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[[Image:Collagentriplehelix.png|thumb|right|200px|Tropocollagen triple helix.]]
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'''Collagen''' is the main [[protein]] of [[connective tissue]] in animals and the most abundant protein in [[mammal]]s, <ref> Gloria A. Di LulloDagger , Shawn M. Sweeney, Jarmo Körkkö, Leena Ala-Kokko, and James D. San Antonio; [http://www.jbc.org/cgi/content/abstract/277/6/4223 Mapping the Ligand-binding Sites and Disease-associated Mutations on the Most Abundant Protein in the Human, Type I Collagen]; ''J. Biol. Chem.'', Vol. 277, Issue 6, 4223-4231, February 8, 2002 </ref> making up about 25% of the total protein content. 

==Uses==
Collagen is one of the long, [[fibrous protein|fibrous structural proteins]] whose functions are quite different from those of [[globular protein]]s such as [[enzyme]]s; 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]], [[ligament]]s, [[tendon]]s, [[bone]] and [[tooth|teeth]]. Along with soft [[keratin]], it is responsible for [[skin]] strength and elasticity, and its degradation leads to [[wrinkle]]s that accompany [[ageing|aging]]. It strengthens [[blood vessel]]s and plays a role in [[biological tissue|tissue]] development. It is present in the [[cornea]] and lens of the [[eye]] in crystalline form. It is also used in [[plastic surgery|cosmetic surgery]] and [[burn (injury)|burns surgery]].  

===Industrial uses===
If collagen is partially [[hydrolysis|hydrolyzed]], the three tropocollagen strands separate into globular, [[random coil]]s, producing [[gelatin]], which is used in many [[food]]s, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.<ref>http://www.gmap-gelatin.com/gelatin_adv.html</ref>
Nutritionally, collagen and gelatin are poor quality protein since they do not contain all the [[essential amino acid]]s that the human body requires - they are not [[complete protein]]s. Manufacturers of collagen-based [[dietary supplement]]s claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown any evidence to support these claims. Individuals with problems in these areas are more likely to be suffering from some other underlying condition rather than 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 [[tendon|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]] [[skull]]s.<ref>http://www.archaeology.org/online/news/glue.html</ref> 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, [[chemical synthesis|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 [[glyoxal|ethanedial]]) has been used to repair experimental incisions in rabbit [[lung]]s.<ref>''Ann Thorac Surg.'' 1994 Jun; 57(6): 1622-7</ref>

===Medical uses===
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:
#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 
#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 and New Zealand. 
#porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes.
#due to the care in donor animal breeding and selection, as well as the technology used in the preparation of collagen from animal sources, the chance of immune reactions or disease transmission has been virtually eliminated.
#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 [[burn (injury)|burns]], as well as for a wide range of dental, orthopedic, and surgical purposes.  These collagens may be derived from bovine, equine or porcine, and even human, sources and are sometimes used in combination with [[silicone]]s, [[glycosaminoglycans]], [[fibroblasts]], [[growth factors]] and other substances.

Collagen is also sold commercially as a joint mobility supplement. This lacks supportive research as the proteins would just be broken down into its base amino acids during digestion, and could go to a variety of places besides the joints depending upon need and DNA orders.

Recently an alternative to animal-derived collagen has become available.  Although expensive, this human collagen, derived from donor cadavers, [[placenta]]s and aborted fetuses,<ref>http://www.lipaugmentation.com/bioimplants.htm</ref> may minimize the possibility of immune reactions.

==Composition and structure==
The ''tropocollagen'' or "collagen molecule" subunit is a rod about 300 nm long and 1.5 nm in diameter, made up of three [[polypeptide]] strands, each of which is a left-handed [[helix]], not to be confused with the commonly occurring alpha helix, which is right-handed. These three left-handed helices are twisted together into a right-handed [[coiled coil]], a triple helix, a cooperative [[quaternary structure]] stabilized by numerous [[hydrogen bond]]s. Tropocollagen [[protein subunit|subunits]] spontaneously [[molecular self-assembly|self-assemble]], with regularly staggered ends, into even larger arrays in the [[extracellular]] spaces of tissues. There is some [[covalent bond|covalent]] crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices, to form the different types of collagen found in different mature tissues — similar to the situation found with the [[keratin|α-keratins]] in [[hair]]. Collagen's [[soluble|insolubility]] was a barrier to study until it was found that tropocollagen from young animals can be extracted because it is not yet fully [[cross-link|crosslinked]].

Collagen fibrils are collagen molecules packed into an organized overlapping bundle. Collagen fibers are bundles of fibrils.

