 3 and 4: CONTENTS ORIGINAL PUBLICATIONS 5 AB
Page 5 and 6: ORIGINAL PUBLICATIONS This thesis i
Page 7 and 8: ABSTRACT A tight balance between co
Page 9 and 10: INTRODUCTION The regulation of extr
Page 11 and 12: REVIEW OF THE LITERATURE WOUND HEAL
Page 13 and 14: days, and neutrophils are themselve
Page 15 and 16: Formation of Granulation Tissue New
Page 17 and 18: emodeled by contraction of the woun
Page 19: Table I Collagen types, their genes
Page 23 and 24: A B COL1A1 COL3A1 COL5A1 C COL1A1 C
Page 25 and 26: TATA box GC box (Sp1/Sp3 binding el
Page 27 and 28: y sequences in their 3’ untransla
Page 29 and 30: espectively (160). Liver has as muc
Page 31 and 32: in the matrix as compared to type I
Page 33 and 34: is the need to generate mechanical
Page 35 and 36: and the catalytic domain, which con
Page 37 and 38: specific binding and cleavage of th
Page 39 and 40: constitutively expressed and contro
Page 41 and 42: inflammatory cells (283). MMP-9 may
Page 43 and 44: TG F-β ligand Receptor II Receptor
Page 45 and 46: and the core proteins of the ECM pr
Page 47 and 48: hydrophobic stretch of the C-termin
Page 49 and 50: similarities to insulin-like growth
Page 51 and 52: CTGF and TGF-β distinguishes them
Page 53 and 54: OUTLINE OF THE PRESENT STUDIES The
Page 55 and 56: were determined: reduced hemoglobin
Page 57 and 58: (Minneapolis, MN, USA). Anti-PDGF A
Page 59 and 60: solution, 10% dextran sulphate and
Page 61 and 62: sequencer, Model 373A (Applied Bios
Page 63 and 64: histology. The hemoglobin content o
Page 65 and 66: especially at the later stages. The
Page 67 and 68: owing to the high standard deviatio
Page 69 and 70: A Staining index A 50 45 40 35 30 2
Page 71 and 72:
the proliferative phase of wound re
Page 73 and 74:
type V collagen expression is assoc
Page 75 and 76:
healing model presented here lacks
Page 77 and 78:
PDGF-A and -B protein was observed
Page 79 and 80:
CTGF functions as a downstream medi
Page 81 and 82:
I am also grateful for all my frien
Page 83 and 84:
19. Brown LF, Yeo KT, Berse B, et a
Page 85 and 86:
56. Phillips C, Wenstrup RJ. Biosyn
Page 87 and 88:
89. Lohi J, Lehti K, Valtanen H, Pa
Page 89 and 90:
124. Wiestner M, Krieg T, Horlein D
Page 91 and 92:
159. Gay S, Vijanto J, Raekallio J,
Page 93 and 94:
196. Saelman EU, Nieuwenhuis HK, He
Page 95 and 96:
237. Knäuper V, Cowell S, Smith B,
Page 97 and 98:
273. Rajavashisth TB, Liao JK, Gali
Page 99 and 100:
307. Geng Y, Weinberg RA. Transform
Page 101 and 102:
346. Heldin CH, Östman A, Rönnstr
Page 103 and 104:
382. Frazier KS, Grotendorst GR. Ex
Page 105 and 106:
416. Glumoff V, Mäkelä JK, Vuorio
Page 107:
454. Pierce GF, Tarpley JE, Tseng J
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