Undenatured Type II Collagen (UC-II®) for Joint Health

Denatured type II collagen (UC-II) appears to exert joint-health benefits by oral tolerance, based on pre-clinical research. ^[1]

Figure 1.  Gut-associated lymphoid tissue (GALT) are MALT located in gut
Image Source: DOI: 10.1183/13993003.01701-2015

Oral Tolerance

Oral tolerance is an immune process the body uses to distinguish between 

• Innocuous compounds and
• e.g., dietary proteins, intestinal bacteria
• Harmful foreign invaders

It takes place in the gut-associated lymphoid tissue (GALT). The GALT is mostly made up of mesenteric lymph nodes and patches of lymphoid tissue neighboring the small intestine (Peyer’s patches). ^[2]

Peyer’s patches take in and screen compounds from the gut lumen and, depending on the compound, switch the body’s immune response on or off. 

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut. GALT makes up about 70% of the immune system by weight; compromised GALT may significantly affect the strength of the immune system as a whole.

One of the best things you can do to improve oral tolerance is to support a rich diversity of gut bacteria. These bacteria produce short chain fatty acids (SCFA), which help dampen inflammation and manage autoimmune diseases. A limited diet can reduce gut bacteria diversity.

Figure 2.  Synovial fluid (By Madhero88)

What's Collagens

Cartilage — the smooth tissue at the end of bones that cushions the joints, allowing them to glide together smoothly — cannot regenerate itself. The key structural macromolecules of the cartilage tissue in the mammals are:

• Collagen 
• Proteoglycans

Glucosamine, hyaluronic acid, and chondroitin sulfate are vital basic natural constituents of cartilage and synovial fluid. 

Collagens are extracellular matrix molecules used by the cells for structural integrity and a range of further functions. 

Denatured type II collagen, by contrast, lacks these essential structural components.

Figure 3.  Schematic diagram of the proposed mode of action for type II collagen (UC-II) 

How Intaking UC-II Can Help Joint-Health

The interaction between gut-associated lymphoid tissue in the duodenum and epitopes of orally administered undenatured type II collagen facilitates oral tolerance to the antigen and stems systemic T-cell attack on joint cartilage.^[2]

UC-II® contains active epitopes that are able to interact with Peyer’s patches and induce oral tolerance.  A possible mechanism of action for UC-II activity is briefly summarized below (see Figure 3):

1. Transforms naive T-cells into Treg 
• When consumed, UC-II® is believed to be taken up by the Peyer’s patches, where it activates immune cells. It transforms naive T-cells into T regulatory (Treg) cells that specifically target type II collagen. 
2. Treg cells then migrate through the circulation
3. Encounters type II collagen in joint cartilage
1. When they recognize type II collagen in joint cartilage, Treg cells secrete anti-inflammatory mediators (cytokines), including the transforming growth factor-beta (TGF-beta), interleukin 4 (IL-4) and interleukin 10 (IL-10). 
2. This action helps reduce joint inflammation and promotes cartilage repair. 

This process initiates anti-inflammatory and cartilage protective pathways that prevent the immune system from injuring its joint cartilage while promoting cartilage repair and regeneration. 

Summary of cytokines and their functions

Cytokine	Family	Main sources	Function
IL-1β	IL-1	Macrophages, monocytes	Pro-inflammation, proliferation, apoptosis, differentiation
IL-4	IL-4	Th-cells	Anti-inflammation, T-cell and B-cell proliferation, B-cell differentiation
IL-6	IL-6	Macrophages, T-cells, adipocyte	Pro-inflammation, differentiation, cytokine production
IL-8	CXC	Macrophages, epithelial cells, endothelial cells	Pro-inflammation, chemotaxis, angiogenesis
IL-10	IL-10	Monocytes, T-cells, B-cells	Anti-inflammation, inhibition of the pro-inflammatory cytokines
IL-12	IL-12	Dendritic cells, macrophages, neutrophils	Pro-inflammation, cell differentiation, activates NK cell
IL-11	IL-6	Fibroblasts, neurons, epithelial cells	Anti-inflammation, differentiation, induces acute phase protein
TNF-α	TNF	Macrophages, NK cells, CD4+lymphocytes, adipocyte	Pro-inflammation, cytokine production, cell proliferation, apoptosis, anti-infection
IFN-γ	INF	T-cells, NK cells, NKT cells	Pro-inflammation, innate, adaptive immunity anti-viral
GM-CSF	IL-4	T-cells, macrophages, fibroblasts	Pro-inflammation, macrophage activation, increase neutrophil and monocyte function
TGF-β	TGF	Macrophages, T cells	Anti-inflammation, inhibition of pro-inflammatory cytokine production

Preclinical Studies

Preclinical studies support oral tolerance as the mode of action of UC-II® undenatured type II collagen and confirm that the undenatured form of type II collagen is critical for joint-health benefits: 

• In an animal model (mouse) of RA, only UC-II protected against joint damage, an action attributed to oral tolerance.^[4]
• In an animal model (rat) of RA, UC-II provided symptom relief, an action attributed to oral tolerance and modulating inflammatory pathways.^[3]
• In a cell study, Treg cells specific for type II collagen secreted anti-inflammatory cytokines, which play a chief role in the cells’ ability to induce oral tolerance.^[5]
• In a cell study with human chondrocytes (cells that make up cartilage), the anti-inflammatory action of IL-10 protects against damage from tumor necrosis factor-alpha (TNF-α), a pro-inflammatory mediator elevated in osteoarthritis.^[6] 
• Clinically validated lab assays confirm active epitopes in UC-II® undenatured type II collagen resist digestion and retain the undenatured 3D-structure needed to interact with Peyer’s patches and induce oral tolerance.^[2]

References

1. Undenatured Type II Collagen (UC-II) in Joint Health and Disease: A Review on the Current Knowledge of Companion Animals
2. Bagchi D., Misner B., Bagchi M., Kothari S.C., Downs B.W., Fafard R.D., Preuss H.G. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: A mechanistic exploration. Int. J. Clin. Pharmacol. Res. 2002;22:101–110.
3. Tong T., Zhao W., Wu Y.-Q., Chang Y., Wang Q.-T., Zhang L.-L., Wei W. Chicken type II collagen induced immune balance of main subtype of helper T cells in mesenteric lymph node lymphocytes in rats with collagen-induced arthritis. Inflamm. Res. Off. J. Eur. Histamine Res.
4. Nagler-Anderson C., Bober L.A., Robinson M.E., Siskind G.W., Thorbecke G.J. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc. Natl. Acad. Sci. USA. 1986;83:7443–7446. Soc. 2010;59:369–377.
5. Asnagli H., Martire D., Belmonte N., Quentin J., Bastian H., Boucard-Jourdin M., Fall P.B., Mausset-Bonnefont A.-L., Mantello-Moreau A., Rouquier S., et al. Type 1 regulatory T cells specific for collagen type II as an efficient cell-based therapy in arthritis. Arthritis Res. Ther. 2014;16:R115.
6. Müller R.D., John T., Kohl B., Oberholzer A., Gust T., Hostmann A., Hellmuth M., Laface D., Hutchins B., Laube G., et al. IL-10 overexpression differentially affects cartilage matrix gene expression in response to TNF-alpha in human articular chondrocytes in vitro. Cytokine. 2008;44:377–385.
7. Mucosa Associated Lymphoid Tissues (MALT)