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 [[glycine|Gly]]-X-[[proline|Pro]] or Gly-X-[[hydroxyproline|Hyp]], where X may be any of various other amino acid residues. Gly-Pro-Hyp occurs frequently. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk [[fibroin]]. 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 chain|side group]] is a small, inert [[methyl]]. Such high glycine and regular repetitions are never found in globular proteins. [[Chemical reaction|Chemically-reactive]] side groups are not needed in structural proteins as they are in enzymes and [[transport protein]]s. The high content of Proline and Hydroxyproline rings, with their geometrically constrained [[carboxyl]] and (secondary) [[amino]] groups, 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, 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 thermally stabilize the triple helix — Hyp even more so than Pro — and less of them is required in animals such as fish, whose [[thermoregulation|body temperatures]] are low. 

In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) [[hydroxylapatite|hydroxyapatite]], Ca<sub>5</sub>(PO<sub>4</sub>)<sub>3</sub>(OH), with some [[phosphate]]. It is in this way that certain kinds of cartilage turn into bone. Collagen gives bone its elasticity and contributes to [[bone fracture|fracture]] resistance.

==Types of collagen and associated disorders==
Collagen occurs in many places throughout the body. There are 28 types of collagen described in literature.

Collagen diseases commonly arise from genetic defects that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes in the normal production of collagen.

{| class="wikitable"
| '''Type''' || '''Notes''' || '''Gene(s)'''  || '''Disorders'''
 |- 
 | [[Type-I collagen|I]]  || This is the most abundant collagen of the human body. It is present in [[Scar|scar tissue]], the end product when tissue [[healing|heals]] by repair. It is found in [[tendon]]s, the endomysium of myofibrils, fibrocartilage, and the organic part of bone. || {{Gene|COL1A1}}, {{Gene|COL1A2}} || [[osteogenesis imperfecta]], [[Ehlers-Danlos Syndrome]]
 |- 
 | [[Type-II collagen|II]] || [[Hyaline cartilage]], makes up 50% of all cartilage protein || {{Gene|COL2A1}} || [[Collagenopathy, types II and XI]]
 |- 
 | [[Type-III collagen|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, intestines and the uterus || {{Gene|COL3A1}} || [[Ehlers-Danlos Syndrome]]
 |- 
 | [[Type-IV collagen|IV]] || [[basal lamina]]; [[eye lens]]. Also serves as part of the filtration system in [[capillaries]] and the [[glomeruli]] of [[nephron]] in the [[kidney]]. || {{Gene|COL4A1}}, {{Gene|COL4A2}}, {{Gene|COL4A3}}, {{Gene|COL4A4}}, {{Gene|COL4A5}}, {{Gene|COL4A6}} || [[Alport syndrome]]
 |- 
 | V || most interstitial tissue, assoc. with type I, associated with [[placenta]] || {{Gene|COL5A1}}, {{Gene|COL5A2}}, {{Gene|COL5A3}} || [[Ehlers-Danlos syndrome]] (Classical)
 |- 
 | VI || most interstitial tissue, assoc. with type I || {{Gene|COL6A1}}, {{Gene|COL6A2}}, {{Gene|COL6A3}} || Ulrich myopathy and [[Bethlem myopathy]]
 |- 
 | VII || forms anchoring fibrils in [[dermal]] [[epidermal junctions]] || {{Gene|COL7A1}} || [[epidermolysis bullosa]]
 |- 
 | VIII || some endothelial cells || {{Gene|COL8A1}}, {{Gene|COL8A2}} || -
 |- 
 | IX || [[FACIT collagen]], cartilage, assoc. with type II and XI fibrils || {{Gene|COL9A1}}, {{Gene|COL9A2}}, {{Gene|COL9A3}} || -
 |- 
 | X || [[hypertrophic]] and mineralizing cartilage || {{Gene|COL10A1}} || -
 |- 
 | XI || cartilage || {{Gene|COL11A1}}, {{Gene|COL11A2}} || [[Collagenopathy, types II and XI]]
 |- 
 | XII || [[FACIT collagen]], interacts with type I containing fibrils, [[decorin]] and glucosaminoglycans || {{Gene|COL12A1}} || -
 |- 
 | XIII || transmembrane collagen, interacts with integrin a1b1, [[fibronectin]] and components of basment membranes like [[nidogen]] and [[perlecan]]. || {{Gene|COL13A1}} || -
 |- 
 | XIV|| [[FACIT collagen]] || {{Gene|COL14A1}} || -
 |- 
 | XV ||  - || {{Gene|COL15A1}} || -
 |- 
 | XVI ||  - || {{Gene|COL16A1}} || -
 |- 
 | [[Collagen XVII|XVII]] ||  transmembrane collagen, also known as BP180, a 180 kDa protein  || {{Gene|COL17A1}} || [[Bullous Pemphigoid]] and certain forms of junctional [[epidermolysis bullosa]]
 |- 
 | [[Type XVIII collagen|XVIII]] ||  source of [[endostatin]] || {{Gene|COL18A1}} || -
 |- 
 | XIX ||  [[FACIT collagen]] || {{Gene|COL19A1}} || -
 |- 
 | XX ||  - || {{Gene|COL20A1}} || -
 |- 
 | XXI ||  [[FACIT collagen]] || {{Gene|COL21A1}} || -
 |- 
 | XXII ||  - || {{Gene|COL22A1}} || -
 |- 
 | XXIII ||  - || {{Gene|COL23A1}} || -
 |- 
 | XXIV ||  - || {{Gene|COL24A1}} || -
 |- 
 | XXV ||  - || {{Gene|COL25A1}} || -
 |- 
 | XXVI ||  - || {{Gene|EMID2}} || -
 |- 
 | XXVII ||  - || {{Gene|COL27A1}} || -
 |- 
 | XXVIII || - || {{Gene|COL28A1}} || -
|}

