Collagen is the most abundant form of protein in the animal kingdom. It serves primarily a structural role, and in humans it is the principal component of skin, nails, cartilage, tendons and ligaments. It is present in virtually every body organ and its importance from a biological perspective is reflected in the fact that collagens are quite similar across species.

Collagen is a general term used to refer to a family of fibrous proteins. The characteristic feature of each is a long, stiff, triple-stranded helical structure in which three collagen polypeptide chains (alpha chains) are wound around each other to form a ropelike superhelix, called a trimer. More than 20 different alpha chains have been identified so far. Each is rich in the amino acids glycine and proline, but is encoded by a different gene and is molecularly and immunologically unique. Combinations of these genes are expressed in different tissues and result in the production of more than a dozen types of collagen molecules, derived from the mixtures of different collagen alpha chains forming a distinct triple helix. Each collagen triple helix serves a distinct biological purpose. The nature of the ends of each collagen trimer determine if and how it polymerizes into fibrils and larger structures. The type, distribution and orientation of collagen molecules reflect the function of the tissue in which it is found. For example, type I collagen provides structural support to skin, and type II collagen forms the cartilage found in joints.

Collagen formulations have been used for health purposes for at least 800 years, partly based on fact and partly on anecdote and assumption. The diversity of applications is quite striking:

Skin tightness enhancement—As we mature, the body's production of collagen slows and this is believed to contribute to an "older" appearance. Oral and topical collagen formulations, typically hydrolyzed (digested) into small pieces to facilitate absorption, are thought to help alleviate these age-related skin changes.

Blood clotting—Exposure to the collagen in a blood vessel wall is known to cause platelets to clump in the coagulation process. Dry fibrous collagen formulations are very effective and frequently used topical hemostatic (blood-clot promoting) agents.

Cosmetic augmentation—A highly purified and viscous formulation of collagen can be injected by a physician as a tissue-bulking agent to remove facial lines and/or increase the fullness of lips. This cosmetic procedure is widely accepted.

Protein supplementation—Hydrolyzed collagen protein formulations are often used as a general protein source in bodybuilding, protein-enriched and weight loss products because they are relatively inexpensive. While not considered a good source of "high quality" protein because it lacks tryptophan and is low in sulfur-containing amino acids such as cysteine and methionine, hydrolyzed collagen is thought to nourish collagen-containing tissues throughout the body.

Joint health—A variety of different collagen formulations are sold as nutritional supplements to enhance joint function and mobility. The scientific evidence supports this use of certain collagen preparations.

Collagen For Joint Function And Mobility
It is well documented in both rheumatoid arthritis and osteoarthritis that there is often significant deterioration of type II collagen-containing cartilage in the joints.^1,2

There are two theories as to why orally consumed collagen supplements might be useful in restoring joint health. The first is that they simply provide increased availability of the specific amino acids and other companion components found in collagen extracts (e.g., glucosamine, hyaluronate), which are needed by the body to create and maintain the collagen found in healthy joints. There is only preliminary evidence suggesting this as the reason for the efficacy of such supplements in people who have a well-balanced diet.

The second theory is that type II collagen-containing dietary supplements act by inducing what is called mucosal tolerance. Mucosal tolerance is a strategy involving feeding of a certain protein, which is similar or identical to one produced in the body, resulting in a reduced reactivity to that protein. This can also be described as "oral immunization," but the body's immune response to the protein (antigen) is greatly attenuated. In the case of type II collagen, the intestinal mucosa mediate many of the immunological signals that result in a greater tolerance to the antigen, which leads to suppression of inflammation in the joints. The inflammation results, in part, from autoimmune reactions to type II collagen. Through a wide range of studies in a variety of different animal models of arthritis, researchers have demonstrated that there are three mechanisms of mucosal tolerance: 1) the generation of regulatory T cells (active suppression) that release anti-inflammatory cytokines to reduce inflammation regardless of its source, 2) the neutralization of antigen-specific inflammatory T cells (anergy), and 3) the destruction of antigen specific inflammatory T cells (clonal deletion). 3 The mechanism that dominates is a function of the nature of the collagen consumed and the dose at which it is administered. Lower doses tend to work by active suppression and higher doses by either anergy or clonal deletion.

