Introduction

Collagen is protein molecules made up of amino acids. It provides structural support to the extracellular space of connective tissues. Due to its rigidity and resistance to stretching, it is the perfect matrix for skin, tendons, bones, and ligaments.

Collagen can be further divided into several groups depending on the type of structures they form. There are 28 various types of collagen that have been discovered, but by far, the most common are types I through IV, with type I comprising over 90% of the collagen in the human body.[1][2][3]

Fundamentals

Amino acids are the building blocks of proteins; therefore, it is no surprise that collagen is comprised of amino [4]acids. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline [5]

X can be any of the other 17 amino acids, and every third amino acid is glycine.

Collagen is composed of 3 chains. The chains are wound together to form a triple helix. Since glycine is the smallest of all the amino acids, it allows the chain to form a tight configuration, and and it can withstand stress.

The process of collagen synthesis occurs mainly in the cells of fibroblasts which are specialized cells with the main function of synthesizing collagen and stroma. Collagen synthesis occurs both intracellularly and extracellularly. Although different types of collagen may undergo different post-translational modifications, the basic outline for collagen synthesis is listed below.

Issues of Concern

As with any biochemical pathway, there are numerous steps that are carefully executed and are tightly regulate and controlled. However, with many steps in processing collagen, there can be genetic mutations which can lead to errors in assembly, posttranslational modification or nutritional deficiencies which can affect enzymatic function. Some examples include:

Osteogenesis imperfecta which is an autosomal dominant disorder of type 1 collagen, which can present with a spectrum of findings from mild to lethal. Ehlers-Danlos syndrome which is also an inherited collagen disorder with at least 6 different subtypes with different mutations of different collagen types. Lastly, Vitamin C deficiency is a nutritional deficiency which leads to altered hydroxylase enzyme function which requires Vitamin C as a cofactor.

Cellular Level

Intracellular

Transcription of mRNA in the nucleus 

• Genes for pro-a1 and pro-a2 chains are transcribed 

Translation 

• mRNA moves into the cytoplasm and interacts with ribosomes for translation.
• After translation, it is referred to as pre-pro-polypeptide chain; this chain then travels to the endoplasmic reticulum (ER) for post-translational modification. 

Post-translational modification 

• Once in the ER, the pre-pro-polypeptide undergoes post-translational processing where three major modifications are made to the pre-pro-polypeptide for it to become pro-collagen. 

1. The signal peptide on the N-terminal is removed
2. The lysine and proline residues get additional hydroxyl groups added to them via hydroxylase enzymes which require vitamin C as a cofactor
3. Glycosylation of the selected hydroxyl groups on lysine with galactose and glucose b

• Three of the hydroxylated and glycosylated pro-a-chains assemble by twisting into a triple helix by zipper-like folding. The triple helix configuration is 3 left-handed helices twisted into a right-handed coil
• Now the pro-collagen molecule is ready to move to the Golgi apparatus for final modifications and assembled into secretory vesicles to enter the extracellular space

Extracellular

Propeptide cleavage 

• Enzymes known as collagen peptidases preform propeptide cleavage and remove the ends of the procollagen molecule and the molecule becomes tropocollagen

Collagen Fibril Assembly 

• Lysyl oxidase a copper-dependent enzyme acts on lysine and hydroxylysines, and covalent bonding between tropocollagen molecules form a collagen fibril

Function

Collagen is the most abundant protein in the human body. Therefore, it can be divided into many types. The most common types of collagen are types I through V each serving different functions.

Clinical Significance

As discussed earlier, there are issues of concern in the biochemical synthesis of collagen. Errors of collagen synthesis can present with clinical manifestations. A few notable diseases are scurvy, osteogenesis imperfecta, and Ehlers–Danlos syndrome.

Scurvy

A nutritional deficiency of water-soluble vitamin C or ascorbic acid most commonly causes scurvy. Scurvy is rare in the developing world and is mostly seen in infants, the elderly, and alcoholics, all who may have inadequate nutritional intake and malnutrition.[6]

Patients may present with general fatigue, weakness, poor wound healing, anemia, and gum disease. Clinically, one of the first signs of scurvy occurs on the skin and manifests as perifollicular hemorrhage where follicles of the skin are plugged with keratin. These areas appear as bruise-like spots around the hair follicles. There can also be fragile hairs arranged in a corkscrew confirmation. Scurvy is diagnosed clinically with a dietary history, and x-rays may show subperiosteal hemorrhage or cortical thinning. Ascorbic acid levels less than 11 micromols/L can help confirm the diagnosis. Treatment is vitamin C supplementation and a diet that includes tomatoes, citrus fruits, and other vegetables high in vitamin C.

Osteogenesis Imperfecta (OI)

This is a family of genetic disorders that affect the bones making them weak and easily breakable. Inheritance is autosomal dominant, and most cases are due to mutations in the COL1A1 or COL1A2 genes. There are 8 types, each with differing degrees of severity with type 1 the mildest and type II the most severe.[7]

Gene mutations affect procollagen formation in which the small glycine amino acid is substituted for bulkier amino acids which alter the collagen triple helix structure.

OI affects 1 in 15,000 people, and diagnosis is made clinically and can be confirmed by DNA or collagen testing. Prognosis depends on the type of OI. There is no cure and treatment is supportive and based on the prevention of fractures. Bisphosphonates, surgery, and physiotherapy have been shown to help.

Ehlers-Danlos Syndrome (EDS)

This is a group of inherited connective tissue disorders that affect about 1 in 5000 individuals globally. There are 13 EDSs, and signs and symptoms vary based on the type of EDS. Most forms of EDS are autosomal dominantly inherited, and mutations are in the COL1A1, COL1A2, COL1A2, COL3A1, COL5A1, to name a few. Mutations in genes affect extracellular peptide cleavage and alter collagen fibril cross-linking and aggregation, which causes altered stability and functionality of the fibers.[8]

Depending on the genetic mutation and type of collagen affected patients may show an array of clinical findings; however, there are some common manifestations in EDS patients that range from mild to life-threatening.

Diagnosis is made clinically, DNA studies and collagen mutation studies can be used as adjuncts. The prognosis largely depends on the type of EDS a patient has. However, there is no cure for EDS, and treatment is supportive.