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

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

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

Collagen is [[birefringent]] when stained with Sirius red F3B (C.I. 35782). <ref>Junqueira LCU, Bignolas G, Brentani RR. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J 1979).</ref>

==Synthesis==
===Amino acids===
Collagen has an unusual [[amino acid]] composition and sequence:
* [[Glycine]] (Gly) is found at almost every third [[residue]]
* [[Proline]] (Pro) makes up about 9% of collagen
* Collagen contains two uncommon derivative amino acids not directly inserted during [[translation (genetics)|translation]]. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require [[vitamin C]] as a [[cofactor (biochemistry)|cofactor]].   
** [[Hydroxyproline]] (Hyp), derived from proline.
** [[Hydroxylysine]], derived from [[lysine]]. Depending on the type of collagen, varying numbers of hydroxylysines have [[disaccharide]]s attached to them.

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

#Inside the cell
##Three [[peptide]] chains are formed (2 alpha-1 and 1 alpha-2 chain) in ribosomes along the [[Rough endoplasmic reticulum|Rough Endoplasmic Reticulum]] (RER). These peptide chains (known as preprocollagen) have registration peptides on each end; and a [[signal peptide]] is also attached to each
##Peptide chains are sent into the lumen of the RER
##Signal Peptides are cleaved inside the RER and the chains are now known as procollagen
##[[Hydroxylation]] of [[lysine]] and [[proline]] amino acids occurs inside the lumen. This process is dependent on [[Ascorbic Acid]] (Vitamin C) as a [[cofactor]]
##[[Glycosylation]] of specific hydroxylated amino acid occurs
##Triple helical structure is formed inside the RER
##Procollagen is shipped to the [[golgi apparatus]], where it is packaged and secreted by [[exocytosis]]
#Outside the cell
##Registration peptides are cleaved and tropocollagen is formed by [[procollagen peptidase]].
##Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers
##Collagen is 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]]. [[Gingiva|Gums]] deteriorate and bleed, with loss of teeth; skin discolors, and [[wound]]s 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. In the human body, a malfunction of the [[immune system]], called an [[autoimmune disease]], results in an immune response in which healthy collagen fibers are systematically destroyed with inflammation of surrounding tissues. The resulting disease processes are called [[Lupus erythematosus]], and [[rheumatoid arthritis]], or collagen tissue disorders.<ref>[http://ard.bmjjournals.com/cgi/content/abstract/41/1/33 AJR article about lupus and other collagen disorders]</ref>

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



==See also==
* [[Osteoid]]
* Trout pout
* [[Fibrous protein]]

==References==
<references/>

==Additional images==
<gallery>
 Image:Collagen.gif|Collagen
 Image:Action de la lysyl oxydase.jpg|Action of lysyl oxydase (in French)
</gallery>

==External links==
* [http://web.indstate.edu/thcme/mwking/extracellularmatrix.html 12 types of collagen]
* [http://www.le.ac.uk/genetics/collagen/ Database of type I and type III collagen mutations]
* [http://science.dirbix.com/biology/collagen Science.dirbix Collagen]
* [http://www.mc.vanderbilt.edu/cmb/collagen/ Computer-generated animations of the assembly of Type I and Type IV Collagens]
* [http://www.cosmeticdoctors.co.uk/fillers.asp The British Association of Cosmetic Doctors - Collagen For Cosmetic Use Information Page] 

{{Connective tissue}}
{{Fibrous proteins}}
{{Antihemorrhagics}}


[[Category:Structural proteins]]
[[Category:Edible thickening agents]]
[[Category:Hematology]]

[[ar:كولاجين]]
[[bg:Колаген]]
[[ca:Col·lagen]]
[[cs:Kolagen]]
[[da:Collagen]]
[[de:Kollagen]]
[[es:Colágeno]]
[[fr:Collagène]]
[[it:Collagene]]
[[he:קולגן]]
[[lt:Kolagenas]]
[[nl:Collageen]]
[[ja:コラーゲン]]
[[no:Kollagen]]
[[pl:Kolagen]]
[[pt:Colágeno]]
[[ru:Коллаген]]
[[sl:Kolagen]]
[[sr:Колаген]]
[[fi:Kollageeni]]
[[sv:Kollagen]]
[[th:คอลลาเจน]]
[[tr:Kollajen]]
[[zh:膠原蛋白]]

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