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Undenatured type II collagen (UC-II®) for joint support: A randomized,

double-blind, placebo-controlled study in healthy volunteers

Article  in  Journal of the International Society of Sports Nutrition · October 2013

DOI: 10.1186/1550-2783-10-48 · Source: PubMed

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Lugo et al. Journal of the International Society of Sports Nutrition 2013, 10:48
http://www.jissn.com/content/10/1/48

RESEARCH ARTICLE Open Access

Undenatured type II collagen (UC-II®) for joint

support: a randomized, double-blind,
placebo-controlled study in healthy volunteers
James P Lugo1, Zainulabedin M Saiyed1, Francis C Lau1, Jhanna Pamela L Molina2, Michael N Pakdaman2,
Arya Nick Shamie3 and Jay K Udani2,4*

Abstract
Background: UC-II contains a patented form of undenatured type II collagen derived from chicken sternum.
Previous preclinical and clinical studies support the safety and efficacy of UC-II in modulating joint discomfort in
osteoarthritis and rheumatoid arthritis. The purpose of this study was to assess the efficacy and tolerability of UC-II
in moderating joint function and joint pain due to strenuous exercise in healthy subjects.
Methods: This randomized, double-blind, placebo-controlled study was conducted in healthy subjects who had no
prior history of arthritic disease or joint pain at rest but experienced joint discomfort with physical activity. Fifty-five
subjects who reported knee pain after participating in a standardized stepmill performance test were randomized
to receive placebo (n = 28) or the UC-II (40 mg daily, n = 27) product for 120 days. Joint function was assessed by
changes in degree of knee flexion and knee extension as well as measuring the time to experiencing and
recovering from joint pain following strenuous stepmill exertion.
Results: After 120 days of supplementation, subjects in the UC-II group exhibited a statistically significant
improvement in average knee extension compared to placebo (81.0 ± 1.3º vs 74.0 ± 2.2º; p = 0.011) and to baseline
(81.0 ± 1.3º vs 73.2 ± 1.9º; p = 0.002). The UC-II cohort also demonstrated a statistically significant change in average
knee extension at day 90 (78.8 ± 1.9º vs 73.2 ± 1.9º; p = 0.045) versus baseline. No significant change in knee
extension was observed in the placebo group at any time. It was also noted that the UC-II group exercised longer
before experiencing any initial joint discomfort at day 120 (2.8 ± 0.5 min, p = 0.019), compared to baseline
(1.4 ± 0.2 min). By contrast, no significant changes were seen in the placebo group. No product related adverse
events were observed during the study. At study conclusion, five individuals in the UC-II cohort reported no pain
during or after the stepmill protocol (p = 0.031, within visit) as compared to one subject in the placebo group.
Conclusions: 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.
Keywords: UC-II, Undenatured type II collagen, Joint function, Knee extension, Stepmill, Joint pain

* Correspondence: [email protected]
2
Medicus Research LLC, 28720 Roadside Drive, Suite 310, Agoura Hills, CA
91301, USA
4
Northridge Hospital Integrative Medicine Program, Northridge, CA 91325,
USA
Full list of author information is available at the end of the article

© 2013 Lugo et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Lugo et al. Journal of the International Society of Sports Nutrition 2013, 10:48 Page 2 of 12
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Introduction TNF-α, IL-1β, and IL-6. It therefore appears that in

