Connective Tissue Formation in Wound Healing - E-thesis

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Collagenases MMP-1 MMP-8 MMP-13 Gelatinases MMP-2 MMP-9 Pre Pro Pre Pro Pre Pro Pre Pro Cataly ltic Zn Cataly ltic Zn Cataly ltic Zn H Hemopexin TM Pre Pro F Catalyltic Zn C Pre Pro F Cataly ltic Zn Cataly ltic Zn Figure 7. Domain structure of the MMPs. Pre, signal sequence; Pro, propeptide; F, furin-susceptible site; Zn, zinc-binding site; II, collagen-binding fibronectin type II inserts; H, hinge region; TM, transmembrane domain; C, cytoplasmic tail; GPI, glycophosphatidyl inositol-anchoring domain; C/P, cysteine/proline; IL-1R, interleukin-1 receptor; α2V col, α2V collagen domain. The hemopexin/vitronectin-like domain contains four repeats with the first and last linked by a disulfide bond. Modified from (Sternlicht et al, 2001 and Cawston et al, 1998) (217, 236). 36 H H H Hemop exin S S Pre Pro Catalyltic II II II Zn Hemopexin H S S Pre Pro Catalyltic II II α2V col II Zn domain Stromelysins and matrilysins MMP-3 MMP-10 MMP-12 MMP-7 MMP-26 Membrane-type MMPs MMP-14 MMP-15 MMP-16 MMP-24 MMP-17 MMP-25 Other MMPs MMP-11 MMP-28 MMP-23 MMP-19 MMP-20 Hemop exin S S S S H Hemopexin Pre Pro F Catalyltic Zn GPI Hemop exin S S Pre Pro F Catalyltic Zn C/P-rich IL-1R-like H H S S Hemop exin Hemop exin S S S S
specific binding and cleavage of the substrate (228, 237). The fibrillar collagens are cleaved at a specific site to yield N-terminal ¾ and C-terminal ¼ fragments, which denature to gelatin and can be further degraded by other MMPs, e.g., gelatinases (36, 224). MMP-1 degrades preferentially type III collagen, while MMP-8 has preference for monomeric types I and II collagens (238, 239). MMP-13 is ten-fold more effective in degrading type II collagen, has a stronger gelatinolytic activity than collagense-1 and a broader substrate specificity than the other collagenases (237). The initial cleavage of native collagen by collagenases represents the rate-limiting step in the degradation of interstitial collagens (238). MMP-1 is expressed in various normal cell types such as fibroblasts, keratinocytes, endothelia cells, monocytes, macrophages, chondrocytes and osteoblasts (224). MMP-8 is synthesized by polymorphonuclear leukocytes during their maturation in bone marrow, stored in intracellular granules, and released in response to external stimuli (240). In addition, fibroblasts, bronchial epithelial cells and macrophages express MMP-8 (241, 242). Both MMP-1 and MMP-8 are present at high levels during the inflammatory and early proliferative phases of wound repair (243). MMP-13 is expressed during fetal bone development, postnatal bone remodeling, and gingival wound repair (244, 245). The stromelysin subgroup contains stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and two other MMPs with similar substrate specificities that are structurally less closely related: namely MMP-7 and macrophage metalloelastase (MMP-12). An important feature of this group of enzymes is their capacity to activate pro-collagenases. MMP-3 and MMP-10 are expressed by fibroblastic cells and by normal and transformed squamous epithelial cells (246, 247). Stromelysins degrade basement membrane components, type IV collagen nidogen, and fibronectin; both matrilysin and macrophage metalloelastase have the ability to degrade elastin (36, 224). The existence of membrane-bound MMPs was suggested by the finding that plasma membranes from various tumor cells contained proMMP-2 activator sensitive to MMP inhibitors (248, 249). This lead to the identification of MMP-14 (MT1-MMP), with a transmembrane domain that directs a cell surface localization (250). MMP-14 is a type I transmembrane protein. It has a typical five-domain modular structure resembling collagenases and sromelysins. It also contains a domain susceptible to intracellular proteolytic activation by furin, an additional short carboxyl-terminal transmembrane domain, and intracellular domain 37
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 and 20: Table I Collagen types, their genes
Page 21 and 22: Structure and biosynthesis of colla
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 the catalytic domain, which con
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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