Collagen

Tropocollagen triple helix.

Collagen is a group of naturally occurring proteins. In nature, it is found exclusively in animals, especially in the flesh and connective tissues of mammals.[1] It is the main component of connective tissue, and is the most abundant protein in mammals,[2] making up about 25% to 35% of the whole-body protein content. Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendon, ligament and skin, and is also abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc.

In muscle tissue it serves as a major component of endomysium. Collagen constitutes 1% to 2% of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles.[3] Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed.

Contents

History and background

The molecular and packing structures of collagen have eluded scientists over decades of research. The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s.[4][5] Since that time many prominent scholars, including Nobel laureates Crick, Pauling, Rich, Yonath, Brodsky, Berman, and Ramachandran, concentrated on the conformation of the collagen monomer. Several competing models, although correctly dealing with the conformation of each individual peptide chain, gave way to the triple-helical "Madras" model which provided an essentially correct model of the molecule's quaternary structure[6][7][8] although this model still required some refinement.[9][10][11][12] The packing structure of collagen has not been defined to the same degree outside of the fibrillar collagen types, although it has been long known to be hexagonal ...or quasi-hexagonal.[13][14][15] As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is 'sheet-like' or microfibrillar.[16][17] The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron microscopy.[18][19][20] In 2006, it was confirmed that the microfibrillar structure of adult tendon as described by Fraser, Miller, Wess (amongst others) was closest to the observed structure, although it over-simplified the topological progression of neighboring collagen molecules and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril.[21]

Molecular structure

The tropocollagen or "collagen molecule" is a subunit of larger collagen aggregates such as fibrils. It is approximately 300 nm long and 1.5 nm in diameter, made up of three polypeptide strands (called alpha chains), each possessing the conformation of a left-handed helix (its name is not to be confused with the commonly occurring alpha helix, a right-handed structure). These three left-handed helices are twisted together into a right-handed coiled coil, a triple helix or "super helix", a cooperative quaternary structure stabilized by numerous hydrogen bonds. With type I collagen and possibly all fibrillar collagens if not all collagens, each triple-helix associates into a right-handed super-super-coil that is referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring microfibrils to a degree that might suggest that they are individually unstable although within collagen fibrils they are so well ordered as to be crystalline.

A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern Gly-Pro-X or Gly-X-Hyp, where X may be any of various other amino acid residues. Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means that approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX1X2 character of collagen alpha-peptides. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. About 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala- with 10% serine, and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small, inert methyl group. Such high glycine and regular repetitions are never found in globular proteins save for very short sections of their sequence. Chemically-reactive side groups are not needed in structural proteins as they are in enzymes and transport proteins, however collagen is not quite just a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its non-proline rich regions have cell or matrix association / regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.

Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix—Hyp even more so than Pro; a lower concentration of them is required in animals such as fish, whose body temperatures are lower than most warm-blooded animals.

Fibrillar structure

The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues.[22][23] In the fibrillar collagens, the molecules are staggered from each other by about 67 nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains 4 and a fraction collagen molecules. This is because 300 nm divided by 67 nm does not give an integer (the length of the collagen molecule divided by the stagger distance D). Therefore in each D-period repeat of the microfibril, there is a part containing five molecules in cross-section—called the “overlap” and a part containing only 4 molecules, called the "gap".[21] The triple-helices are also arranged in a hexagonal or quasi-hexagonal array in cross-section, in both the gap and overlap regions.[21][13]

There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils).[24] Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players.[23] Collagen's insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked. However, advances in microscopy techniques electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure in situ. These later advances are particularly important to better understanding the way in which collagen structure affects cell-cell and cell-matrix communication, and how tissues are constructed in growth and repair, and changed in development and disease.[25][26]

Collagen fibrils are semicrystalline aggregates of collagen molecules. Collagen fibers are bundles of fibrils.

Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. Forty nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) hydroxyapatite, Ca10(PO4)6(OH)2 with some phosphate. It is in this way that certain kinds of cartilage turn into bone. Type I collagen gives bone its tensile strength.

