Collagen

Collagen is the main component of connective tissue and the most abundant protein in the human body. It is mostly found in fibrous tissues such as tendons, ligaments and skin.

Types
There are over 28 types of collagen found in the human body. Over 90% is made of of these fives types : The main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament. Elastin is also found at 4–9% of the dry weight in ligaments.
 * Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone)
 * Type II: cartilage (main collagenous component of cartilage)
 * Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
 * Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
 * Type V: cell surfaces, hair, and placenta

Components
Collagen is made up primarily of the amino acids glycine and proline. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline. X can be any of the other 17 amino acids. Every third amino acid is glycine.

Co-factors
Vitamin C is a co-factor of many of the chemical reactions involved in collagen production. Vitamin C is also a mast cell stabilizer. Vitamin C deficiency can result in impaired collagen synthesis and scurvy.

Structure
Collagen is composed of three chains that wind together to form a triple helix.

Biosynthesis
Collagen synthesis occurs mainly in fibroblasts, cells whose many function is the synthesis of collagen and stroma. Synthesis occurs in both intracellular and extracellular spaces.

Pathogens
Infection can degrade collagen via direct secretion of collagenases and other enzymes (in the case of bacteria) or increased host production of matrix metalloproteinases (MMPs) as part of the normal immune response (in the case of bacteria and viruses). Numerous bacteria secrete their own collagenases. Borrelia spirochetes upregulate production of human collagenase (MMP-1) and gelatinase B (MMP-9), an enzyme that can degrade both elastin and partially hydrolyzed collagen. Borrelia infection has been associated with damage to collagen and elastin fibres, causing "spontaneous ruptures of tendons after slight strain, dislocation of vertebrae and an accumulation of prolapsed intervertebral discs as well as ossification of tendon insertions." MMP-8 and MMP-9 are upregulated in bacterial meningitis and the latter is associated with an increased risk of blood-brain barrier breakdown and neurological sequale such as epilepsy and cognitive dysfunction. Herpes simplex virus, HHV-6 and Coxsackie B infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation. Coxsackie B infection induces immune cells to secrete MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12.

Infection and Ehlers-Danlos Syndromes
Ehlers-Danlos Syndromes are a group connective tissue disorders caused by genetic defects in the production of collagen. Type III, hypermobile EDS (hEDS), is also thought to be genetic but as a genetic marker has not yet been identified; it is diagnosed via signs and symptoms. A 2018 case study of a patient who met the diagnostic criteria for hEDS and had a chronic Bartonella infection found their hEDS symptoms resolved with antibiotic treatment for Bartonella. Mycoplasma pneumoniae has been associated with mitral valve degeneration, a complication of EDS.

Fluoroquinolone antibiotics
“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.” A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas. In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.

Doxycycline, by contrast, inhibits MMP production.

Mold
Stachybotrys chartarum (black mold) release proteinases that can hydrolyze gelatin and collagen I and IV. Three Mycotoxins, deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, were study in an the context of an experimental cartilage model. They were found to increase the expression of MMPs and result in the loss of aggrecan and type II collagen. Selenium partially inhibited the effects of these mycotoxins.

Sex hormones
Several animal studies of collagen in muscle and the aorta have found that estrogen decreases and testosterone increases collagen and elastin. A study of collagen in male cattle found that collagen synthesis increased with puberty, possibly as a result of testosterone. Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle). An in vitro study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.

ME/CFS
Preliminary data from the UK ME/CFS biobank show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of prolyl 4-hydroxylase subunit alpha 1 (P4HA1), which encodes for procollagen-proline dioxygenase, an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of energy metabolism via downregulation of pyruvate dehydrogenase during hypoxia. The data are based on self-reported diagnosis of chronic fatigue syndrome and involve a sample size that is very small for genome-wide association studies (n=1829), making confidence intervals difficult to estimate.

Elevated levels of hydroxyproline, a marker of collagen breakdown, was found by Wenzhong Xiao in the Severely Ill Patient Study. Robert Naviaux’s work has suggested it as a possible biomarker for female ME/CFS patients. Maureen Hanson failed to find elevated hydroxyproline in her metabolomics study.

As a supplement
When hydrolyzed, collagen is reduced to small peptides, which can be ingested in the form of dietary supplement or functional foods and beverages with the intent to aid joint and bone health and enhance skin health. These hydroxyproline-containing peptides are transported into the target tissues (e.g., skin, bones, and cartilage), where they act as building blocks for local cells and help boost the production of new collagen fibers.

Potential modulators
The following are compounds that can or might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength. Compounds proven to promote connective tissue repair in vivo, or proven to reduce connective tissue-degrading matrix metalloproteinase (MMP) enzymes in vivo, are indicated by the "shown effective in vivo" column.