Journal of Orthopedic Research and Therapy
Devasia S, et al. J Orthop Res Ther 6: 1205.
www.doi.org/10.29011/2575-8241.001205
www.gavinpublishers.com

Research Article

Bioactive Collagen Peptides Ameliorate
Monoiodoacetic acid Induced
Osteoarthritis in Rats

Sheena Devasia1, Jinu T Joseph1, Stephena PS1, Seiko Koizumi2, Ai
Himeno2, Veeraraghavan Gayathri3, Shajil Madhavan1*
Nitta Gelatin India Limited, KINFRA Industrial Parks Ltd, Kakkanad, Cochin, India

1

Nitta Gelatin Inc., 2-22, Futamata, Yao-City, Osaka, Japan

2

Center for Toxicology and Developmental Research, Sri Ramachandra Institute of Higher Education and Research, Chennai, India

3

Corresponding author: Shajil Madhavan, Nitta Gelatin India Limited, KINFRA Industrial Parks Ltd, Kakkanad, Cochin-682042,
India

*

Citation: Devasia S, Joseph JT, Stephena PS, Koizumi S, Himeno A, et al. (2021) Bioactive Collagen Peptides Ameliorate
Monoidoacetic acid Induced Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205
Received Date: 16 November, 2021; Accepted Date: 13 December, 2021; Published Date: 22 December, 2021

Abstract
This study was conducted to evaluate the efficacy of different doses of Bioactive Collagen Peptide (BACP) in Monoiodo
Acetic Acid (MIA) induced Osteoarthritis (OA) rats in comparison with conventional Collagen Peptide (CP). Animals were
supplemented with daily doses of CP (1033 mg/kg) and BACPs with a dosage of 1033mg/kg, 517mg/kg, 258 mg/kg, 103mg/kg
which are equivalent to human dosage of 10g, 5g, 2.5g and 1g respectively. Etoricoxib (10mg/kg) was used as reference drug.
Different efficacy parameters such as Rotarod fall latency, heat hyperalgesia, cold hypersensitivity, knee thickness and IL -6
levels were measured at different time intervals. All doses of BACP and CP showed significant improvement (p<0.05) in Rotarod
fall latency, heat hyperalgesia, cold hypersensitivity and knee thickness when compared to vehicle control on days 14, 21 and28. CP 1033mg/kg, BACP 1033 mg/kg and 517 mg/kg supplementation showed significant improvement (p<0.05) in all above
mentioned parameters on day 28 when compared to day 7. All test groups except BACP 103 mg/kg group showed significant
decrease in IL-6 levels when compared to the vehicle control on the day 28. Based on the study results under tested condition,
BACP at 517 mg/kg showed potent anti-osteoarthritis effect similar to that of conventional Collagen Peptide (CP) at a dosage of1033 mg/kg against MIA induced osteoarthritis in rats. It can be concluded that 517 mg/kg dose of bioactive collagen peptide isequivalent to 1033 mg/kg of CP supplementation in the management of osteoarthritis in the tested conditions.

Introduction
Osteoarthritis (OA) is one of the most prevalent diseases
in the world, with estimates projecting that >300 million people
are affected globally [1]. The characteristic features of thischronic, progressive and degenerative disorder of the entire
joint include, variable inflammation and changes in the structureof bone bordering the joint and in the protective cushion called
articular cartilage. Clinical manifestations include joint pain,
tenderness, limitation of movement, effusion and varying degrees
of inflammation, and finally induce disability in many patients[2]. Recent pathological understandings elaborate that OA is
not restricted to the articular cartilage but involves entire joint
including the subchondral bone and synovium and thus it isdefined as a collection of overlapping distinctive joint disorders
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J Orthop Ther, an open access journal
ISSN: 2575-8241

which result in similar biological, morphological and clinicaloutcomes [3]. The quality of life is impaired due to persistent
pain and difficulties in routine activities like stair climbing,squatting, etc [4]. Therefore, effective management of OA is
necessary to improve the quality of life. OA is treated mainly
by exercise along with the use of analgesics like Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs). These medications thoughrelieve the symptoms, do not play disease modifying role and areassociated with increased risk of adverse effects over long termuse. Studies show that supplementation with collagen hydrolysates
may induce the synthesis of cartilage matrix, by stimulating thechondrocytes [5], after intestinal absorption and accumulation inarticular cartilage through blood circulation. In fact, experimental
studies have demonstrated that peptides from orally administrated
collagen hydrolysates accumulated in cartilage tissue a few hours
Volume 6; Issue 05