Types and associated disorders

Collagen occurs in many places throughout the body. So far, 29 types of collagen have been identified and described. Over 90% of the collagen in the body, however, is of type I, II, III, and IV.

Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen production.

Type Notes Gene(s) Disorders
I This is the most abundant collagen of the human body. It is present in scar tissue, the end product when tissue heals by repair. It is found in tendons, skin, artery walls, the endomysium of myofibrils, fibrocartilage, and the organic part of bones and teeth. COL1A1, COL1A2 osteogenesis imperfecta, Ehlers-Danlos Syndrome, Infantile cortical hyperostosis aka Caffey's disease
II Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour of the eye. COL2A1 Collagenopathy, types II and XI
III This is the collagen of granulation tissue, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Reticular fiber. Also found in artery walls, skin, intestines and the uterus COL3A1 Ehlers-Danlos Syndrome
IV basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney. COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6 Alport syndrome, Goodpasture's syndrome
V most interstitial tissue, assoc. with type I, associated with placenta COL5A1, COL5A2, COL5A3 Ehlers-Danlos syndrome (Classical)
VI most interstitial tissue, assoc. with type I COL6A1, COL6A2, COL6A3 Ulrich myopathy and Bethlem myopathy
VII forms anchoring fibrils in dermal epidermal junctions COL7A1 epidermolysis bullosa dystrophica
VIII some endothelial cells COL8A1, COL8A2 Posterior polymorphous corneal dystrophy 2
IX FACIT collagen, cartilage, assoc. with type II and XI fibrils COL9A1, COL9A2, COL9A3 - EDM2 and EDM3
X hypertrophic and mineralizing cartilage COL10A1 Schmid metaphyseal dysplasia
XI cartilage COL11A1, COL11A2 Collagenopathy, types II and XI
XII FACIT collagen, interacts with type I containing fibrils, decorin and glycosaminoglycans COL12A1 -
XIII transmembrane collagen, interacts with integrin a1b1, fibronectin and components of basement membranes like nidogen and perlecan. COL13A1 -
XIV FACIT collagen COL14A1 -
XV - COL15A1 -
XVI - COL16A1 -
XVII transmembrane collagen, also known as BP180, a 180 kDa protein COL17A1 Bullous pemphigoid and certain forms of junctional epidermolysis bullosa
XVIII source of endostatin COL18A1 -
XIX FACIT collagen COL19A1 -
XX - COL20A1 -
XXI FACIT collagen COL21A1 -
XXII - COL22A1 -
XXIII MACIT collagen - COL23A1 -
XXIV - COL24A1 -
XXV - COL25A1 -
XXVI - EMID2 -
XXVII - COL27A1 -
XXVIII - COL28A1 -
XXIX epidermal collagen COL29A1 Atopic dermatitis[27]

In addition to the above mentioned disorders, excessive deposition of collagen occurs in scleroderma.

Staining

In histology, collagen is brightly eosinophilic (pink) in standard H&E slides. The dye methyl violet may be used to stain the collagen in tissue samples.

The dye methyl blue can also be used to stain collagen and immunohistochemical stains are available if required.

The best stain for use in differentiating collagen from other fibers is Masson's trichrome stain.

Synthesis

Action of lysyl oxidase

Amino acids

Collagen has an unusual amino acid composition and sequence:

Cortisol stimulates degradation of (skin) collagen into amino acids.[28]

Collagen I formation

Most collagen forms in a similar manner, but the following process is typical for type I:

  1. Inside the cell
    1. Two types of peptide chains are formed during translation on ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide.
    2. Polypeptide chains are released into the lumen of the RER.
    3. Signal peptides are cleaved inside the RER and the chains are now known as pre-alpha chains.
    4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on ascorbic acid (Vitamin C) as a cofactor.
    5. Glycosylation of specific hydroxylysine residues occurs.
    6. Triple helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain.
    7. Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis.
  2. Outside the cell
    1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
    2. Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
    3. Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.

Synthetic pathogenesis

Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the eighteenth century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of foods containing Vitamin C.