The impact of strenuous exercise on knee joints may healthy subjects undergoing strenuous exertion, the in-
cause localized pain and stiffness, which are hallmark duction of proinflammatory cytokines is offset by the
features of pathologic inflammatory disease [1]. It has synthesis of anti-inflammatory agents as part of the re-
been shown that when dogs undergo a strenuous run- covery process. This view is supported by the observa-
ning regimen, significant losses in articular cartilage and tion that IL-10 reduces the catabolic impact of IL-1β
glycosaminoglycans occur [2]. Such studies suggest that and TNF-α on cartilage explants from healthy volun-
strenuous exercise may activate some of the same teers, and this effect is enhanced by combining IL-10
physiological processes that occur in arthritic disease with IL-4 [13].
[2-4]. In fact, in vitro studies have shown that many of Another protein released by dynamically compressed
the cytokines implicated in the onset and progression of chondrocytes is transforming growth factor (TGF)-β
both rheumatoid arthritis (RA) and osteoarthritis (OA) [16-18]. This factor is secreted by many cell types and is
also appear to regulate the remodeling of the normal known to interfere with the cell cycle and arrest differenti-
knee extracellular matrix (ECM) following strenuous ation [19]. With regard to chondrocytes, TGF-β induces cell
exertion [5]. proliferation in vitro and slows terminal differentiation into
When normal chondrocytes undergo strenuous mechan- hypertrophic cells [20]. Numerous studies have shown that
ical stimulation under static conditions, their physiology TGF-β reverses the in vitro catabolic effect of various
shifts towards ECM breakdown, as indicated by the up- proinflammatory cytokines on normal chondrocytes as well
regulation of several metalloproteinases (MMPs), such as as chondrocytes harvested from RA and OA donors
MMP-13 as well as tumor necrosis factor (TNF)-α, inter- [21-23].
leukin (IL)-1β, IL-6, and various aggrecanases [5,6]. This The overall findings discussed above point to a new, uni-
in vitro catabolic response is mediated by changes in the fying view of joint physiology. It suggests that many of the
phosphorylation, expression, or translocation of several biological processes occurring in knee joints affected by RA
transcription factors to the cell nucleus such as NF-κB, and OA also participate in the maintenance of healthy
p38 MAPK, Akt, and ERK [7,8]. By contrast, normal knees [1,4,5]. It therefore seems appropriate to test the effi-
chondrocytes produce the anti-inflammatory cytokine IL-4 cacy of natural supplements or ingredients, which have
when mechanically stimulated under moderate and dy- been shown to moderate joint pain in RA and OA, as
namic conditions [9]. The secretion of this autocrine mol- possible candidates for treating the joint discomfort that
ecule not only helps in shifting chondrocyte metabolism occasionally results from strenuous exercise in healthy
towards the synthesis of aggrecan and type II collagen, it individuals.
also downregulates production of nitric oxide (NO) and UC-II is a natural ingredient which contains a
various MMPs and aggrecanases [10-12]. This conclusion glycosylated, undenatured type-II collagen [24]. Previous
is corroborated by the finding that pretreatment of studies have shown that small doses of UC-II modulate
strenuously compressed normal chondrocytes with IL-4 joint health in both OA and RA [24-26]. Tong et al. [27],
attenuates their catabolic response [11]. This suggests using an in vivo model of collagen induced arthritis (CIA),
that IL-4 plays a key role in downregulating remodeling demonstrated that ingesting microgram quantities of
functions, restoring articular cartilage homeostasis, as undenatured type II collagen significantly reduces circulat-
well as decreasing chondrocyte apoptosis following ing levels of inflammatory cytokines, potentially serving to
strenuous mechanical loading [12,13]. decrease both the incidence and the severity of arthritis
Mechanically stressed chondrocytes also produce a [28]. The ability to alter immunity via the ingestion of a
number of other molecules known to participate in in- food, or an antigen, is called oral tolerance. This is an on-
flammatory responses, including prostoglandin E2, NO, going normal physiological process that protects the ali-
and vascular endothelial growth factor [14]. These are mentary tract against untoward immunological damage
proinflammatory molecules that, in conjunction with [29,30]. Research into its mechanism of action has revealed
TNF-α, IL-6 and IL-1β, result in a localized, and transi- that several distinct types of T regulator cells mediate this
tory inflammatory-like response that is part of the nor- phenomenon by releasing IL-10 and TGF-β [30]. It has
mal repair process occurring in knee joints, serves to also been shown that this effect is transitory in nature
moderate remodeling events [3]. Ostrowski et al. [15] requiring that the food, or antigen, be consumed con-
showed that healthy individuals express up to 27-fold tinuously in order to maintain the tolerogenic state
greater concentrations of the anti-inflammatory cytokine [30]. Given these findings, plus our current understand-
IL-10 in blood following a marathon run when com- ing of the role of various cytokines in normal joint
pared to IL-10 blood levels at rest. This finding is not physiology, it was hypothesized that supplementation
surprising given that these same individuals also show with UC-II might relieve joint discomfort and restore
marked increases in the proinflammatory cytokines joint function in healthy subjects.
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The aim of this randomized, double blind, placebo- subject was excluded. Once the requisite pain level was
controlled study was to assess the impact of UC-II on achieved the subject was asked to continue stepping for
knee function in otherwise healthy subjects with no an additional two minutes in order to record the max-
prior history of arthritic disease who experienced knee imum pain level achieved before disembarking from the
pain upon strenuous physical exertion. The primary effi- stepmill. The following knee discomfort measures were
cacy variable for assessing knee function included mea- recorded from the start of the stepmill test: (1) time to
surements of flexibility using range of motion (ROM) onset of initial joint pain; (2) time to onset of maximum
goniometry. joint pain; (3) time to initial improvement in knee joint
pain; (4) time to complete recovery from knee joint pain.
Methods Subjects who experienced a pain score of 5 (or greater)
Investigational product within one minute of starting the stress test were ex-
The investigational study product UC-II is derived from cluded. Out of 106 screened candidates, 55 subjects were
chicken sternum. It is manufactured using a patented, low- enrolled in the study. Each subject voluntarily signed the
temperature process to preserve its native structure. For IRB-approved informed consent form. After enrollment,
the clinical study, 40 mg of UC-II material (Lot 1109006), the subjects were randomly assigned to either the pla-
which provides 10.4 ± 1.3 mg of native type-II collagen, was cebo or the UC-II group.
encapsulated in an opaque capsule with excipients. Placebo
was dispensed in an identical capsule containing only excip- Study design and trial site
ients (microcrystalline cellulose, magnesium stearate and This randomized, double blind, placebo-controlled study
silicon dioxide). Both study materials were prepared in a was conducted at the Staywell Research clinical site lo-
good manufacturing practice (GMP)-certified facility and cated in Northridge, CA. Medicus Research (Agoura
provided by InterHealth Nutraceuticals, Inc. (Benicia, CA). Hills, CA) was the contract research organization (CRO)
Subjects were instructed to take one capsule daily with of record. The study protocol was approved by Coperni-
water before bedtime. cus Group IRB (Cary, NC) on April 25th 2012. The
study followed the principles outlined in the Declaration
Recruitment of subjects of Helsinki (version 1996).
One hundred and six subjects were screened for eligibil-
ity using the inclusion–exclusion criteria defined in Randomization and blinding
Table 1. Only healthy adults who presented with no knee Simple randomization was employed using a software al-
joint pain at rest and no diagnosable markers indicative gorithm based on the atmospheric noise method (www.
of active arthritic disease, as outlined by the American random.org). Sequential assignment was used to deter-
College of Rheumatology (ACR) guidelines [31,32], mine group allocation. Once allocated, the assignment
were admitted into the study. To accomplish this, all was documented and placed in individually numbered
potential subjects were screened by a board certified envelopes to maintain blinding. Subjects, clinical staff,
clinician. Subjects presenting with any knee pain at plus data analysis and management staff remained
rest and at least 3 of 6 clinical classification criteria, blinded throughout the study.
which included age greater than 50 years, morning
stiffness in the joint lasting 30 minutes or less, crepi- Study schedule
tus on knee joint manipulation, body tenderness, bony The study duration was 17 weeks with a total of 7 visits
enlargements, knee swelling or presence of excess that included screening, baseline, days 7, 30, 60, 90 and
fluid, and palpable warmth, were excluded. Potential 120 (final visit). Table 2 summarizes the study visits and
subjects reporting the occasional use of NSAIDs, other activities. Figure 1 depicts the sequence of study proce-
pain relief medication, or anti-inflammatory supple- dures that subjects underwent during each visit. All sub-
ments underwent a 2-week washout period before jects completed a medical history questionnaire at
randomization. baseline and compliance reports during follow-up evalu-
Subjects were required to undergo a 10 minute period ations at 7, 30, 60, 90 and 120 days. Subjects were
of performance testing using a standardized stepmill test assessed for anthropometric measures, vital signs, knee
developed and validated by Medicus Research (Udani JK, range of motion (flexion and extension), six-minute
unpublished observation). It involved exercising at level timed walk, as well as the onset and recovery from pain
4 on a StepMill® model 7000PT (StairMaster® Health & using the Udani Stepmill Procedure. A Fitbit (San
Fitness Products, Inc., Kirkland, WA) until one or both Francisco, CA) device was used to measure daily dis-
knees achieved a discomfort level of 5 on an 11 point tance walked, steps taken and an average step length for
(0–10) Likert scale [33]. This pain threshold had to be study participants. Subjects were also asked to complete
achieved within a 10 minute period otherwise the the KOOS survey as well as the Stanford exercise scales.
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Table 1 Inclusion–exclusion criteria Table 1 Inclusion–exclusion criteria (Continued)