Citation: Devasia S, Joseph JT, Stephena PS, Koizumi S, Himeno A, et al. (2021) Bioactive Collagen Peptides Ameliorate Monoidoacetic acid Induced
Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205

after administration [6-8]. Investigating the efficacy of exogenous
administration of collagen derivatives in treating OA in animalmodels, recent preclinical studies have reported promising results[9,10] suggesting some potential for cartilage repair in OA patients.
In our previous study we have demonstrated Collagen
Peptide (conventional) as an effective supplement for the
improvement in overall physical problems associated with OA andthereby help to improve the quality of life. It is hypothesized thatthe supplementation of collagen peptide regulates chondrocyte
differentiation and stimulates synthesis of proteoglycans,resulting in the initiation of repair processes in cartilage tissue [2].
Etoricoxib, the reference drug used in the study is a Non-Steroidal
Anti-Inflammatory Drug (NSAIDs) that has anti-inflammatory
effect. The drug acts by inhibiting the Cyclo-Oxygenase-2 (COX2) enzyme. Pain and inflammation are caused by prostaglandins,
which are released at sites of injury or damage. Since COX-2
enzymes are inhibited, fewer prostaglandins are released, reducing
pain and inflammation. New Bio Active Collagen Peptide(BACP) is developed by Nitta Gelatin India Ltd, with enhanced
level of active dipeptides like Proline- Hydroxyproline (PO) andHydroxyproline- Glycine (OG). The product has been tested
by LC/MS for the active dipeptide content in comparison with
Conventional CP. Being the key regulatory factor in functionality,
the 200 fold increase in the active molecule content in newly
developed BACP shall exhibit high functional property in joint
health compared to existing conventional collagen peptides. The
average molecular weight of the new bioactive collagen peptides
is ≤1000 Da. The objective of this study was to evaluate thepotential anti-osteoarthritis effects of bioactive collagen peptides,
in comparison with conventional collagen peptide against MIA(Monoiodoacetic acid) induced osteoarthritis in Wistar rats
following consecutive oral dose for 21 days. In the present paper,
we discuss the evidence on the efficacy on bioactive low dosage
collagen peptides in management of OA.
Materials and Methods
BACP and Conventional Collagen peptides are products of
Nitta Gelatin India Ltd. Etoricoxib tablet, manufactured by Sun
Pharma Laboratories Ltd was procured as Reference drug for the
study. Male Wistar Rats were sourced from CPCSEA approved
vendor. Animal experiments were conducted with due clearance
from the Institutional Animal Ethics committee at Centre for
Toxicology and Developmental Research (CEFTE), GLP certified
Facility. Approval was obtained from the institutional review
board and animal care complied with the guidelines of theinstitution on the care and use of laboratory animals. Sixty fourmale Wistar rats of 6-8 weeks age were selected for the study.
Animals were acclimatized in the experimental room for a periodof 5 days. Young healthy rats were selected and grouped based on
the stratified body weight method. After acclimatization, animals
were randomized based on stratified body weight and assigned
to eight groups (each group comprises of 8 animals) viz., ShamControl (GI), vehicle control (GII), Reference Drug (Etoricoxib
10mg/kg) (GIII), Conventional Collagen Peptide (GIV - 1033 mg/kg), Test item BACP (GV -1033mg/kg), Test item BACP (GVI2J Orthop Ther, an open access journal
ISSN: 2575-8241

