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Practitioner Dietary Supplement Reference Guide 2015 Update
Joint Flex Plus (Biocell Collagen II)
Goal
Supply natural components in proper amounts which are not available through typical diets, but shown to help
maintain joint and skin health. JointFlexPlus (JFP) ingredients are designed to improve the ratio of the normal
biological processes of cartilage degradation and synthesis to favor synthesis when compared to a nonsupplemented state, and to provide lubrication to help enhance or maintain healthy joint tissue and function. The
ingredients also help to maintain the integrity of the extracellular matrix in the dermis below the skin, which is
crucial for youthful skin appearance. JFP helps reduce visible aging signs such as wrinkles and fine lines as well as
the dehydration and scaling of the skin.
Rationale
Osteoarthritis (OA) is a condition of degeneration of the protective covering at bone articular surfaces (cartilage).
Age and injury are associated with an increased risk of development with other lifestyle factors intervening, such
as obesity.1 Because cartilage is used as a cushion between bones, its loss causes friction, pain and stiffness.1
BioCell Collagen II is a patented dietary supplement containing low molecular weight undenatured type II
collagen combined with hyaluronic acid (HA) and chondroitin sulfate (CS).
Type II Collagen
The role of articular cartilage is to bear load, absorb shock and minimize wear between articulating joint surfaces.
Chondrocytes, the cells of articular cartilage, do not directly contribute to these physical properties; only the
extracellular matrix (ECM) plays a direct structural role. However, as the only cell type normally resident within
articular cartilage, chondrocytes are responsible for the synthesis and maintenance of the extracellular matrix
which is suitably adapted to cope with the physical pressures of its environment.2,3
The health of articular cartilage, then, is dependent upon the maintenance of the ECM. The ECM is a
macromolecular framework made of two main components, proteoglycans and collagens. Type II collagen is the
predominant type in cartilage. Type II collagen forms a 3D fibrous network which provides tensile stiffness and
strength to cartilage and provides the basic architecture to the tissue. Aggrecans (and other types of
proteoglycans) are embedded within this fibrous network, providing compressibility and elasticity to the tissue.
Chondrocytes are responsible for the synthesis, organization and maintenance of the ECM. Communication
between chondrocytes and the ECM determine degradation or synthesis. OA can alter the sensitivity of
chondrocytes to regulatory signals. This leads to a progressive imbalance between degradation and
synthesis/regeneration, leading to a marked decrease in the content of type II collagen in the ECM, eventually
leading to cartilage damage.4,5
Type II collagen and collagen fragments (as found in JFS) are proposed to regulate metabolic activities in
chondrocytes thus may act as signals to increase cartilage synthesis as well as provide lubrication.5
The theory behind supplementation is this role that collagen fragments have in regulating chondrocyte activity.
The presence of collagen fragments (hydrolyzed) gives the appearance that ECM degradation has occurred. This
stimulates the chondrocytes to increase ECM synthesis, in an attempt to "repair" the damaged structure.3,6
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
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Practitioner Dietary Supplement Reference Guide 2015 Update
Several studies featuring in vitro and in vivo designs have shown significant improvement in the ECM as well as
standard tests to assess pain, physical activity and quality of life in both animal and human models. Animal
studies in rats showed reduced articular cartilage degradation in an OA model with oral supplementation of
chicken collagen type II.7 Obese-arthritic dogs given 4 mg or 40 mg doses of UC II (undenatured type II collagen
from chicken sternum) for 90 days showed significant reductions in overall pain, pain during limb manipulation
and lameness after physical activity. There was a dose dependent response. Additionally, after a 30 day
withdrawal, all animals experienced a relapse and increases in pain measures.8 In 2002, researchers in Germany
explored the effect of type II collagen biosynthesis by bovine chondrocytes when cultured with different types
and molecular weight (MW) of collagen (type I and II hydrolyzed, type I and II native and collagen free wheat
protein). Their results indicated a stimulatory effect on type II collagen biosynthesis and secretion by
chondrocytes when cultured with hydrolyzed collagen, in a dose dependent manner. The researchers found that
only hydrolyzed collagen, and primarily of lower MW (<10 kDa) was able to exert this influence. This illuminated
a possible feedback mechanism for the regulation of collagen turnover in cartilage.9 A study in 2003 also showed
that type II collagen increased the ECM content, as well as subtle differences in biochemical markers.10 In 2000,
Moskowitz reviewed the results of studies using collagen hydrolysates in the US, United Kingdom and Germany.