An autoimmune disease such as lupus erythematosus or rheumatoid arthritis[29] may attack healthy collagen fibers.

Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production.

Use

Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins such as enzymes. Tough bundles of collagen called collagen fibers are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments, tendons, bone and skin.[30][31] Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany ageing. It strengthens blood vessels and plays a role in tissue development. It is present in the cornea and lens of the eye in crystalline form. It is also used in cosmetic surgery and burns surgery. Hydrolyzed collagen can play an important role in weight management, as a protein, it can be advantageously used for its satiating power.

Industrial uses

If collagen is sufficiently denatured, e.g. by heating, the three tropocollagen strands separate partially or completely into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII), e.g. random coils. This process describes the formation of gelatin, which is used in many foods, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.[32] From a nutritional point of view, collagen and gelatin are a poor-quality sole source of protein since they do not contain all the essential amino acids in the proportions that the human body requires—they are not 'complete proteins' (as defined by food science, not that they are partially structured). Manufacturers of collagen-based dietary supplements claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown strong evidence to support these claims. Individuals with problems in these areas are more likely to be suffering from some other underlying condition (such as normal aging, dry skin, arthritis etc.) rather than just a protein deficiency.

From the Greek for glue, kolla, the word collagen means "glue producer" and refers to the early process of boiling the skin and sinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it in bows about 1,500 years ago. The oldest glue in the world, carbon-dated as more than 8,000 years old, was found to be collagen—used as a protective lining on rope baskets and embroidered fabrics, and to hold utensils together; also in crisscross decorations on human skulls.[33] Collagen normally converts to gelatin, but survived due to the dry conditions. Animal glues are thermoplastic, softening again upon reheating, and so they are still used in making musical instruments such as fine violins and guitars, which may have to be reopened for repairs—an application incompatible with tough, synthetic plastic adhesives, which are permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.

Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial) has been used to repair experimental incisions in rabbit lungs.[34]

Medical uses

The cardiac valve rings, the central body and the cardiac skeleton of the heart summarily represent a unique and moving collagen anchor to the fluid mechanics of the heart. Individual valvular leaflets are arguably held in shape by collagen under great extremes of pressure. Calcium deposition within collagen occurs as a natural consequence of aging. These fixed points in an otherwise moving display of blood and muscle enable current cardiac imaging technology to arrive at ratios essentially stating blood in cardiac input and blood out cardiac output. Specified imaging such as calcium scoring illustrates the utility of this methodology, especially in an aging patient subject to pathology of the collagen underpinning.

Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic and surgical purposes. Some points of interest are:

  1. when used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use, and
  2. most medical collagen is derived from young beef cattle (bovine) from certified BSE (Bovine spongiform encephalopathy) free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia, Brazil and New Zealand.
  3. porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes.
  4. alternatives using the patient's own fat, hyaluronic acid or polyacrylamide gel are readily available.

Collagens are widely employed in the construction of artificial skin substitutes used in the management of severe burns. These collagens may be derived from bovine, equine or porcine, and even human, sources and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.

Collagen is also sold commercially as a joint mobility supplement.[35] Because proteins are broken down into amino acids before absorption, there is no reason for orally ingested collagen to affect connective tissue in the body, except through the effect of individual amino acid supplementation.

Recently an alternative to animal-derived collagen has become available. Although expensive, this human collagen, derived from donor cadavers, placentas and aborted fetuses, may minimize the possibility of immune reactions.

Although it cannot be absorbed through the skin, collagen is now being used as a main ingredient for some cosmetic makeup.[36]

Collagen is also frequently used in scientific research applications for cell culture, studying cell behavior and cellular interactions with the extracellular environment.[37] Suppliers such as Trevigen manufacture rat and bovine Collagen I and mouse Collagen IV.