517mg/kg), Test item BACP (GVII -258 mg/kg), Test item BACP(GVIII-103mg/kg). The weight variation of animals was minimaland did not exceed ±20% of the mean body weight. Temperature,humidity and air exchange was maintained in the range of 1923°C, 30- 70% and 12-15 air changes per hour respectively. The
animals were provided with photo period of 12 h artificial light and
12 h dark. They were provided with standard rodent pelleted feed.
On day 0, rats were anaesthetized with ketamine hydrochloride (50 mg/kg body weight) and xylazine (10 mg/kg body weight)
and the right knee was shaved and disinfected with 70% ethanol
followed by povidone iodine. A single dose of 50μl sterile normal saline containing 3 mg monosodium iodoacetate was injected
into right knee joint through infrapatellar ligament using a 300μl
syringe fitted with a 29 G needle in two phases. Induction of Osteoarthritis in animals of all groups was confirmed by comparing
the parameters of behavioral assessment of nociception, heat hyperalgesia and cold hypersensitivity before injection of MIA (0Day) and on 7th day of injection. The test item was formulatedusing sterile water. On day 8 of post MIA induction, respective test
items were orally treated to respective test groups till 28th day. The
vehicle control animals received the same dose volume of vehicle(10 ml/kg/day weight) of sterile water during the treatment period.
The dose volume of individual animal was calculated and adjusted
based on their respective week body weight recorded during thetreatment period. The parameters in the study were Rotarod falllatency monitoring, heat hyperalgesia, cold hypersensitivity, knee
thickness, IL6 estimation and histopathology.
Rotarod Fall Latency Monitoring: Each animal was trained for
4 minutes (240 sec) at a constant speed of 40 rpm on the Rotarod.
Every day, each animal was received a number of trials, separated
by 30 minutes, at speeds accelerating from 4 to 40 rpm (with a
4 rpm increase every 30 seconds). Each animal was tested for anumber of consecutive days. The latency to falling off the Rotarod
was recorded on days 0 (before drug and MIA injection), 7, 14, 21
and 28 day during the period of the treatment.
Heat Hyperalgesia: Sensitivity to heat was determined bymeasuring paw flick latency to heat source. Plantar side of paw ofanimal was placed above the hot plate at 50°C and paw withdrawal
latency were noted in seconds. A maximum cut-off time of 20 sec
was used to minimize paw damage. Measurements were taken 2-3
times with at least 5 min gaps between the tests. Sensitivity toheat was assessed for each group before and after the induction ofarthritis on days 0 (before drug and MIA injection), 7, 14, 21 and28 day during the period of the treatment.
Cold Hypersensitivity: Paw withdrawal latency was recorded
in seconds by submerging ipsilateral paw in cold water (4±1°C).
Measurements were taken 2-3 times with at least 5 min gaps
between the tests. Paw withdrawal latency was assessed for eachgroup before and after the induction of arthritis on days 0 (before
drug and MIA injection), 7, 14, 21 and 28 day during the period of
the treatment.
Volume 6; Issue 05

Citation: Devasia S, Joseph JT, Stephena PS, Koizumi S, Himeno A, et al. (2021) Bioactive Collagen Peptides Ameliorate Monoidoacetic acid Induced
Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205

Knee Thickness: Knee thickness was assessed with Verniercaliper of each group before and after the induction of arthritis
on days 0 (before drug and MIA injection), 7, 14, 21 and 28 day
during the period of the treatment.
IL6 Estimation: Blood was collected from retro-orbital plexus
under anesthetic condition on day 28 of post MIA induction. The
collected blood was centrifuged and the serum was separated andstored in a freezer at −80°C and subjected to IL-6 estimation. The
Rat IL-6 (Interleukin 6) ELISA Kit (E-EL-R0015) of Elabscience
was used for analysis. This ELISA kit works on Sandwich-ELISA
principle.
Histopathology: Necropsy: On 28th day of post MIA induction,
animals of all groups were sacrificed by CO2 inhalation andsubjected to gross pathological examination. Right knee joints
were collected in 10% neutral buffered formalin solution from all
the rats after CO2 euthanasia. The collected joints were decalcified
using 10% formic acid and routinely processed. The sections were
stained with hematoxylin and eosin stains and evaluated into 5
severity grades: minimal, mild, moderate, marked and severe.
Statistical Analysis
Statistical Analysis was performed using One Way Analysis
of Variance, Tukey Multiple comparison, post hoc test with Sigma
Plot 12.3 software. P value <0.05 is considered as significant.