Inclusion • Untreated or unstable hypothyroidism, an active eating disorder, or
evidence of any neurological disorders
• Subject must be ≥30 and ≤65 years of age
• Recent history of (within 12 months) or strong potential for alcohol
• Body mass index (BMI) must be ≥18 and ≤35 kg/m2
or substance abuse
• Knee joint criteria: (1) no knee joint discomfort at rest; (2) must
• Females who are pregnant, lactating, or unwilling to use adequate
achieve a knee joint discomfort score of at least 5 on an 11-point
contraception during the study
Likert scale within 10 minutes of initiating the stepmill protocol
• Maintain existing food and physical activity patterns throughout the
study period Knee range of motion measurements
• Judged by Investigator to be in general good health on the basis of Knee extension was measured by goniometry. Briefly,
medical history subjects were instructed to sit in an upright position on
• Subject understands the study procedures and provides signed a table edge with their backs straight (knee position de-
informed consent to participate in the study and authorizes the fined as 90°). The axis of a goniometer was placed at the
release of relevant health information to the study investigator
intersection of the thigh and shank at the knee joint.
• Females of child bearing age must agree to use approved birth Subjects were asked to bring their knees to full exten-
control methods during the study
sion without changing the position of the pelvis and
Exclusion lumbar spine. The extended knee joint angle was mea-
• Subjects with any indicators of arthritis, joint disorders, or history of sured and recorded. For knee flexion measurement, sub-
immune system or autoimmune disorders
jects were asked to actively flex their knees while lying
• Daily use of NSAIDs; however, daily use of 81 mg of aspirin for in a prone position with their shins off the end of the
cardioprotection is allowed
table. The range of knee flexion motion was then mea-
• Daily use of anti-inflammatory or omega-3-fatty acid dietary sured and documented.
supplements or using supplements to maintain joint health 30 days
prior to screening
• Subjects with a history of knee or hip joint replacement surgery, or Timed joint discomfort measurements
any hip or back pain which interferes with ambulation Briefly, a stopwatch was started when subjects began
• Use of any immunosuppressive drugs in the last 12 months climbing the stepmill. Time to onset of pain was
(including steroids or biologics) recorded at the first sign of pain in the target knee. The
• Glucocorticoid injection or hyaluronic acid injection in affected knee baselines at each time point were normalized to account
within 3 months prior to enrollment
for dropouts. Percent change in time to complete recov-
• History of surgery or significant injury to the target joint within ery from pain was measured as follows: a new stopwatch
6 months prior to study enrollment, or an anticipated need for
surgical or invasive procedure that will be performed during the was started when the subjects disembarked from the
study stepmill and the time to complete recovery from pain
• Subjects with a chronic pain syndrome and in the judgment of the was recorded. The baselines at each time point were
Investigator is unlikely to respond to any therapy normalized to account for dropouts then compared
• Participation in a clinical study with exposure to any non-registered against the reference interval which was defined as the
drug product within 30 days prior percentage change between the study baseline and day 7.
• Subjects who have any physical disability which could interfere with
their ability to perform the functional performance measures
included in this protocol KOOS knee survey & Stanford exercise scales
• Any significant GI condition that would potentially interfere with the
The KOOS survey is a validated instrument consisting
evaluation of the study product of 42 questions that are classified into sub-scales such as
• Clinically significant renal, hepatic, endocrine (including diabetes symptoms, stiffness, pain, daily activities, recreational ac-
mellitus), cardiac, pulmonary, pancreatic, neurologic, hematologic, or tivities and quality of life [34]. It measures the subjects’
biliary disorder opinion about their knees and their ability to perform
• Subjects with vascular condition which interferes with ambulation daily activities during the past week. The Stanford exer-
• Known allergy or sensitivity to herbal products, soy or eggs cise behavior scale comprises 6 questions designed to as-
• Vegetarian or Vegan sess exercise behaviors during the previous week [35].
• History or presence of cancer in the prior two years, except for non-
melanoma skin cancer. Six minute timed walk
• Individual has a condition the Investigator believes would interfere Subjects were instructed to walk up and down a hallway
with his or her ability to provide informed consent, comply with the for 6 minutes as rapidly as possible without causing any
study protocol, which might confound the interpretation of the study
results or put the person at undue risk pain. A measuring wheel (RoadRunner Wheel, Keson In-
dustries, Aurora, IL) was used to measure distance trav-
elled in 6 minutes.
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Table 2 Protocol summary

Protocol activities V1 V2 V3 V4 V5 V6 V7
Day −7 Day 0 Day Day Day Day Day 120
7 30 60 90
Screen Baseline End
Informed consent x
Inclusion/Exclusion x
Medical history and physical exam x
Vital signs/anthropometric measures x x x x x x x
Urine pregnancy test x x
Administer and review scales/questionnaires/diaries x x x x x x x
Stressor (Udani Stepmill protocol) x x x x x x x
Functional measures (6-min timed walk) x x x x x x x
Goniometry (range of motion) x x x x x x
Review concomitant therapies x x x x x x x
Intercurrent medical issues review x x x x x x
Compliance assessment (including phone calls) x x x x x x
Randomization x
Study supplement preparation & dispensing x x x x x

Rescue medication prohibited substances were excluded from further par-

No rescue medications were allowed during the course ticipation in the study as per protocol.
of the study. At all study visits, subjects were given a list
of the 43 prohibited medications and supplements Statistics
(Table 3). Changes in overall medication history, or the Outcome variables were assessed for conformance to the
use of these substances, were then recorded by the study normal distribution and transformed as required. Within
coordinator. Subjects found to have used any of these group significance was analyzed by non-parametric Sign

Figure 1 Sequence of study procedures at a typical clinic visit.

