A collection of technical documents for customers wishing to understand more of the science behind our products.

Written by:  Dr Tom Shurlock for and on behalf of GWF Nutrition Limited.

Copyright GWF Nutrition Limited December 2018 - Not for reproduction.

What is collagen?

Collagen is the main structural protein in the extracellular space in the various connective tissues in animal bodies. As the main component of connective tissue, it is the most abundant protein in mammals, making 25% to 35% of the whole-body protein content.

 

Collagen consists of amino acids wound together to form triple-helices to form of elongated fibrils (Fig. 1). In each strand there is a sequence, where every third amino acid is glycine; the other two in the sequence could be any amino acid, although proline or hydroxyproline are the most likely in mammalian collagen. Furthermore, hydrogen bonds between glycine and proline from neighbouring strands give characteristic twisting, and so flexibility, of various types (Fig. 2). This is in addition to other protein structural bonds, such as sulphur bridges from methylsulphonylmethane and proteoglycan ligands.

Collagen

December 2018

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Figure 1. Triple strand of Collagen.

Figure 2. Hydrogen bonding between collagen strands.

Collagen is mostly found in fibrous tissues such as tendons, ligaments and skin. It is synthesised in wound healing and muscle generation after damage caused by excessive exercise; it can be mineralised as bone (rigid) or cartilage (compliant) and is present in all areas of the body that require varying amounts of elasticity.

Structurally, three strands of amino acid chains twisted into a triple helix, provide elasticity which is critical for its function in tendons, ligaments, the vascular system, musculature and most connective tissue and organelles within the body. Of all the types of collagen present, the most prevalent is Type I.

Type I collagen is that found in scar tissue, the end product when tissue heals by repair. Collagen is found in tendons, skin, artery walls, the endomysium surrounding muscle fibres, the cornea and cartilage (Type II), and the organic part of bones and teeth. It is present in many forms, including fibrils, networks, and transmembrane collagenous domains. Although the forms & types of collagen vary in amino acid make-up and structure, there is a generalised mechanism of synthesis. Only collagen types I, II, III, V, and XI self-assemble into fibrils. The fibrils are composed of collagen molecules, which consist of a triple helix of approximately 300 nm in length and 1.5 nm in diameter. Collagen fibril formation is an extracellular process which occurs through the cleavage of terminal procollagen peptides by specific procollagen metalloproteinases. Some collagens form networks (types IV, VIII, and X). A typical example of such a network is the basement membrane, which is mostly made of collagen IV. Other collagens associate with fibril surfaces (types VI, IX, XII, and XIV). Yet other collagens are transmembranous proteins (types XIII and XVIII) or form periodic beaded structures (type VI).

 

Also involved in the collagen “family” of compounds are the associated products laminins, tenascins, and proteoglycans, and regulatory enzymes such as the matrix metalloproteases (MMP). These latter are also complicit in the role of inflammatory and oxidative processes and so tie in regeneration of mechanical wounds, cartilage wear and tear, and muscular development.

 

Collagen, being a protein, is synthesised by building individual amino acids, and groups, into strands in the nucleus of cells, via the mechanism of m-RNA. Addition of hydroxyl groups to specific amino acids – e.g. proline – gives potential for hydrogen bonds to link the three strands into fibrils. Thereafter, there is a divergence in synthesis. In the cytoplasm of cells, expression of peptides diverge; fibrils continue their linking sequences whilst other forms move towards meshes, nets etc. Individual tissue cells (for example skin) express relevant collagen structures. As a divergence from this, wound healing is characterised by migration of type I collagen m-RNA, hormone-like growth factors (TGF)-β1, and myofibroblasts (specialised wound healers). At the same time there is a decrease in MMP, and a concomitant decline in collagen degradation.

 

There are base units for collagen synthesis. They are small leucine rich proteoglycans (SRLPG), which exist in the extracellular matrix and contribute to the production, organisation and remodelling of collagen and elastin through complex biological systems.

 

In the dog, seven SLRPG have been identified across tissues and organs including bone, cartilage, cruciate ligament, skin, ventricular myocardium, mitral valve and cornea. Six of the SLRPG are classified into three groups, and the seventh, Versican, is a larger molecule and has its own group. It is also known as chondroitin sulphate proteoglycan-2 (CSPG2). The shape of these leucine rich molecules also supports the bonding in the triple helix of collagen fibres, by creating strong ligand bonds. Proteoglycans are covalently bonded protein and glycosaminoglycan (GAG) groups.

 

In articular joints of horses, it was noted that normal synthesis of proteoglycans was not significantly different from chondrocytes of damaged cartilage, inferring that collagen synthesis is a constant mechanism that does not distinguish between damaged and intact material. Therefore, although collagen can repair, its structure is specific to the collagen it replaces, except in the case of physical wounds, and scar tissue.