The evidence from clinical trials among rheumatoid arthritis patients strongly supports the use of a liquid formulation of undenatured (native), type II collagen (collagen II) that has been acid solubilized by limited enzymatic digestion. Native collagen II is adhesive and requires a low pH (more acidic) environment. Taken once each morning at very low doses on an empty stomach, it has been shown to elicit substantial decreases in inflammation without side effects, even when taken in combination with over-the-counter analgesics. The majority of these preparations have needed to be kept under refrigeration until just prior to use and are delivered in a liquid form.

Trentham and coworkers were the first to use this preparation, derived from chicken-sternal cartilage and rendered stable by acetic acid and orange juice, which demonstrated a statistically significant improvement versus placebo in a variety of measures of inflammation, including the number of swollen joints, tender joints and 15-meter walk time.4 The dose used was 100 micrograms of solubilized collagen/day for the first month and then 500 mcg/day for two more months. One primary weakness of this study is that the patients were allowed to use their anti-RA drugs up until the day before starting dosing with the collagen II preparation. This allows the persisting effects of the drug to "mix" with the collagen II effects.

In another study that did not employ a placebo control group, Barnett and colleagues from Beth Israel Hospital/Harvard showed this same formulation to be of substantial value to patients with juvenile rheumatoid arthritis.5 Eight of the 10 patients enrolled in this study were judged "responders" and displayed more than a 50 percent reduction from baseline in swollen and tender joint counts. Additionally, no adverse events were reported. The researchers concluded that this soluble, chicken type II liquid collagen may be a safe and effective therapy meriting further investigation.

Myers and coworkers from the University of Tennessee in Memphis obtained similar results with eight of nine patients meeting the pre-established criteria for clinical improvement.6 However, in this study they used fetal bovine cartilage as the source of native collagen II, which also was solubilized in acetic acid and added to orange juice just before consumption. Initial doses were either 100 or 50 mcg of soluble collagen II/day for the first four weeks (depending on body weight), followed by 250 or 500 mcg/day for the remaining eight weeks. As in the previous study, which enrolled a total of 10 patients, no control group was used. Five of the patients showed improvements greater than 30 percent and five exceeded 50 percent improvement, with one going into complete remission after the study concluded. Significant changes in cytokine profiles were also observed. No adverse effects were reported, leading the researchers to describe the results as "encouraging" and deserving additional investigations.

Barnett and colleagues conducted a large multi-centered, placebo-controlled double-blind trial with the liquid soluble native chicken collagen II formulation described above. Two hundred seventy-four people with active RA were assigned to receive either placebo or four different doses of the collagen liquid for 24 weeks.7 The four doses were: 20, 100, 500, or 2,500 mcg collagen II/day. Two hundred twenty-eight subjects completed the full six-month study. The outcome measures used to determine efficacy and a clinical "response" were one of three different composite criteria that assess joint pain and function. Only the lowest dose (20 mcg/day) group had a percentage of responders that was greater and statistically significant compared to placebo (but not the higher doses of collagen), and only for a certain composite criteria and not for the American College of Rheumatology (ACR20) criteria. Also, the collagen group as a whole (all dose groups; 216 subjects) did not have a statistically significant advantage in percent responders compared to placebo.

Choy and colleagues from King's College Hospital in London performed a double-blind, placebo-controlled study with 51 RA patients.8 Three different doses of soluble bovine collagen II (extracted from nasal cartilage) were administered (50, 500, or 5,000 mcg/day for 24 weeks) but in a tablet form. Using a composite criteria called a Disease Activity Score as the primary outcome measure of efficacy, they found only the 500 mcg/day group to show statistically significant improvements relative to placebo, both with the DAS and ACR20 criteria. As with previous studies, no significant adverse effects were reported. The authors concluded that this dose and form of collagen may be able to deliver a more precise dose than a liquid form, and that the 500 mcg/day dose was able to reduce inflammation but not adequately control the disease.

Sieper and coworkers from Berlin conducted a double-blind, placebo-controlled trial in 90 early stage (RA for less than three years) patients with a bovine-derived, native collagen II tableted preparation. The patients were given either a placebo or 1 or 10 mg of the collagen for three months.9 Although neither dose of collagen treatment produced a statistically significant improvement in ACR20 criteria, the higher-dose group did show strong trends for improvement with both doses being very well tolerated.