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Table 3 Representative list of prohibited medications* by basis using SPSS, v19 (IBM, Armonk, NY). Results were
category presented as mean ± SEM.
Category Medications
Joint supplements (Omega-3, Alpha-Linolenic acid Results
Omega-6 plus others) Baseline demographics
Docosapentaenoic acid
A total of 55 individuals met the eligibility criteria and
Docosahexaenoic acid
were randomized to the placebo (n = 28) or to the UC-II
Eicosatrienoic acid
(n = 27) group. Baseline demographic characteristics for
Eicosatetraenoic acid subjects in both groups were similar with respect to age,
Eicosapentaenoic acid gender, height, weight and BMI (Table 4). A total of nine
Hexadecatrienoic acid subjects, three in UC-II group and six in placebo group,
Heneicosapentaenoic acid were lost to follow-up. The results presented herein en-
compass 46 total subjects, 22 subjects in the placebo
Stearidonic acid
group plus 24 subjects in the UC-II group. It should be
Tetracosapentaenoic acid
noted that the average age of the study participants was
Tetracosahexaenoic acid approximately 46 years which is about 16 years younger
Glucosamine (all forms) than the average age observed in many OA studies
Chondroitin (all forms) [36-38].
Other herbal ingredients
Knee extension and flexion
NSAIDs (OTC and prescription) Aspirin
Figure 2 summarizes the average knee extension changes
Diflunisal
over time for subjects supplemented with either UC-II
Diclofenac or placebo. The UC-II supplemented cohort presented
Celecoxib with a statistically significant greater increase in the abil-
Etodolac ity to extend the knee at day 120 as compared to the
Fenoprofen placebo group (81.0 ± 1.3º vs 74.0 ± 2.2º, p = 0.011) and
to baseline (81.0 ± 1.3º vs 73.2 ± 1.9º, p = 0.002). The UC-
Flurbiprofen
II group also demonstrated a significant increase in knee
Ibuprofen
extension at day 90 (78.8 ± 1.9º vs 73.2 ± 1.9º, p = 0.045)
Indomethacin compared to baseline only. An intent to treat (ITT) ana-
Ketoprofen lysis of these data also demonstrated a statistically sig-
Meclofenamate nificant net increase in knee extension at day 120 versus
Mefenamic acid placebo (80.0 ± 1.3º vs 73.7 ± 1.8º, p = 0.006). No statisti-
cally significant changes were observed in the placebo
Meloxicam
group at any time during this study. With respect to
Nabumetone
knee flexion, no significant changes were noted in either
Naproxen study group (p > 0.05). The power associated with the
Oxaprozin former per protocol statistical analyses was 80%.
Piroxicam
Rofecoxib Time to onset of initial joint pain
Supplementation with UC-II resulted in statistically sig-
Sulindac
nificant increases in the time to onset of initial joint pain
Tolmetin
at day 90 (2.75 ± 0.5 min, p = 0.041) and at day 120 (2.8
Valdecoxib ± 0.5 min, p = 0.019) versus a baseline of 1.4 min for
*Selected from a list of 43 prohibited medications and supplements. each visit. No statistically significant differences were
noted for either the placebo group or between groups
test or by non-parametric Wilcoxon Signed Rank test, (Figure 3).
while Wilcoxon Mann–Whitney test was used to analyze Five individuals in the UC-II group and one in the pla-
between groups significance. The Fisher Exact test was cebo group reported no onset of pain by the end of
used to evaluate the complete loss of pain between study study (see below and Table 5). Given this unexpected
cohorts whereas the binomial test was used to assess the finding, an additional analysis was undertaken which in-
likelihood of complete loss of pain at each visit. P-values cluded these individuals in the time to onset of initial
equal to or less than 0.05 were considered statistically pain analysis. The 10 minute limit of the stepmill pro-
significant. All analyses were done on a per protocol cedure was used as the lower limit to pain onset. Under
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Table 4 Demographic and baseline characteristics of Time to complete loss of knee joint pain
enrolled subjects During the course of this study it was noted that a num-
Characteristics UC-II Placebo ber of subjects in both the placebo and the
Total number of subjects 27 28 supplemented cohorts no longer reported any pain dur-
Number of males 11 12 ing the stepmill protocol. For the UC-II group, 5 sub-
jects (21%) no longer reported pain by day 120, whereas
Number of females 16 16
only 1 subject (5%) in placebo group reported complete
Age (years) 46.1 ± 1.5 46.6 ± 1.8
loss of pain (Table 5). This effect did not reach statistical
Weight (kg) 75.5 ± 2.9 77.5 ± 3.1 significance between groups but there was an evident
Height (cm) 167.1 ± 2.0 168.4 ± 2.0 trend in the data towards a greater number of subjects
BMI (kg/m2) 26.8 ± 0.8 27.1 ± 0.7 losing pain in the UC-II cohort (p = 0.126). A binomial
Values are expressed as Mean ± SEM. analysis for complete loss of pain at each visit demon-
strated a statistical significance for the UC-II group by
these conservative assumptions, supplementation with day 120 (p = 0.031). It is important to note that the
UC-II yielded statistically significant increases in time to complete loss of knee pain was not a random event. The
onset of pain at day 90 (3.65 ± 0.7 min, p = 0.011) and pattern among the subjects indicates that loss of knee
day 120 (4.31 ± 0.7 min, p = 0.002) versus a baseline of pain appeared to be a persistent phenomenon that
1.4 min for each visit. The between-group comparison at spanned multiple visits (Table 5). A detailed review of
day 120 approached the statistical level of significance the clinical report forms showed that none of these indi-
favoring the UC-II cohort (p = 0.051). viduals consumed pain relief medication prior to their
visits.

Time to onset of maximum joint pain Six-minute timed walk & Daily number of steps
A statistically significant difference between groups was No significant differences were observed between the
noted at day 60 (6.39 ± 0.5 min vs 4.78 ± 0.5 min; study groups for the six-minute time walk or the daily
p = 0.025) favoring the UC-II cohort. This significance number of steps taken (p > 0.05). The distance walked in
did not persist during the remainder of the study six-minutes by the UC-II (range = 505 to 522 meters)
suggesting that this was a random occurrence. and the placebo (range = 461 to 502 meters) groups were
within the reference range previously reported [39] for
healthy adults (399 to 778 meters, males; 310 to 664 me-
Time to initial improvement in knee joint pain ters, females). Similarly, the average step length calcu-
The time to offset of joint pain was recorded immedi- lated from Fitbit data for both study groups (0.69 to 0.71
ately upon the subject stepping off the stepmill. Both meters) also agreed with previously published results for
groups began to recover from pain with the same rate normal adults [40].
resulting in no significant differences between groups in
the time to initial offset of joint pain (p > 0.05).
KOOS knee survey & Stanford exercise scales
No significant differences were seen between the study
groups for either the KOOS survey or the Stanford exer-
Time to complete recovery from knee joint pain
cise scale (p > 0.05).
The time to complete recovery from joint pain showed
significant reductions at days 60, 90 and 120 compared
to baseline for both the UC-II group as well as the pla- Use of analgesics and NSAIDs
cebo group (Figure 4). Percent changes in times were Review of the clinical report forms showed that no sub-
calculated after normalizing the baselines against the ref- ject in either study cohort consumed any of the 43
erence range of baseline to day 7. The UC-II group prohibited medicines or supplements during the study.
exhibited average reductions of 31.9 ± 11.7% (p = 0.041),
51.1 ± 6.1% (p = 0.004) and 51.9 ± 6.0% (p = 0.011) at Safety assessments
days 60, 90 and 120, respectively. By contrast, the reduc- A total of eight adverse events, equally dispersed be-
tions for the same time points for the placebo cohort, tween both groups, were noted (Table 6). None of the
21.9 ± 10.2% (p = 0.017), 22.2 ± 15.5% (p = 0.007) and adverse events was considered to be associated with UC-
30.0 ± 11.8% (p = 0.012), were of lower magnitude but II supplementation. All events resolved spontaneously
nonetheless statistically significant versus baseline. None without the need for further intervention. No subject
of these between group differences achieved statistical withdrew from the study due to an adverse event. Fi-
significance. nally, no differences were observed in vital signs after
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Figure 2 Knee extension as measured by goniometry. Values are presented as Mean ± SEM. *p ≤ 0.05 indicates a statistically significant
difference versus baseline or placebo. Number of completers: n = 24 in UC-II group (n = 3 dropouts); n = 20 in placebo group (n = 6 dropouts;
n = 2 did not participate in ROM assessment).