Fossil record

Because the synthesis of collagen requires a high level of atmospheric oxygen, complex animals may not have been able to evolve until the atmosphere was oxygenic enough for collagen synthesis.[38] The origin of collagen may have allowed cuticle, shell and muscle formation. However, the preservation of collagen in the fossil record is very scarce.[39] There is mounting evidence—which remains controversial—that collagen has been preserved in dinosaur specimens dated as long ago as 80 million years ago.[40]

Also worth noting are the actinofibrils, collagen fibers present on the wings of pterosaurs.

Art

Julian Voss-Andreae's sculpture Unravelling Collagen (2005), stainless steel, height 11'3" (3.40 m).

Julian Voss-Andreae has created sculptures out of bamboo and stainless steel based on the collagen structure. His piece Unravelling Collagen is, according to him, a "metaphor for aging and growth".[41][42]

See also

References

  1. ↑ Müller, Werner E. G. (2003). "The Origin of Metazoan Complexity: Porifera as Integrated Animals". Integrated Computational Biology 43 (1): 3–10. doi:10.1093/icb/43.1.3. 
  2. ↑ Di Lullo, Gloria A.; Sweeney, Shawn M.; Körkkö, Jarmo; Ala-Kokko, Leena; San Antonio, James D. (2002). "Mapping the Ligand-binding Sites and Disease-associated Mutations on the Most Abundant Protein in the Human, Type I Collagen". J. Biol. Chem. 277 (6): 4223–4231. doi:10.1074/jbc.M110709200. 
  3. ↑ Sikorski, Zdzisław E. (2001). Chemical and Functional Properties of Food Proteins. Boca Raton: CRC Press. p. 242. ISBN 1566769604. 
  4. ↑ Wyckoff, R.; Corey, R.; Biscoe, J. (1935). "X-ray reflections of long spacing from tendon". Science 82 (2121): 175–176. doi:10.1126/science.82.2121.175. 
  5. ↑ Clark, G.; Parker, E.; Schaad, J.; Warren, W. J. (1935). "New measurements of previously unknown large interplanar spacings in natural materials". J. Amer. Chem. Soc 57 (8): 1509. doi:10.1021/ja01311a504. 
  6. ↑ "GNR — A Tribute - Resonance - October 2001". http://www.ias.ac.in/resonance/Oct2001/Oct2001p2-5.html. 
  7. ↑ Leonidas, Demetres D.; et al. (2001). "Binding of Phosphate and pyrophosphate ions at the active site of human angiogenin as revealed by X-ray crystallography". Protein Science 10 (8): 1669–1676. doi:10.1110/ps.13601. 
  8. ↑ Subramanian, Easwara (2001). "Obituary: G.N. Ramachandran". Nature Structural & Molecular Biology 8 (6): 489–491. doi:10.1038/88544. 
  9. ↑ Fraser, R. D.; MacRae, T. P.; Suzuki, E. (1979). "Chain conformation in the collagen molecule". J Mol Biol 129 (3): 463–481. doi:10.1016/0022-2836(79)90507-2. 
  10. ↑ Okuyama, K.; et al.. "Crystal and molecular structure of a collagen-like polypeptide (Pro-Pro-Gly)10". J Mol Biol 152 (2): 427–443. doi:10.1016/0022-2836(81)90252-7. 
  11. ↑ Traub, W.; Yonath, A.; Segal, D. M. (1969). "On the molecular structure of collagen". Nature 221 (5184): 914–917. doi:10.1038/221914a0. 
  12. ↑ Bella, J.; Eaton, M.; Brodsky, B.; Berman, H. M. (1994). "Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution". Science 266 (5182): 75–81. doi:10.1126/science.7695699. 
  13. ↑ 13.0 13.1 Hulmes, D. J.; Miller, A. (1979). "Quasi-hexagonal molecular packing in collagen fibrils". Nature 282 (5741): 878–880. doi:10.1038/282878a0. 
  14. ↑ Jesior, J. C.; Miller, A.; Berthet-Colominas, C. (1980). "Crystalline three-dimensional packing is general characteristic of type I collagen fibrils". FEBS Lett 113 (2): 238–240. 
  15. ↑ Fraser, R. D. B.; MacRae, T. P. (1981). "Unit cell and molecular connectivity in tendon collagen". Int. J. Biol. Macromol. 3 (3): 193–200. doi:10.1016/0141-8130(81)90063-5. 
  16. ↑ Fraser, R. D.; MacRae, T. P.; Miller, A. (1987). "Molecular packing in type I collagen fibrils". J Mol Biol 193 (1): 115–125. doi:10.1016/0022-2836(87)90631-0. 
  17. ↑ Wess, T. J.; et al. (1998). "Molecular packing of type I collagen in tendon". J Mol Biol 275 (2): 255–267. doi:10.1006/jmbi.1997.1449. 