A significant impact on pain measures was noted; see Figure 1 and Figure 2. As with the GAIT study, the benefits
seem to be greatest in those who suffer OA to a greater degree.11
120
100
WOMAC Score
80
BioCell Collagen II
60
Glucosamine/Chondroitin
40
20
0
0
30
60
90
The WOMAC* (Western Ontario and McMaster Universities) Index of Osteoarthritis
Figure 1 WOMAC scores were reduced by 33% in the UC-II group vs. 14% with GS (UC-II = BioCell Collagen II).
*The WOMAC index is used to assess patients with osteoarthritis of the hip or knee using 24 parameters. It can be used to monitor the course of the
disease or to determine the effectiveness of anti-rheumatic medications. In this study the WOMAC score measured the difficulty in physical function,
stiffness and pain in the knee.
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
www.dotFIT.com/PDSRG2015Update
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Practitioner Dietary Supplement Reference Guide 2015 Update
120
100
VAS Score
80
BioCell Collagen II
60
Glucosamine/Chondroitin
40
20
0
0
30
60
90
The VAS** (Visual Analogue Scale) Index of Osteoarthritis
Figure 2 VAS scores were decreased by 40% for UC-II vs. 15% for GS (UC-II = BioCell Collagen II).
A 2004 abstract looked at the efficacy of BioCell collagen specifically. In this randomized double blind placebo
controlled trial, 16 subjects with OA of the knee or hand used BioCell 1000 mg twice daily for two months.
Adverse events were the same as placebo and were insignificant and not related to the study substances. The
BioCell group experienced significant improvement in all WOMAC subscales and in total WOMAC score
compared to placebo.12
In 2009, a clinical trial was presented that looked not only at the effectiveness of undenatured type II collagen
(UC-II) on OA pain, but also compared it to glucosamine and chondroitin (GC) use. A daily dose of 40 mg of UC-II
was used, providing 10 mg of bioactive undenatured type II collagen. WOMAC scores were reduced by 33% in
the UC-II vs. 14% with GC. VAS scores were decreased by 40% for UC-II vs. 15% for GC. The Lequesne Score (used
to determine the effect on pain during daily activities) was reduced by 20.1% for UC-II vs 5.9% for GC. Overall,
the UC-II group experienced significant reductions in all measures of pain and pain during activities and did so to
a significantly greater degree than GC supplementation.13
A double blind placebo controlled study published in 2012 divided healthy subjects with joint pain into two
groups and administered either 2 g of BioCell collagen (BCC) or placebo for 70 days. Outcome measurements
included visual analogue scale (VAS) for pain and Western Ontario and McMaster Universities Arthritis Index
(WOMAC) scores taken on days 1, 35, and 70. The tolerability profile of the treatment group was comparable to
that of the placebo. Intent-to-treat analysis showed that the treatment group, as compared to placebo, had a
significant reduction of VAS pain on day 70 (p < 0.001) and of WOMAC scores on both days 35 (p = 0.017) and 70
(p < 0.001). The BCC group experienced a significant improvement in physical activities compared to the placebo
group on days 35 (p = 0.007) and 70 (p < 0.001). BCC was well tolerated and found to be effective in managing
OA-associated symptoms over the study period, thereby improving patient's activities of daily living.14
Most recently a double blind placebo controlled study assessed the efficacy and tolerability of UC-II in
moderating joint function and joint pain due to strenuous exercise in healthy subjects. The conclusion was that
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
www.dotFIT.com/PDSRG2015Update
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Practitioner Dietary Supplement Reference Guide 2015 Update
daily supplementation with 40 mg of UC-II was well tolerated and led to improved knee joint extension in
healthy subjects. UC-II also demonstrated the potential to lengthen the period of pain free strenuous exertion
and alleviate the joint pain that occasionally arises from such activities.15
Additionally, there are several studies that have looked at the effects of UC-II on rheumatoid arthritis (RA), an
autoimmune disorder. Results are promising and may be due to an auto-antigen action, suppressing T cell
activity and autoimmune responses.16
Ultimately, it appears that oral administration of UC-II is effective and appears to follow a dose response to
symptoms of OA. The proposed mechanism of action is through increases in undenatured type II collagen in the
ECM signaling type II collagen synthesis by chondrocytes, leading to a more advantageous ECM environmentone that favors a better ratio of synthesis vs. degradation.15
** A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a
continuum of values and cannot easily be directly measured. An example of a VAS would be a numeric scale of 1 to 10 to represent severity of pain (1
being little to no pain and 10 representing excruciating pain).