 

The biochemistry of collagens is complex. Being a family of proteins, as well as other components their regulation is also complex. However, protein synthesis is a continuous process and, as with all metabolic functions, protein degradation also occurs. It has been noted previously (Muscle Maintenance) that proteolysis (breakdown) is accelerated by inflammatory factors, such as cytokines and tumour necrosis factors (TNF), and this is the same process in cartilage breakdown (Glucosamine and Chondroitin: What is it and what does it do?). In all cases, the interplay of oxidative factors, inflammatory markers and anabolic and catabolic enzymes have a significant impact on the balance between protein build-up and breakdown.  Although each protein cycle will have its own specifics, a classic example of the interplay is the role of collagen Type II on articular cartilage.

 

Cartilage is a mix of collagen II proteoglycans (generated by chondrocytes and including chondroitin as a structural component) and elastin (fig 3.). 

Figure 3. Layout of Articular Cartilage.

As with all protein systems, there is a stasis between anabolism and catabolism that allows renewal of cartilage through the animal’s life. When there are negative factors (infection, wear and tear and injury for example) the stasis shifts towards catabolism and cartilage is lost.

 

Looking at the role of collagen II fibres, there are two major routes of action, one affecting collagen synthesis and one degradation; both are subject to oxidative and inflammatory effects, and so the whole cycle is interdependent (fig 4.).

Figure 4. Factors affecting collagen synthesis & stasis.

Pro-inflammatory factors, released by protein breakdown, have two distinct effects. Firstly, pro-oxidative enzymes initiate oxidative stress and release pronitrite. The former suppresses proline production and enhances lipid peroxidation, and the latter leads to telomere erosion. These pathways suppress collagen II synthesis.

 

The second leg is the production of metalloproteases, themselves a type of collagen. Along with lipid peroxidation they actively cause collagen breakdown. As mentioned with wound healing (where the stasis is shifted towards collagen synthesis), a reduction in MMP reduces breakdown.

 

Therefore, collagen production is regulated by its inflammatory markers; under the normal cycle of events, as pro-inflammatory cues give way to anti-inflammatory markers, the cycle continues, and new material replaces old. It is only when the stasis between the markers is altered (positively in wound healing, negatively in arthritis) it is noticed.

 

One further factor needs to be mentioned. Metabolic processes are dependent on biochemical reactions. In the main these reactions are two way - that is they can be reversible - and for many the direction of the reaction at any time depends on the relative concentrations of the reactants (the starting point) and the products (the end point); high levels of glucose, for example, will react to form phosphoenolpyruvate (PEP) but if the levels of glucose are low, PEP – derived from, for example, propionic acid – will generate glucose. Incidentally, this is one route of energy production from the volatile fatty acids.

 

The same holds true for all systems. If nutrition supplies a surplus of nutrients, they will drive the metabolism forward. So, by supplying selected nutrients, like glucosamine and chondroitin, metabolism can be supported in its anabolic function. Coupled with factors that impact on oxidative or inflammatory processes, the building blocks of repair can have a significant, positive effect.

 

Dietary supplements that help maintain normal structural processes, and have an effect on supporting connective tissue, whether it is the tendons in the hoof, articular cartilage, or even muscle regeneration after exercise, will benefit from having peptides that support collagen synthesis, which is why GWF Nutrition includes its collagen matrix in relevant supplements.

 

References

 

Bertone AL, Bramlage LR, McIlwraith CW, Malemud CL.  Comparison of proteoglycan and collagen

in articular cartilage of horses with naturally developing osteochondrosis and healing osteochondral fragments of experimentally induced fractures Am J Vet Res 2005;66:1881–1890

 

Bosman FT, Stamenkovic I. Functional structure and composition of the extracellular matrix. J Pathol 2003; 200: 423–428

 

Manka SW, Carafoli F, Visse R, Bihan D, Raynal N, Farndale RW, Murphy G, Enghild JJ,  E,  Nagase H. Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1. www.pnas.org/cgi/doi/10.1073/pnas.1204991109

 

McIlwraith CW, Can nutrition or supplements help In the treatment of joint disease? European equine health and nutrition congress. 8th Edition, 2017. 71-88.

 

Schwartz AJ, Wilson DA, Keegan KG, Ganjam VK, Sun Y, Weber KT, Zhang J. Factors regulating collagen synthesis and degradation during second-intention healing of wounds in the thoracic region and the distal aspect of the forelimb of horses. Am J Vet Res 2002;63:1564–1570)

 

Shoulders MD, Raines RT. COLLAGEN STRUCTURE AND STABILITY. Annu Rev Biochem. 2009 ; 78: 929–958

 

Yang CH, Culshaw GJ, Liu MM, Lu CC, French AT, Clements DN, Corcoran BM. Canine tissue-specific expression of multiple small leucine rich proteoglycans. The Veterinary Journal 193 (2012) 374–380

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