  18. ↑ Raspanti, M.; Ottani, V.; Ruggeri, A. (1990). "Subfibrillar architecture and functional properties of collagen: a comparative study in rat tendons". J Anat. 172: 157–164. 
  19. ↑ Holmes, D. F.; Gilpin, C. J.; Baldock, C.; Ziese, U.; Koster, A. J.; Kadler, K. E. (2001). "Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization". PNAS 98 (13): 7307–7312. doi:10.1073/pnas.111150598. 
  20. ↑ Holmes, K. E.; Kadler (2006). "The 10+4 microfibril structure of thin cartilage fibrils". PNAS 103 (46): 17249–17254. doi:10.1073/pnas.0608417103. 
  21. ↑ 21.0 21.1 21.2 Orgel, J. P.; et al. (2006). "Microfibrillar structure of type I collagen in situ". PNAS 103 (24): 9001–9005. doi:10.1073/pnas.0502718103. 
  22. ↑ Hulmes, D. J. (2002). "Building collagen molecules, fibrils, and suprafibrillar structures". J Struct Biol 137 (1–2): 2–10. doi:10.1006/jsbi.2002.4450. 
  23. ↑ 23.0 23.1 Hulmes, D. J. (1992). "The collagen superfamily—diverse structures and assemblies". Essays Biochem 27: 49–67. 
  24. ↑ Perumal, S.; Antipova, O.; Orgel, J. P. (2008). "Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis". PNAS 105 (8): 2824–2829. doi:10.1073/pnas.0710588105. 
  25. ↑ Sweeney, S. M.; et al. (2008). "Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates". J Biol Chem 283 (30): 21187–21197. doi:10.1074/jbc.M709319200. 
  26. ↑ Twardowski, T.; et al. (2007). "Type I collagen and collagen mimetics as angiogenesis promoting superpolymers". Curr Pharm Des 13 (35): 3608–3621. http://www.ingentaconnect.com/content/ben/cpd/2007/00000013/00000035/art00009. 
  27. ↑ Söderhäll, C.; Marenholz, I.; Kerscher, T.. "Variants in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis". PLoS Biology 5 (9): e242. doi:10.1371/journal.pbio.0050242. 
  28. ↑ Houck, J. C.; Sharma, V. K.; Patel, Y. M.; Gladner, J. A. (1968). "Induction of Collagenolytic and Proteolytic Activities by AntiInflammatory Drugs in the Skin and Fibroblasts". Biochemical Pharmacology 17 (10): 2081–2090. doi:10.1016/0006-2952(68)90182-2. 
  29. ↑ Al-Hadithy, H.; et al. (1982). "Neutrophil function in systemic lupus erythematosus and other collagen diseases". Ann Rheum Dis 41 (1): 33–38. doi:10.1136/ard.41.1.33. 
  30. ↑ Fratzl, P. (2008). Collagen: Structure and Mechanics. New York: Springer. ISBN 038773905X. 
  31. ↑ Buehler, M. J. (2006). "Nature designs tough collagen: Explaining the nanostructure of collagen fibrils". PNAS 103 (33): 12285–12290. doi:10.1073/pnas.0603216103. 
  32. ↑ "Gelatin's Advantages: Health, Nutrition and Safety". http://www.gmap-gelatin.com/gelatin_adv.html. 
  33. ↑ Walker, Amélie A. (May 21, 1998). "Oldest Glue Discovered". Archaeolgy. http://www.archaeology.org/online/news/glue.html. 
  34. ↑ Ennker, I. C.; et al. (1994). "Formaldehyde-free collagen glue in experimental lung gluing". Ann Thorac Surg. 57 (6): 1622–1627. http://ats.ctsnetjournals.org/cgi/content/abstract/57/6/1622. 
  35. ↑ "Hydrolyzed Collagen pills usages". http://www.articlecat.com/Article/Hydrolyzed-Collagen--Protein-Hydrate/21273. 
  36. ↑ "www.articlesbase.com". http://www.articlesbase.com/skin-care-articles/can-collagen-be-absorbed-into-the-skin-or-is-it-all-just-one-big-hoax-674325.html. 
  37. ↑ Blow, Nathan (2009). "Cell culture: building a better matrix". Nature Methods 6 (8): 619–622. doi:10.1038/nmeth0809-619. 
  38. ↑ http://facstaff.gpc.edu/~pgore/geology/geo102/cambrian.htm
  39. ↑ doi:10.1111/j.1502-3931.1996.tb01844.x
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  40. ↑ doi:10.1126/science.1165069
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  41. ↑ Ward, Barbara (April 2006). "'Unraveling Collagen' structure to be installed in Orange Memorial Park Sculpture Garden". Expert Rev. Proteomics 3 (2): 174. doi:10.1586/14789450.3.2.169. http://www.future-drugs.com/doi/pdf/10.1586/14789450.3.2.169. 
  42. ↑ Interview with J. Voss-Andreae "Seeing Below the Surface" in Seed Magazine