Hyaluronic Acid
Hyaluronic acid (HA) is an anionic, non-sulfated glycosaminoglycan distributed widely throughout connective
tissues and is one of the chief components of the extracellular matrix. It is a major component of the synovial
fluid and contributes to the viscosity of the fluid. Along with lubricin, it is one of the fluid's main lubricating
components.
HA is an important component of articular cartilage, where it is present as a coat around chondrocytes. When
aggrecan monomers bind to hyaluronan in the presence of link protein, large highly negatively-charged
aggregates form. These aggregates wick water and are responsible for the resilience of cartilage (its resistance
to compression). In OA or joint degradation, HA levels are decreased.
The proposed mechanism of action would be to support a healthy ECM and provide the raw materials for joint
health as well as bringing water to cartilage and aid in synovial fluid viscosity and protection/reaction to
pressure and shock.17 Intra-articular injections with HA are quite common and have repeatedly shown
improvement in symptoms of OA and joint degeneration. Effective absorption and uptake by oral
supplementation of high MW hyaluronic acid has been shown in rats and dogs.18
Chondroitin Sulfate
Chondroitin sulfate is a necessary substrate for cartilage metabolism and assists in maintaining joint viscosity. In
vitro studies show that chondroitin also inhibits enzymes that degrade cartilage. In recent reviews of
chondroitin, the researchers concluded that the safety and tolerability of CS are confirmed, CS is effective, at
least in part, for the treatment of OA and its therapeutic benefits occur through three main mechanisms: 1)
stimulation of ECM production by chondrocytes; 2) suppression of inflammatory mediators; and 3) inhibition of
cartilage degeneration. Its effects include benefits that are not achieved by current medicines and include
chondroprotection and the prevention of joint space narrowing.19,20
dotFIT Joint Flexibility Plus (Biocell Collagen II) and Skin Tone
A pilot study demonstrated that the ingestion of BioCell Collagen enhanced blood microcirculation and reduced
facial aging signs including reduced wrinkles, improved skin tone, improved hydration and smoother, more
supple skin.21
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
www.dotFIT.com/PDSRG2015Update
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Practitioner Dietary Supplement Reference Guide 2015 Update
Mechanism of Actions
Maintaining the integrity of the extracellular matrix in the dermis below the skin is crucial for a youthful
appearance.22 Both collagen and hyaluronic acid (HA) are key molecules essential for the healthy structure and
function of the dermal structure.23 Unfortunately, both natural and photoaging (chronic UVA and UVB exposure)
processes involve the breakdown of collagen and HA. This gradually causes the dermal layer to be increasingly
disorganized resulting in the visible aging signs such as wrinkles and fine lines as well as the dehydration and
scaling of the skin.24
The Formula and Solution
BioCell Collagen II is a patented dietary supplement containing low molecular weight undenatured type II
collagen combined with hyaluronic acid (HA) and chondroitin sulfate (CS).
BioCell Collagen® can counteract both natural and photoaging processes via multiple mechanisms including
increases in collagen and HA content and inhibition of the enzyme that breaks down HA.21
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
www.dotFIT.com/PDSRG2015Update
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Practitioner Dietary Supplement Reference Guide 2015 Update
Study results from the Journal of Clinical Interventions in Aging:21
1. Reduction of wrinkles and fine lines. Daily ingestion of BioCell Collagen® for 12 weeks led to a
significant decrease in facial lines and wrinkles.
2. Improvement of skin texture by increasing hydration and reducing skin scaling. A majority of the study
subjects enjoyed remarkable improvement of their skin tone.