Results and Discussion
Mortality was not observed in animals of different groups
during the study. All the animals treated at the intended dose levels
were observed to be normal throughout the experimental period.
There was no significant change observed in the body weight
between the groups on day 0, 7, 14, 21 and 28 day between thegroups during inter group analysis. However, significant increasein body weight was noted from day 0 day 28 in all groups.
Behavioral Assessment of Nociception
Rotarod Fall Latency
Significant (p<0.05) improvement in the latency of fall
was observed in all test groups and reference drug group whencompared to Vehicle Control on days 14, 21 and 28 (Figure 1).
When latency of fall on day 7 was compared with the same ondays 14, 21 and 28; however, Etoricoxib group showed significant(p<0.05) improvement in all the days 14, 21 and 28. Conventional
collagen peptide and BACP 1033 mg/kg groups showed asignificant (p<0.05) improvement on day 28 when compared
to day 7. BACP 517 mg/kg group showed significant (p<0.05)
improvement on day 21 and 28. BACP 258 mg/kg and 103 mg/kg
groups showed no significant (p>0.05) improvement in latency offall on days 14, 21 and 28 when compared to day 7.

Figure:1 Rotarod Fall Latency

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J Orthop Ther, an open access journal
ISSN: 2575-8241

Volume 6; Issue 05

Citation: Devasia S, Joseph JT, Stephena PS, Koizumi S, Himeno A, et al. (2021) Bioactive Collagen Peptides Ameliorate Monoidoacetic acid Induced
Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205

Heat Hyperalgesia
Significant (p<0.05) improvement in the paw withdrawal latency was observed in all test and reference drug groups when compared
to Vehicle Control on days 14, 21 and 28 (Figure 2). When paw withdrawal latency on day 7 was compared with the same on days 14, 21
and 28, Etoricoxib, conventional collagen peptide, BACP 1033 mg/kg and 513 mg/kg groups showed significant (p<0.05) improvement
on days 14, 21 and 28. BACP 258 mg/kg group showed a significant (p<0.05) improvement on day 21 when compared to day 7. BACP
103 mg/kg group has not shown any significant (p>0.05) improvement in latency of fall on days 14, 21 and 28 when compared to day 7.

Figure:2 Paw Withdrawal Latency-Heat Hyperalgesia
Cold Hypersensitivity
Significant (p<0.05) improvement in the paw withdrawal latency was observed in all test groups and reference drug group whencompared to vehicle control on days 14, 21 and 28 (Figure 3). When paw withdrawal latency on day 7 was compared with the same ondays 14, 21 and 28; Etoricoxib group showed significant (p<0.05) improvement on days 14, 21 and 28. Conventional collagen peptide
showed significant (p<0.05) improvement on day 28 when compared to day 7. BACP 1033 mg/kg group showed significant (p<0.05)
improvement on days 21 and 28 when compared to day 7. BACP 517 mg/kg and 258 mg/kg showed significant (p<0.05) improvement
on days 14, 21 and 28 when compared to day 7. BACP 103 mg/kg group showed no significant improvement (p>0.05) in latency of fallon days 14, 21 and 28.

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J Orthop Ther, an open access journal
ISSN: 2575-8241

Volume 6; Issue 05

Citation: Devasia S, Joseph JT, Stephena PS, Koizumi S, Himeno A, et al. (2021) Bioactive Collagen Peptides Ameliorate Monoidoacetic acid Induced
Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205

Figure: 3 Paw Withdrawal Latency-Cold Hypersensitivity
Knee Thickness
Significant (p<0.05) decrease in the knee thickness was observed in all test groups and reference drug group when compared to
Vehicle Control on days 14, 21 and 28 (Figure 4).