seventeen weeks of supplementation, and no serious ad- joint changes due to daily physical activities that are not
verse events were reported in this study. attributable to a diagnosable disease. In the same way
that nominally elevated blood levels of lipids, glucose
Discussion plus high blood pressure and obesity can be predictive
In this study, the UC-II supplement, consisting of of future progression to diabetes and heart disease [41],
undenatured type II collagen, was investigated for its the development of joint pain upon strenuous exercise
ability to improve joint function in healthy subjects who may be indicative of possible future joint problems.
develop joint pain while undergoing strenuous exercise. At study conclusion, we found that subjects ingesting
The rationale behind this approach centered on the hy- the UC-II supplement experienced a significantly greater
pothesis that strenuous exercise might uncover transient forward ROM in their knees versus baseline and placebo

Figure 3 Impact of stepmill procedure on the onset of pain. Values are presented as Mean ± SEM. *p ≤ 0.05 indicates a statistically significant
difference from baseline. Number of completers: n = 19 in UC-II group (n = 3 dropouts; n = 5 did not have pain); n = 20 in placebo group
(n = 6 dropouts; n = 1 did not have pain; n = 1 did not use stepmill).
Lugo et al. Journal of the International Society of Sports Nutrition 2013, 10:48 Page 9 of 12
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Table 5 Subjects reporting complete loss of knee pain on stepmill test

UC-II Placebo
Visit No. of pain free Continuity of P value No. of pain free Continuity of P value
subjects (%) pain loss# (Binomial test) subjects (%) pain loss# (Binomial test)
Baseline 0.0 (0) 0 NA 0.0 (0) 0 NA
Day 7 0.0 (0) 0 NA 0.0 (0) 0 NA
Day 30 1.0 (4) 1N 0.5 0.0 (0) 0 NA
Day 60 3.0 (13) 1R, 2N 0.125 0.0 (0) 0 NA
Day 90 3.0 (13) 2R, 1N 0.125 1 (5) 1N 0.5
Day 120 5.0 (21) 3R, 2N 0.031† 1 (5) 1R 0.5
Values denote number of subjects while parenthesis provides the percent of total subjects who did not have any pain on stepmill. Continuity indicates the
number of subjects in whom the absence of pain was maintained across visits. †Significant at p ≤ 0.05 based on independent binomial testing of each visit using
the null hypothesis that the probability of a subject experiencing no joint pain is equal to zero. There was no statistical difference between groups. #R Repeat
subject (i.e. same subject who reported no pain in previous visit), N New subject who reports no pain for the first time.

as measured by knee extension goniometry. Knee exten- of OA there is an apparent preferential loss of knee exten-
sion is necessary for daily function and sport activities. sion over knee flexion, and this loss has been shown to cor-
Loss of knee extension has been shown to negatively im- relate with WOMAC pain scores [45,46]. In addition, MRI
pact the function of the lower extremity [42,43]. For ex- imaging of the early osteoarthritic knee has shown that ini-
ample, loss of knee extension can cause altered gait tial changes in knee structure appear to center on articular
patterns affecting ankles and the hip which could result cartilage erosions (fibrillations) about the patella and other
in difficulty with running and jumping [42,43]. Studies weight bearing regions of the knee [47]. Such changes
have further shown that a permanent loss of 3-5º of ex- might favor a loss in knee ROM that preferentially affects
tension can significantly impact patient satisfaction and extension over flexion. The pathophysiology of the early
the development of early arthritis [44]. osteoarthritic knee, we believe, provides insight regarding
By contrast, when knee flexion, another measure of knee the effect of daily physical activities on the healthy knee in-
function, was assessed via goniometry, no differences in sofar as it helps explain the discordance in clinical out-
clinical outcomes were observed between the two study co- comes between knee extension and flexion.
horts. From a structure-function perspective this outcome Both the time to onset of initial joint pain as well as
is not surprising. During the earliest characterized phases time to full recovery were measured in this study. For