3. Maintenance of the integrity and healthy level of HA. HA plays an essential role in skin hydration by
retaining water in the dermis. BioCell Collagen® helps maintain healthy levels of HA not only by elevating
HA levels about 60 fold in the bloodstream but also by inhibiting HA degradation.
4. Increase in collagen content. The aging process leads to the loss of dermal collagen, which is the key
factor of wrinkle generation. BioCell Collagen® antagonizes it and increases collagen content in the
dermis.
5. Enhancement of blood microcirculation in the face. Various cells reside in the skin including dermal
fibroblasts which produce collagen, elastin, HA, and other ground substances that fill the skin layer.
Improved blood microcirculation effectively nourishes the cells with oxygen and nutrients while
removing wastes from the tissue.
In 2010, BioCell Technology LLC, received Generally Recognized As Safe (GRAS) approval by an independent
expert panel for its patented, clinically-substantiated ingredient, BioCell Collagen II®.
Summary
Joint Flexibility Plus is a safe alternative to the more dangerous NSAIDS for the treatment of mild to moderate
osteoarthritis and should be a strong consideration to those who suffer from OA. JFP would be targeted to those
adults who experience mild to severe joint pain due to the loss of cartilage that leads to OA.
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Joint Flexibility Plus is one component of the dotFIT longevity program which is made available to all
program users and appears on the dotFIT website.
Studies show that the ingredients in the new JSF may provide greater relief than glucosamine and
chondroitin combined.
The ingredients have been shown to support cartilage, joint and skin health.
BioCell Collage II reduces symptoms of joint pain and increases functional capacity without the side
effects of NSAIDS.
Unique Features
 Contains the patented formula BioCell Collagen II
 Dosages and compounds are in the amounts used in research that have shown to improve mobility, joint
comfort, and knee‐joint strength
 Formula considers use of other dotFIT products to help the user maintain a safe and optimal range of
total nutrient intake
 Manufactured in compliance with Good Manufacturing Practices (GMP’s)
Typical Use
 Individuals concerned with joint and cartilage health
 For overuse or age-related joint discomfort
 Take 1 capsule in the morning and 1 capsule at night before a meal with least 8 oz. of water.
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
www.dotFIT.com/PDSRG2015Update
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Practitioner Dietary Supplement Reference Guide 2015 Update

For optimal results, take 2 capsules in the morning and 2 capsule at night before a meal or as directed by
your health care professional.
Precautions
The ingredients in the Joint Flexibility Plus are generally considered to be safe at the recommended dose.13
Contraindications
The use of JSF is not recommended during pregnancy or lactation due to the absence of use data for these
populations. No known contraindications exist at this time.
Adverse Reactions
Study participants who used 1000 mg of BioCell Collage II twice daily for two months experienced the same
adverse events as the placebo group and were insignificant and not related to the study substances. No adverse
events were reported in the literature for the other substances.
Upper Limit/Toxicity
There are no known overdoses of the BioCell Collage II ingredients either individually or as the formula.
Supplement Facts Panel
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
www.dotFIT.com/PDSRG2015Update
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Practitioner Dietary Supplement Reference Guide 2015 Update
References
1
Guilak F: Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol 2011, 25:815–823.
Honda K, Ohno S, Tanimoto K, et al: The effects of high magnitude cyclic tensile load on cartilage matrix metabolism in
cultured hondrocytes. Eur J Cell Biol 2000, 79:601–609
3
Ramage L, Nuki G, Salter DM: Signalling cascades in mechanotransduction: cell-matrix interactions and mechanical
loading. Scand J Med Sci Sports 2009, 19:457–469
4
van Meegeren ME, Roosendaal G, Jansen NW, et al: IL-4 alone and in combination with IL-10 protects against bloodinduced cartilage damage. Osteoarthritis Cartilage 2012, 20:764–772.
5
Roman-Blas JA, Stokes DG, Jimenez SA: Modulation of TGF-beta signaling by proinflammatory cytokines in articular
chondrocytes. Osteoarthritis Cartilage 2007, 15:1367–1377.
6
Kawamura S, Lotito K, Rodeo SA: Biomechanics and healing response of the meniscus. Oper Tech Sports Med 2003, 11:68–
76.