Figure: 4 Knee Thickness
When knee thickness on day 7 was compared with the same on days 14, 21 and 28, Etoricoxib and conventional collagen peptidegroups showed significant (p<0.05) improvement on days 14, 21 and 28. BACP 1033 mg/kg and 517 mg/kg groups showed significant(p<0.05) improvement on day 28 when compared to day 7. BACP 258 mg/kg and 103 mg/kg groups showed no significant (p>0.05)
improvement in knee thickness on days 14, 21 and 28.
Rotarod fall latency, heat hyperalgesia, cold hypersensitivity and knee thickness data of days 14, 21, 28 were compared with thatof day 7 because arthritis induction in all groups was significantly evidenced on day 7 post MIA induction. After arthritis confirmation(day 7), supplementataion was initiated and continued till day 28. Hence comparison of data with day 7 provides the protective effect of
supplements against arthritis progression
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J Orthop Ther, an open access journal
ISSN: 2575-8241

Volume 6; Issue 05

Citation: Devasia S, Joseph JT, Stephena PS, Koizumi S, Himeno A, et al. (2021) Bioactive Collagen Peptides Ameliorate Monoidoacetic acid Induced
Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205

IL6
Significant (p<0.05) decrease in interleukin (IL6) level was observed in Etoricoxib, Conventional collagen peptide, BACP 1033
mg/kg, 517 mg/kg and 258 mg/kg groups on day 28 when compared to Vehicle Control (Figure 5). BACP 103 mg/kg group did not show
any significant change in IL-6 levels on day 28 when compared with the vehicle control.

Figure: 5 Serum IL6 levels on Day 28
Histopathology Results
Histopathological evaluation was made for synovial hyperplasia, inflammatory cell infiltration, cartilage degeneration, cartilage
necrosis, subchondralosteolysis/ trabaculae fragmentation. Scoring was done as per Janusz, et al. [11] using hematoxylin and eosin(H & E) stain. As scoring severity was not same in all the animals in all groups, statistical analysis between the group was not
performed and the results are semi quantitative. Severity differences are also evidenced in vehicle control group. Cartilage necrosis andsubchondralosteolysis/ trabeculae fragmentation occurrences (number of joints) at the end of treatment are given below in the Table 1.
Sham
Control

MIA +VehicleMIA +Etoricoxib(10mg/kg)

MIA
+ CP
1033
mg/ kg

MIA +BACP1033 mg/kg

MIA +BACP 517
mg/kg

MIA +
BACP 258
mg/kg

MIA +
BACP 103
mg/kg

Synovial
hyperplasia

0

4

5

8

3

6

7

7

Inflammatory
cell infiltration

2

1

1

4

2

6

7

7

0

0

4

2

1

2

1

0

0

8

4

6

6

6

7

8

0

5

3

3

3

4

6

6

Cartilage
degeneration
Cartilage
Necrosis
Sub chondral
osteolysis/
trabeculae
fragmentation

Table 1: Summary of Histopathology Study.
CP, BACP 1033 mg/kg and BACP 517 mg/kg treated groups had cartilage necrosis occurrences in 6 joints out of 8 joints examined.
Vehicle control showed all 8 joints showing cartilage necrosis. CP and BACP 1033 mg/kg had sub chondral osteolysis/ trabeculae
fragmentation occurrences in 3 joints, BACP 517 mg/kg showed 4; BACP 258 mg/kg and BACP 103 mg/kg showed sub chondral
osteolysis/ trabeculae fragmentation occurrences in 6 joints. The representative micrographs of each group are shown below (Figure 6).
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J Orthop Ther, an open access journal
ISSN: 2575-8241

Volume 6; Issue 05

Citation: Devasia S, Joseph JT, Stephena PS, Koizumi S, Himeno A, et al. (2021) Bioactive Collagen Peptides Ameliorate Monoidoacetic acid Induced
Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205