McKown and associates from the University of Tennessee undertook a large double-blind, placebo-controlled trial with 190 RA patients who were allowed to maintain their anti-RA medications (nonsteroidal anti-inflammatories, disease-modifying therapy or prednisone).9 They were randomized to receive either placebo (dilute acetic acid liquid) or a bovine-cartilage-derived, solubilized native collagen II in dilute acetic acid liquid. The collagen II dose was 100 mcg for the first month and then 500 mcg for five additional months. No statistically significant clinical improvement (ACR20) was observed in the collagen II group. The investigators advocated the performance of additional research in animal models, to tease out the optimal conditions and background (anti-RA drugs or no drugs; collagen II antibodies in patients) for oral collagen in RA.

Currently, several different type II collagen preparations purported to enhance joint health and mobility are available in the marketplace. Many of these contain hydrolyzed or denatured collagen and almost all have not been solubilized. Limited and conflicting clinical evidence supports hydrolyzed collagen preparations in osteoarthritis. However, there do not appear to be any studies assessing the effects of native solubilized or non-insolubilized collagen II in this non-autoimmune condition. The vast majority is provided in solid dosage forms, not as liquids. Excluding studies that showed no statistically significant results, the majority of the human evidence to date that does support the efficacy of collagen II rests with refrigerated, liquid, soluble, native preparations. To date, no head-to-head comparisons have been performed with chicken- and bovine-soluble collagen II preparations. Similarly, soluble-liquid and solid-dose forms have not been directly compared. One can hope that additional studies, using commercially available forms, will be presented and published in reviewed journals in the near future. Recently completed clinical studies are slated for presentation later this year, with a commercially available dry, native chicken-sternum collagen II powder in RA and a hydrolyzed chicken-sternum collagen in osteoarthritis.

In summary, the ability of mucosal tolerance mechanisms to promote healthy joints appears dependent upon both the form and amount of type II collagen ingested. Retailers should talk to their suppliers about the research details supporting the exact collagen form being promoted. Thus informed, they can help their customers select the most promising product.

Robert Bishop, Ph.D., is a managing partner of Colloral LLC, a liquid collagen supplement company, and has been involved in health care research for more than 35 years. He is president of AutoImmune Inc. and is on several public company boards.

Disclosure Statement: Colloral LLC and Autoimmune Inc. have a financial interest in a recently introduced collagen-based dietary supplement.

Reviewed by Dan Lukaczer, N.D.
Reviewed and edited by Dena Nishek and Anthony Almada.

The editors of Nutrition Science News invite your response to this article. Please e-mail comments to [email protected].

References

1. Adam M, et al. Collagen in rheumatoid arthritis. Clin Chem Acta 1976; 70:61-9.

2. Adam M, Hulejova H, Miterova S. The development of osteoarthrosis and the role of collagen in the pathophysiology of its development. Acta Chir Orhop Traumatol Cech 1989; 56:377-90.

3. Weiner H, Komagata H. Oral tolerance and the treatment of rheumatoid arthritis. Springer Semin Immunopathol 1998; 20:289-308.

4. Trentham D, et al. Effects of Oral Administration of Type II Collagen on Rheumatoid Arthritis. Science 1993; 261:1727-30.

5. Barnett M, Combitchi D, Trentham D. A Pilot Trial of Oral Type II Collagen in the Treatment of Juvenile Rheumatoid Arthritis. Arthritis Rheum 1996; 39:623-8.

6. Myers L, et al. Juvenile Arthritis and Autoimmunity to Type II Collagen. Arthritis Rheum 2001; 44:1775-81.

7. Barnett M, et al. Treatment of Rheumatoid Arthritis with Oral Type II Collagen. Arthritis Rheum 1998; 41:290-7.

8. Sieper J, et al. Oral Type II Collagen Treatment in Early Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled, Randomized Trial. Arthritis Rheum 1996; 39:41-51.

9. McKown KM, et al. Lack of efficacy of Oral Bovine Type II Collagen Added to Existing Therapy in Rheumatoid Arthritis. Arthritis Rheum 1999; 42:1204-8.

Natural Foods Merchandiser volume XXIV/number 8/p. 40, 42

Natural Foods Merchandiser volume XXIV/number 8/p. 42