Figure 4 Percent change in time to complete recovery from pain. Values are presented as Mean ± SEM. *p ≤ 0.05 indicates a statistically
significant difference from baseline. Number of completers: n = 18 in UC-II group (n = 3 dropouts; n = 5 did not have pain; n = 1 time to complete
recovery from pain was not achieved); n = 20 in placebo group (n = 6 dropouts; n = 1 did not have pain; n = 1 did not use stepmill).
Lugo et al. Journal of the International Society of Sports Nutrition 2013, 10:48 Page 10 of 12
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Table 6 Summary of analysis of adverse events (AEs) in reported that feeding microgram amounts of native type II
all subjects collagen (porcine) prevents monoiodoacetate-induced ar-
Study groups Adverse event Number ticular cartilage damage in this rat model of osteoarthritis,
of AEs as measured by pain thresholds and by circulating levels of
(Body system)
UC-II Upper respiratory infection (Pulmonary) 3 cross linked c-telopeptides derived from type II collagen.
Food poisoning (Gastrointestinal) 1
This finding corroborates the efficacy of undenatured type
II collagen in improving joint comfort in osteoarthritic con-
Total number of AEs 4
ditions [26].
Total number of subjects reporting AEs: n 4/27 In the present study, we show for the first time that
Placebo Bilateral ankle edema (Musculoskeletal) 1 UC-II can improve joint function in healthy subjects
Right ankle fracture (Musculoskeletal) 1 undergoing strenuous physical exercise. This observa-
Sinusitis (Ears/Nose/Throat) 1 tion, when considered in context with normal chondro-
Skin infection right ankle 1
cyte physiology, suggests that activated T regulator cells,
(Dermatological) specific for undenatured type II collagen, home to an
Total number of AEs 4 overstressed knee joint where their release of the anti-
inflammatory cytokines, IL-10 and TGF-β reverse the
Total number of subjects reporting AEs: n 2/28
catabolic changes caused by strenuous exertion
[13,21,57]. In addition, the IL-10 and TGF-β produced
each of these measures the clinical outcomes favored the by these T regulators may tilt the TH balance in the knee
UC-II supplemented cohort versus their baseline status. joint towards TH2 [30,58] responses which preferentially
The ability of UC-II to modulate knee extension may re- result in IL-4 production further fostering a shift in
late to its ability to moderate knee joint pain. Crowley chondrocyte metabolism towards ECM replenishment.
et al. [26] and Trentham et al. [25] demonstrated that Several additional tests were used in this study to as-
UC-II effectively enhances joint comfort and flexibility sess overall joint function, QoL, and physical activity.
thereby improving the quality of life (QoL) in both OA The additional parameters and tests measured included
and RA subjects, respectively. This effect may be attrib- a six minute timed walk plus the Stanford exercise scale
utable to the finding that microgram quantities of and KOOS survey. With respect to the KOOS survey,
undenatured type II collagen moderate CIA in both the both cohorts were statistically significant versus baseline
rat and the mouse via the induction of T regulator cells for symptoms, pain, daily function, recreational activities
[27,28,48]. The induction of these T regulators takes and QoL but were not significant from each other. This
place within gut associated lymphatic tissues (GALT), in- is not an unexpected finding given that this study was
cluding mesenteric lymph nodes, in response to the con- carried out with healthy subjects who do not present
sumption of undenatured type II collagen [27]. Studies with any joint issues at rest. It is only when the knee is
have shown that these regulatory cells produce IL-10 stressed via the stepmill do subjects report any joint dis-
and TGF-β [30,49]. A special class of CD103+ dendritic comfort. Under these conditions, and as indicated above,
cells, found almost exclusively in the GALT, facilitates the UC-II group appears to experience less joint discom-
this process [48,50]. Once activated, T regulator cells ap- fort and greater joint flexibility. No difference in clinical
pear to downregulate a wide range of immunologic and outcomes between groups was seen in the six minute
proinflammatory activities resulting in the moderation of timed walk, the daily distance walked, or the Stanford
the arthritic response initiated by undenatured type II exercise scale questionnaire. Once again we are not sur-
collagen [27]. The phenomenon of oral tolerance has prised by these results given that these tests and ques-
also been demonstrated in humans, and appears to in- tionnaires are designed and clinically validated to assess
volve a similar set of T regulators [30,51-53]. the severity of arthritic disease in unhealthy populations.
The above description of how UC-II might modulate No clinical biomarkers associated with arthritic dis-
joint function is most easily understood in the context of eases were assessed in this study. Healthy subjects would
RA given that the CIA animal model resembles this disease not be expected to present with significant alterations in
most closely [27,28,54]. However, the case for T regulators their inflammatory biomarker profile as they lack clinical
and immune cytokines having a moderating effect on disease [59]. In addition, it should be noted that the joint
healthy or OA knee joint function appears less apparent. discomfort measured in this study is acute pain induced
This view has changed in recent years due to a growing by a stressor rather than due to an ongoing inflamma-
body of evidence suggesting that both OA and normal tory event. Therefore, any elevation in inflammation
chondrocyte biology appears to be regulated by some of the markers that might occur in these healthy subjects may
same cytokines and chemokines that regulate inflammation simply be due to the physiological impact of strenuous
[5,6,55]. For example, Mannelli and coworkers [56] recently exercise.
Lugo et al. Journal of the International Society of Sports Nutrition 2013, 10:48 Page 11 of 12
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There are two study limitations to consider when interpretation that are a part of this manuscript. All the authors read and
reviewing these results. The first, time to onset of initial approved the final draft of the manuscript.