Figure:6 Histopathology Images of Knee Joint of Treated andSham Control Animals
a. Sham Control: Knee joint showing normal articular cartilage(black star) and synovial membrane (black arrow). H&E, 100x
magnification .b. Vehicle control: Knee joint showing marked
cartilage necrosis (black stars) and minimal subchondral osteolysis(white arrow), H&E, 100x magnification .c. Etoricoxib (10mg/kg)- Knee joint showing minimal cartilage degeneration (blackstars), H&E, 100x magnification. d. Conventional CP (1033mg/kg) - Knee joint showing mild cartilage degeneration (blackstars), H&E, 100x magnification e. LDOA 1033mg/kg- Knee
joint showing mild cartilage necrosis (black stars), H&E, 100x
magnification. f. LDOA 517mg/kg- Knee joint showing minimal
cartilage degeneration (black stars), H&E, 100x magnification.
g. LDOA 258mg/kg- Knee joint showing minimal cartilage
degeneration (black stars), H&E, 100x magnification. h. LDOA
103mg/kg- Knee joint showing moderate cartilage necrosis (blackstars) and presence of minimal subchondral osteolysis (whitearrows), H&E, 100x magnification

Discussion
The mechanism of action of collagen peptide has been
extensively studied [12-16]. Experimental investigations havedemonstrated that the degradation products of the collagen are
principally able to influence cell metabolism [17].BACP is a
mixture of Type I collagen peptides of low molecular weightsthat are generated via enzymatic digestion of Type I collagen
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J Orthop Ther, an open access journal
ISSN: 2575-8241

extracted from animal bones. The peptide mixture, contains
an abundance of proline- hydroxyproline and hydroxyprolineglycine dipeptides, which is absorbed to body following the oraldelivery. Thus the potential role of collagen peptide in repair ofdamaged cartilage could be associated with the accumulation oforally administered collagen peptides. Cell culture experiments
investigating the efficacy of collagen peptide on the biosynthesisof articular chondrocytes revealed that the treatment of cartilage
cells with collagen peptide induced a statistically significant dose
dependent increase in type II collagen synthesis of chondrocytes
compared to the untreated controls [17]. The major componentof collagen peptide that remained in the blood was identified as
Pro-Hyp dipeptides [12]. Nakatani et al. concluded that Pro-Hyp,
a dipeptide in Porcine Collagen Peptide (PCP), is an importantfactor that regulates chondrocyte differentiation and plays a
key role in the maintenance of mature chondrocytes in cartilage[18]. They hypothesised that Pro-Hyp in collagen peptide and its
regulatory mechanism seem to explain the therapeutic effect ofcollagen peptide in improving joint conditions. The real working
mechanism of collagen derivatives in OA may be by the stimulationof collagen biosynthesis by chondrocytes [17], the use of collagenspecific peptides as building block for articular cartilage [6], orthe inhibition of apoptosis and hypertrophy of chondrocytes[10]. Being one of the most important symptoms, pain reduction
indirectly indicates the mark of improvement in joint conditions inpatients with OA. Thus the administration of collagen peptide hasmuch relevance with regard to reduction of pain in a patient with
OA. The accumulated collagen peptide helps to maintain structureand function of cartilage, which in turn results in joint comfort andsubsequent improvements in pain. The results clearly indicate thatthe new bioactive collagen peptides slow down or even halt the
progression of OA.

Conclusion
Based on the above results, BACP at 517mg/kg and 1033
mg /kg showed potent anti-osteoarthritis effects along with
Etoricoxib and conventional collagen peptide against MIA
induced osteoarthritis in following consecutive oral dose for 21
days. Hence BACP 517 mg/kg can be considered as a low dosage
supplementation for the management of osteoarthritis in thetested conditions. Clarifying the mechanism of action of collagen
derivatives in OA and conducting randomized placebo-controlled
trials will help in bringing robust evidence on the usefulness of thislow dosage bioactive collagen derivative as a relevant prevention
option for the management of osteoarthritis.

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Osteoarthritis in Rats. J Orthop Res Ther 6: 1205. DOI: 10.29011/2575-8241.001205
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