7
Xu D, Shen W. Chicken collagen type II reduces articular cartilage destruction in a model of osteoarthritis in rats. West
Indian Med J. 2007 Jun; 56(3): 202-7.
8
D'Altilio M, et al. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with
glucosamine and chondroitin in arthritic dogs. Tox Mech Methods. 2007; 17:189-196.
9
Oesser S, Seifert J. Stimulation of type II collagen biosynthesis and secretion in bovine chondrocytes cultured with
degraded collagen. Cell Tissue Res (2003) 311: 393-399.
10
Qi WN, Scully SP. Type II collagen modulates the composition of extracellular matrix synthesized by articular
chondrocytes. J Orthop Res (2003) Mar; 21(2): 282-9.
11
Moskowitz RW. Role of collagen hydrolysates in bone and joint disease. Semin Arthritis Rheum (2000) 30: 87-99.
12
Kalman DS, Schwartz HI, Pachon J, Sheldon E, Almada AL.A randomized double blind clinical trial evaluating the safety and
efficacy of hydrolyzed collagen type II in adults with osteoarthritis. Experimental Biology 2004 meeting abstract.
13
Crowly CC, et al. safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a
clinical trial. Int J Med Sci 2009; 6(6):312-321.
14
Schauss AG, Stenehjem J, Park J, Endres JR, Clewell A. Effect of the novel low molecular weight hydrolyzed chicken sternal
cartilage extract, BioCell Collagen, on improving osteoarthritis-related symptoms: a randomized, double-blind, placebocontrolled trial. J Agric Food Chem. 2012 Apr 25;60(16):4096-101. doi: 10.1021/jf205295u. Epub 2012 Apr 16.
15
Lugo et al.: Undenatured type II collagen (UC-II®) for joint support: a randomized, double-blind, placebo-controlled study
in healthy volunteers. Journal of the International Society of Sports Nutrition 2013 10:48.
16
Bagchi D, Misner B, Bachi M, Kothari SC, Downs BW, Fafard RD, Preuss HG. Effects of orally administered undenatured
type II collagen against arthritic inflammatory diseases: a mechanistic exploration. Int J clin Pharmacol Res. 2002; 22(3-4):
101-10.
17
Akmal M, Singh A, anand A, Kesani A, Aslam N, Goodship A, Bentley G. The effects of hyaluronic acid on articular
chondrocytes. J Bone Joint Surg Br. 2005 Aug; 87(8): 1143-9.
18
Balogh L, et al. Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in
rats and dogs. J Agric Food Chem. 2008 Nov26; 56(22): 10582-93.
19
Uebelhart D. Clinical review of chondroitin sulfate in osteoarthritis. Osteoarthritis Cartilage. 2008; 16 Suppl 3:s19-21.
20
Kubo M, Ando K, Mimura T, Matsusue Y, Mori K. Chondroitin sulfate for the treatment of hip and knee osteoarthritis:
current status and future trends. Life Sci. 2009 Sep 23; 85(13-14): 477-83.
21
®
Schwartz SR, Park J Ingestion of BioCell Collagen , a novel hydrolyzed chicken sternal cartilage extract; enhanced blood
microcirculation and reduced facial aging signs.Clinical Interventions in Aging. Published Date July 2012 Volume 2012:7
Pages 267 - 273. DOI: http://dx.doi.org/10.2147/CIA.S3283
22
Uitto J, Pulkkinen L, Chu M-L. Collagen. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors.
Dermatology in General Medicine. New York, NY: McGraw-Hill; 2003:165–179.
23
Champion RH, Burton JL, Ebling FJG, editors. Rook/Wilkinson/Ebling Textbook of Dermatology, 5th ed. Oxford, UK:
Blackwell Scientific Publications; 1992
24
Helfrich YR, Sachs DL, Voorhees JJ. Overview of skin aging and photoaging. Dermatol Nurs. 2008;20(3):177–183.
2
Practitioner Dietary Supplement Reference Guide
This information is educational material for dotFIT certified fitness professionals.
This literature is not to be used to imply that dotFIT products may diagnose, cure or prevent disease.
www.dotFIT.com/PDSRG2015Update
8