pain, was limited to a 10-minute interval. The current study

design did not address the possibility that subjects might Acknowledgements
Medicus Research thanks InterHealth Nutraceuticals, Inc., Benicia, California,
cease to experience pain on the stepmill. Future studies
for supporting this clinical trial and for providing the treatment and placebo
should allow for an extension of the exertion interval in products. We thank the entire Staywell clinical staff for their tireless efforts
order to gauge how much longer a subject can exercise be- and dedication to the health and welfare of the subjects. The study design
and the protocol preparation was the result of a collaborative effort between
fore reporting pain. In this way better defined parameters
InterHealth Nutraceuticals, Inc., Benicia, California and Medicus Research LLC,
can be placed upon the degree to which UC-II supplemen- Agoura Hills, CA, the Contract Research Organization (CRO) chosen to
tation results in the cessation of joint pain due to strenuous manage the clinical and other logistics of this study.
exercise in healthy subjects.
The second limitation that merits consideration is the Funding
possibility that study subjects may have early signs of arth- InterHealth Nutraceuticals, Inc., Benicia, California.
ritis that do not meet the ACR criteria. This possible limita- Author details
tion was addressed by performing an extensive medical 1
InterHealth Nutraceuticals, Benicia, CA 94510, USA. 2Medicus Research LLC,
examination for signs and symptoms of OA and by exclu- 28720 Roadside Drive, Suite 310, Agoura Hills, CA 91301, USA. 3UCLA Medical
Center, Santa Monica, CA 90401, USA. 4Northridge Hospital Integrative
ding volunteers who experienced pain levels of 5 or greater Medicine Program, Northridge, CA 91325, USA.
within one minute of using the stepmill.
UC-II is a unique ingredient that supports healthy joints. Received: 7 July 2013 Accepted: 10 October 2013
Published: 24 October 2013
Previous studies have focused on the efficacy of this ingre-
dient in OA subjects. By including healthy subjects in this
study, and using non-disease endpoints as a measure of effi- References
1. Shek PN, Shephard RJ: Physical exercise as a human model of limited
cacy, it is believed that the benefits that derive from UC-II inflammatory response. Can J Physiol Pharmacol 1998, 76:589–597.
usage now extends to include healthy individuals. Further, 2. Kiviranta I, Tammi M, Jurvelin J, et al: Articular cartilage thickness and
this ingredient appears to be safe for human consumption glycosaminoglycan distribution in the canine knee joint after strenuous
running exercise. Clin Orthop Relat Res 1992, 283:302–308.
based on an extensive series of in vivo and in vitro toxico- 3. Guilak F: Biomechanical factors in osteoarthritis. Best Pract Res Clin
logical studies as well as the absence of any adverse events Rheumatol 2011, 25:815–823.
in this and in previous human studies [24,26,60]. In conclu- 4. Kawamura S, Lotito K, Rodeo SA: Biomechanics and healing response of
the meniscus. Oper Tech Sports Med 2003, 11:68–76.
sion, daily supplementation with 40 mg of UC-II supports 5. Ramage L, Nuki G, Salter DM: Signalling cascades in
joint function and flexibility in healthy subjects as demon- mechanotransduction: cell-matrix interactions and mechanical loading.
strated by greater knee extension and has the potential both Scand J Med Sci Sports 2009, 19:457–469.
6. Honda K, Ohno S, Tanimoto K, et al: The effects of high magnitude cyclic
to alleviate the joint pain that occasionally arises from tensile load on cartilage matrix metabolism in cultured chondrocytes.
strenuous exercise as well as to lengthen periods of pain Eur J Cell Biol 2000, 79:601–609.
free exertion. 7. Agarwal S, Deschner J, Long P, et al: Role of NF-kappaB transcription
factors in antiinflammatory and proinflammatory actions of mechanical
signals. Arthritis Rheum 2004, 50:3541–3548.
Abbreviations
8. Berg V, Sveinbjornsson B, Bendiksen S, et al: Human articular chondrocytes
RA: Rheumatoid arthritis; OA: Osteoarthritis; ECM: Extracellular matrix; TNF-
express chemR23 and chemerin; chemR23 promotes inflammatory
α: Tumor necrosis factor-alpha; IL-1β: Interleukin-1 beta; IL-6: Interleukin-6;
signalling upon binding the ligand chemerin(21–157). Arthritis Res Ther
IL-4: Interleukin 4; IL-10: Interleukin-10; MMP: Matrix metalloproteinase;
2010, 12:R228.
NF-κB: Nuclear factor-kappa-light-chain-enhancer of activated B cells;
9. Millward-Sadler SJ, Wright MO, Lee H, et al: Integrin-regulated secretion of
MAPK: Mitogen activated protein kinase; ERK: Extracellular receptor kinase;
interleukin 4: a novel pathway of mechanotransduction in human
NO: Nitric oxide; TGF-β: Transforming growth factor-beta; CIA: Collagen
articular chondrocytes. J Cell Biol 1999, 145:183–189.
induced arthritis; KOOS: Knee injury and osteoarthritis outcome score;
10. Millward-Sadler SJ, Wright MO, Davies LW, et al: Mechanotransduction via
ROM: Range of motion; MRI: Magnetic resonance imaging; GALT: Gut
integrins and interleukin-4 results in altered aggrecan and matrix
associated lymphatic tissue; QoL: Quality of life; MIP-1β: Macrophage
metalloproteinase 3 gene expression in normal, but not osteoarthritic,
inflammatory protein-1 beta; IP-10: Interferon gamma-induced protein 10;
human articular chondrocytes. Arthritis Rheum 2000, 43:2091–2099.
TH: T helper cell; WOMAC: Western Ontario and McMaster universities
11. Doi H, Nishida K, Yorimitsu M, et al: Interleukin-4 downregulates the cyclic
osteoarthritis index; ACR: American College of Rheumatology.
tensile stress-induced matrix metalloproteinases-13 and cathepsin B
expression by rat normal chondrocytes. Acta Med Okayama 2008,
Competing interests 62:119–126.
Medicus Research received research grants from InterHealth Nutraceuticals, 12. Yorimitsu M, Nishida K, Shimizu A, et al: Intra-articular injection of
Inc., Benicia, California. Dr. Udani has provided consulting services to interleukin-4 decreases nitric oxide production by chondrocytes and
InterHealth Nutraceuticals, Inc. Drs. JPL, ZMS, and FCL are employees of ameliorates subsequent destruction of cartilage in instability-induced
InterHealth Nutraceuticals, Inc. Medicus Research does not endorse any osteoarthritis in rat knee joints. Osteoarthritis Cartilage 2008, 16:764–771.
brand or product nor does it have any financial interests with any 13. van Meegeren ME, Roosendaal G, Jansen NW, et al: IL-4 alone and in
supplement manufacturer or distributor. combination with IL-10 protects against blood-induced cartilage
damage. Osteoarthritis Cartilage 2012, 20:764–772.
Authors’ contributions 14. Pufe T, Lemke A, Kurz B, et al: Mechanical overload induces VEGF in
JKU was the principal investigator and together with JPL, JKU, ZMS, FCL JPM, cartilage discs via hypoxia-inducible factor. Am J Pathol 2004,
MNP and ANS contributed to the writing, data analyses and data 164:185–192.
 Lugo et al. Journal of the International Society of Sports Nutrition 2013, 10:48 Page 12 of 12
http://www.jissn.com/content/10/1/48

