The Use of Collagen Hydrolysates and Native Collagen in Osteoarthritis

Osteoarthritis is a chronic degenerative disease that dampens the quality of life of those who suffer it. Conventional treatments are palliative, they are targeted to reduce joint pain. However, more efforts are needed to find new therapies that are able to positively affect or at least stop the course of this degenerative disease. Amongst the different therapeutic options that are being studied, collagen emerges as a good candidate due to its safety and preclinical and clinical evidence. Two different approaches have been taken for collagen: collagen hydrolysates and native collagen. Research studies have shown that both types of collagen nutraceuticals are effective in reducing osteoarthritis pain, in animal models and in human clinical trials, however through different mechanisms of action. Hydrolyzed collagen can be absorbed and reach the target site where collagen synthesis is needed, while native collagen, which is poorly absorbed, could work through a mechanism of oral tolerance induction. Thus, collagen represents an interesting therapeutic option to improve osteoarthritis.


Introduction
Osteoarthritis is a chronic degenerative joint disease, where the cartilage progressively gets degraded. This process is accompanied by a certain degree of inflammation, leading to pain and a reduced quality of life.
Longer life expectancy and an increasing aging population has brought up the importance of this disease, since its numbers are rising and is expected to continue doing so. Nowadays, there are several drugs that can be used for osteoarthritis, but they are mainly effective reducing pain but not improving the underneath cause, cartilage destruction. In an attempt to improve cartilage destruction, different alternative therapies have been used, among them, nutraceuticals such as chondroitin sulphate, glucosamine and hyaluronic acid [1]. However, lately a new dietary supplement to improve joint health has gained strength, collagen. Cartilage is made of 10% chondrocytes and 90% extracellular matrix, which is 60-70% water and the rest is organic material. In the cartilage organic material, the main protein found is collagen Type II.

Collagen
Collagen is the most abundant protein in mammals. It is mainly found as part of the extracellular matrix in connective tissues such as cartilage, tendons, ligaments, bones, skin, etc. It is a big protein, of approximately 400KDa, with a complex structure due to its quaternary structure formed by a triple-helix. Its protein sequence is also special, since it is unusually rich in the amino acids hydroxyproline, proline and glycine, making the motif Gly-Pro-Hyp a hallmark of its sequence.

Hydrolyzed Collagen
Collagen hydrolysate (CH) is the product of the enzymatic hydrolysis of native collagen to obtain smaller peptides. The rationality to hydrolyze collagen is not only to improve its solubility but also to improve its bioavailability. Due to its high molecular weight and triple-helix structure, absorption of orally ingested native collagen is scarce. The absorption of CH has been proven in animal models as well as in human studies [2,3] [4,5]. And noteworthy, hydroxyproline was found in blood not just as a free amino acid, but also in the form of small peptides [6]. In a mice study where the animals were fed radiolabeled (14)C-gelatin hydrolysate or 14(C)-proline, 95% of the gelatin hydrolysate was absorbed [7]. Interestingly, in cartilage, the radioactivity accumulation was higher in those animals that consumed gelatin hydrolysate.
The efficacy of CH in osteoarthritis has been studied in human clinical trials. In one randomized, double-blind, controlled multicenter trial, 250 subjects with knee osteoarthritis were given 10g of CH daily for 6 months. At the end of the study significant pain improvement was observed in the visual analogue scales and the WOMAC subscale [8]. Other clinical trials also showed reduction in joint pain upon CH daily consumption for periods ranging from 3 months to one year. In all these clinical trials an improvement in the WOMAC index as well as other indexes of joint functionality and discomfort were observed [9][10][11][12][13].
In animal models, studies of CH oral administration lead to the demonstration of CH pain reduction in osteoarthritis-like lesions as well as the improvement of other disease markers such as the increase in cartilage area, number of chondrocytes, type-

Native Collagen
Another area of study is the administration of native collagen instead of CH. In this case, the mechanism of action is believed to be different to that of CH, where CH could function as bioactive peptides or as a source of the specific amino acids needed to build collagen. Due to the low absorption rate of native collagen, the mechanism of action is believed to take place in the gastrointestinal track. The hypothesis is that, in a similar way as food proteins, native collagen will induce oral tolerance [18]. Native collagen would modulate the response of the gut immune system, gut-associated lymphoid tissue (GALT), to switch to a tolerogenic response against collagen.
This will train the immune system not to recognize collagen joint degradation products as DAMPs (Damage-associated molecular patterns) and avoid joint damage produced by the immune system activation. In two rat studies where osteoarthritis was induced by MIA intra-articular injection, native collagen reduced limb pain in the animals. In one study they also observed a decrease in plasma and urinary CTX-II [19]. And in the other rat study there was a decrease in degraded C2C (a biomarker of cartilage degradation) as well as in the inflammatory cytokines IL-1β and TNFα [20].
In humans the efficacy has been proven in some clinical trials.
In one clinical trial, where the effect of glucosamine and chondroitin sulfate with or without collagen was assessed, the addition of collagen improved the urinary levels of CTX-I and CTX-II as well as the hand radiological score after 1 year of treatment [21]. Another clinical study where knee osteoarthritis patients consumed for 6 months undenatured collagen showed a reduction in WOMAC score improving pain and joint functionality [22]. Moreover, a clinical trial in which collagen was given with acetaminophen, after 3 months of treatment the group that consumed collagen had a greater improvement in WOMAC index, gaining functionality in comparison with the group that took only acetaminophen [23].

Conclusion
Efforts are being made to find new therapeutic options that can not only reduce osteoarthritis pain, but also improve the disease course. Nutraceuticals such as collagen are good candidates due to their safety profile and studies that show osteoarthritis improvement. However, more studies are needed to clarify collagen mechanism of action and larger clinical trials should bring more evidence of the role of collagen supplements in osteoarthritis.