External links

Histology: connective tissue
Classification
Proper/
Fibrous
Loose

Areolar · Reticular

non-fibrous: Adipose (Brown, White)
Dense
Dense irregular connective tissue (Submucosa, Dermis) · Dense regular connective tissue (Ligament, Tendon, Aponeurosis)
Mucous · Mesenchymal
Composition
Extracellular
matrix
(noncellular)
Ground substance
Tissue fluid

Reticular fibers: Collagen

Elastic fibers: Fibrillin (FBN1, FBN2, FBN3)
Resident

Fibroblast · Reticular cell · Tendon cell

Adipocyte

Chondroblast · Osteoblast
Wandering
cell
Mast cell · Macrophage
see also soft tissue

: INT, SF, LCT

anat//devp

noco(i,,d,q,u,,p,,,v)/cong/tumr(n,e,d), sysi/

proc, drug (/3/4/5/8)

: MUS, DF+DRCT

anat (h/n, u, t/d, a/p, l)/phys/hist

noco(m, s, c)/cong(d)/tumr, sysi/, injr

proc, drug (M1A/3)
Protein: scleroproteins
Extracellular matrix
Collagen
1-12
type I (COL1A1, COL1A2) · type II (COL2A1) · type III · type IV (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) · type V (COL5A1, COL5A2, COL5A3) · type VI (COL6A1, COL6A2, COL6A3) · type VII (COL7A1) · type VIII (COL8A1, COL8A2) · type IX (COL9A1, COL9A2, COL9A3) · type X (COL10A1) · type XI (COL11A1, COL11A2) · type XII (COL12A1)
13-29
COL13A1 · COL14A1 · COL15A1 · COL16A1 · COL17A1 · type XVIII (COL18A1, Endostatin) · COL19A1 · COL20A1 · COL21A1 · COL22A1 · COL23A1 · COL24A1 · COL25A1 · COL26A1 · COL27A1 · COL28A1 · COL29A1
Prolyl hydroxylase/Lysyl hydroxylase · Cartilage associated protein/Leprecan · ADAMTS2 · Procollagen peptidase · Lysyl oxidase
Tenascin
Tenascin C · Tenascin X
Other
Laminin · ALCAM · Elastin (Tropoelastin) · Vitronectin · FRAS1 · FREM2 · Decorin · FAM20C · ECM1
Other
Keratin/Cytokeratin · Gelatin · Reticulin · Cartilage oligomeric matrix protein
see also diseases
proteins: BY STRUCTURE: membrane, globular (en, ca, an), fibrous