15. Ostrowski K, Rohde T, Asp S, et al: Pro- and anti-inflammatory cytokine 38. Petrella RJ, DiSilvestro MD, Hildebrand C: Effects of hyaluronate sodium on
balance in strenuous exercise in humans. J Physiol 1999, pain and physical functioning in osteoarthritis of the knee: a randomized,
515(Pt 1):287–291. double-blind, placebo-controlled clinical trial. Arch Intern Med 2002,
16. Allen JL, Cooke ME, Alliston T: ECM stiffness primes the TGFbeta pathway 162:292–298.
to promote chondrocyte differentiation. Mol Biol Cell 2012, 23:3731–3742. 39. Enright PL, Sherrill DL: Reference equations for the six-minute walk in
17. Bougault C, Aubert-Foucher E, Paumier A, et al: Dynamic compression of healthy adults. Am J Respir Crit Care Med 1998, 158:1384–1387.
chondrocyte-agarose constructs reveals new candidate 40. Perry J: Gait analysis: normal and pathological function. Thorofare: SLACK Inc.;
mechanosensitive genes. PLoS One 2012, 7:e36964. 1992.
18. Li TF, O’Keefe RJ, Chen D: TGF-beta signaling in chondrocytes. Front Biosci 41. Viera AJ: Predisease: when does it make sense? Epidemiol Rev 2011,
2005, 10:681–688. 33:122–134.
19. Donovan J, Slingerland J: Transforming growth factor-beta and breast 42. Norkin CC, Levangie PK: Joint structure & function: a comprehensive analysis.
cancer: cell cycle arrest by transforming growth factor-beta and its Philadelphia: F.A. Davis; 1992.
disruption in cancer. Breast Cancer Res 2000, 2:116–124. 43. Shah N: Increasing knee range of motion using a unique sustained
20. Rosier RN, O’Keefe RJ, Crabb ID, et al: Transforming growth factor beta: an method. N Am J Sports Phys Ther 2008, 3:110–113.
autocrine regulator of chondrocytes. Connect Tissue Res 1989, 20:295–301. 44. Shelbourne KD, Biggs A, Gray T: Deconditioned knee: the effectiveness of
21. Roman-Blas JA, Stokes DG, Jimenez SA: Modulation of TGF-beta signaling a rehabilitation program that restores normal knee motion to improve
by proinflammatory cytokines in articular chondrocytes. symptoms and function. N Am J Sports Phys Ther 2007, 2:81–89.
Osteoarthritis Cartilage 2007, 15:1367–1377. 45. Serrao PR, Gramani-Say K, Lessi GC, et al: Knee extensor torque of men
22. Loeser RF: Aging and osteoarthritis: the role of chondrocyte senescence with early degrees of osteoarthritis is associated with pain, stiffness and
and aging changes in the cartilage matrix. Osteoarthritis Cartilage 2009, function. Rev Bras Fisioter 2012, 16:289–294.
17:971–979. 46. Heiden TL, Lloyd DG, Ackland TR: Knee extension and flexion weakness in
23. van Beuningen HM, van der Kraan PM, Arntz OJ, et al: Protection from people with knee osteoarthritis: Is antagonist cocontraction a factor?
interleukin 1 induced destruction of articular cartilage by transforming J Orthop Sports Phys Ther 2009, 39:807–815.
growth factor beta: Studies in anatomically intact cartilage in vitro and 47. Karachalios T, Zibis A, Papanagiotou P, et al: MR imaging findings in early
in vivo. Ann Rheum Dis 1993, 52:185–191. osteoarthritis of the knee. Eur J Radiol 2004, 50(3):37–40.
24. Bagchi D, Misner B, Bagchi M, et al: Effects of orally administered 48. Park MJ, Park KS, Park HS, et al: A distinct tolerogenic subset of splenic
undenatured type II collagen against arthritic inflammatory diseases: IDO(+)CD11b(+) dendritic cells from orally tolerized mice is responsible
a mechanistic exploration. Int J Clin Pharmacol Res 2002, 22:101–110. for induction of systemic immune tolerance and suppression of
25. Trentham DE, Dynesius-Trentham RA, Orav EJ, et al: Effects of oral collagen-induced arthritis. Cell Immunol 2012, 278:45–54.
administration of type II collagen on rheumatoid arthritis. Science 1993, 49. Li MO, Flavell RA: TGF-beta: a master of all T cell trades. Cell 2008,
261:1727–1730. 134:392–404.
26. Crowley DC, Lau FC, Sharma P, et al: Safety and efficacy of undenatured 50. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al: A functionally
type II collagen in the treatment of osteoarthritis of the knee: a clinical specialized population of mucosal CD103+ DCs induces Foxp3+
trial. Int J Med Sci 2009, 6:312–321. regulatory T cells via a TGF-beta and retinoic acid-dependent
27. Tong T, Zhao W, Wu YQ, et al: Chicken type II collagen induced immune mechanism. J Exp Med 2007, 204:1757–1764.
balance of main subtype of helper T cells in mesenteric lymph node 51. Ilan Y, Zigmond E, Lalazar G, et al: Oral administration of OKT3
lymphocytes in rats with collagen-induced arthritis. Inflamm Res 2010, monoclonal antibody to human subjects induces a dose-dependent
59:369–377. immunologic effect in T cells and dendritic cells. J Clin Immunol 2010,
28. Nagler-Anderson C, Bober LA, Robinson ME, et al: Suppression of type II 30:167–177.
collagen-induced arthritis by intragastric administration of soluble type II 52. Caminiti L, Passalacqua G, Barberi S, et al: A new protocol for specific oral
collagen. Proc Natl Acad Sci USA 1986, 83:7443–7446. tolerance induction in children with IgE-mediated cow’s milk allergy.
Allergy Asthma Proc 2009, 30:443–448.
29. Brandtzaeg P: ‘ABC’ of mucosal immunology. Nestle Nutr Workshop Ser
53. Ben Ahmed M, Belhadj Hmida N, Moes N, et al: IL-15 renders conventional
Pediatr Program 2009, 64:23–38. discussion 38–43, 251–7.
lymphocytes resistant to suppressive functions of regulatory T cells
30. Weiner HL, da Cunha AP, Quintana F, et al: Oral tolerance. Immunol Rev
through activation of the phosphatidylinositol 3-kinase pathway.
2011, 241:241–259.
J Immunol 2009, 182:6763–6770.
31. Aletaha D, Neogi T, Silman AJ, et al: 2010 Rheumatoid arthritis
54. Courtenay JS, Dallman MJ, Dayan AD, et al: Immunisation against
classification criteria: an american college of rheumatology/european
heterologous type II collagen induces arthritis in mice. Nature 1980,
league against rheumatism collaborative initiative. Arthritis Rheum 2010,
283:666–668.
62:2569–2581.
55. Pelletier JP, Martel-Pelletier J, Abramson SB: Osteoarthritis, an inflammatory
32. Altman R, Asch E, Bloch D, et al: Development of criteria for the classification
disease: potential implication for the selection of new therapeutic
and reporting of osteoarthritis. Classification of osteoarthritis of the knee.
targets. Arthritis Rheum 2001, 44:1237–1247.
Diagnostic and therapeutic criteria committee of the american rheumatism
56. Di Cesare Mannelli L, Micheli L, Zanardelli M, et al: Low dose native type II
association. Arthritis Rheum 1986, 29:1039–1049.
collagen prevents pain in a rat osteoarthritis model. BMC Musculoskelet
33. Likert R: A technique for the measurement of attitudes. Arch Psychol 1932,
Disord 2013, 14:228.
22:1–55.
57. Muller RD, John T, Kohl B, et al: IL-10 overexpression differentially affects
34. Roos EM, Roos HP, Ekdahl C, et al: Knee injury and osteoarthritis outcome score
cartilage matrix gene expression in response to TNF-alpha in human
(KOOS)–validation of a swedish version. Scand J Med Sci Sports 1998,
articular chondrocytes in vitro. Cytokine 2008, 44:377–385.
8:439–448.
58. Zouali M: Immunological tolerance: mechanisms. eLS: John Wiley & Sons, Ltd;
35. Lorig K, Stewart A, Ritter P, et al: Outcome measures for health education and 2001.
other health care interventions. Outcome measures for health education and 59. Chu CR, Williams AA, Coyle CH, et al: Early diagnosis to enable early
other health care interventions. Thousand Oaks, CA: SAGE Publications, Inc.; treatment of pre-osteoarthritis. Arthritis Res Ther 2012, 14:212.
1996. 60. Marone PA, Lau FC, Gupta RC, et al: Safety and toxicological evaluation of
36. Hawkey C, Laine L, Simon T, et al: Comparison of the effect of rofecoxib (a undenatured type II collagen. Toxicol Mech Methods 2010, 20:175–189.
cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the
gastroduodenal mucosa of patients with osteoarthritis: a randomized,
doi:10.1186/1550-2783-10-48
double-blind, placebo-controlled trial. The rofecoxib osteoarthritis
Cite this article as: Lugo et al.: Undenatured type II collagen (UC-II®) for
endoscopy multinational study group. Arthritis Rheum 2000, 43:370–377. joint support: a randomized, double-blind, placebo-controlled study in
37. Pincus T, Koch GG, Sokka T, et al: A randomized, double-blind, crossover healthy volunteers. Journal of the International Society of Sports Nutrition
clinical trial of diclofenac plus misoprostol versus acetaminophen in 2013 10:48.
patients with osteoarthritis of the hip or knee. Arthritis Rheum 2001,
44:1587–1598.

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