International Journal of Rheumatic Diseases 2018; 21: 114–117

ORIGINAL ARTICLE

Does long term colchicine prevent degradation of collagen

fiber network in osteoarthritis?
Ragini SRIVASTAVA,1 Siddharth K. DAS,1 Gautam GOEL,1 Akash ASTHANA2 and
Girdhar G. AGARWAL2
1
Department of Rheumatology, K.G. Medical University, and 2Department of Statistics, Lucknow University, Lucknow, India

Abstract
Aim: Several studies have shown that colchicine exhibits an improvement in the symptoms of knee osteoarthri-
tis (OA) but its effect on disease progression is unknown. To clarify the mechanism of action this study was
done to see if colchicine prevents degradation of collagen fiber network in OA by studying serum cartilage oligo-
meric matrix protein (COMP) levels, a marker of cartilage turnover, over a period of 1 year.
Methods: Seventy-five patients received colchicine plus paracetamol and 75 received placebo alone for the
same time period. Serum COMP assays were done at baseline, 2 months and 1 year by enzyme-linked
immunosorbent assay. These markers were compared between visits using repeated measures analysis of
variance.
Results: Serum COMP levels in the paracetamol-alone group did not show significant change between baseline
and 2 months; however, there was a significant increase in serum COMP levels from 2 months to 1 year, sug-
gesting increased uncoupling of proteoglycans from collagen and disease progression. No such change was seen
in the colchicine group, signifying lack of progression of disease in this group.
Conclusion: Colchicine may act as a disease-modifying agent in OA.
Key words: Colchicine, collagen, COMP, osteoarthritis.

INTRODUCTION drug known to prevent crystal-induced inflammation, is

Osteoarthritis (OA) is the commonest arthritis, charac-
terized by progressive degradation of articular cartilage,
formation of new bone and acute flares of inflamma-
tion. So far, the mainstay of treatment has been symp-
tomatic, being directed at management of chronic
symptoms and possible prevention of acute attacks of
inflammation. OA is associated with calcium-contain-
ing crystals (Calcium pyrophosphate and Basic Calcium
phosphate) in the majority of patients. Colchicine, a
Correspondence: Professor Siddharth K. Das, Department of
Rheumatology, King George Medical University, Lucknow,
226018, UP, India. Email: rheumatologykgmu@gmail.com
also known to improve symptoms of OA.1–3
In OA there is an increase in cartilage turnover,4 with
increased release of soluble molecular fragments for
degradation of joint components into synovial fluid
and serum. Serum cartilage oligomeric matrix protein
(COMP) or thrombospondin 5 is a non-collagenous
protein present in the extracellular matrix of cartilage
and is predominantly produced in joints. It is released
prior to breakdown of the collagen network; it is
responsible for collagen fibrilogenesis and stabilizes the
collagen network.5,6 An increased concentration of
COMP reflects an on-going disease process and is a
more sensitive and earlier measuring tool than
radiological changes.7 Here we report that long-term
colchicine use prevents a rise in serum COMP,

© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd

suggestive of stabilization of collagen II and proteogly-
can attachment.
MATERIALS AND METHODS
This study was conducted on 150 OA patients attending
the Rheumatology Out Patient Department, King
George’s Medical University (KGMU), Lucknow, India
and who were not taking drugs having effects on carti-
lage metabolism. Patients with raised uric acid
(> 6.0 mg), gout and other inflammatory disorders
were excluded from the study. Non-steroidal anti-
inflammatory medications were not used in patients for
the duration of the study. Seventy-five patients with
visual analogue scale (VAS) pain score of 20–70 were
taking colchicine 0.5 mg twice daily with paracetamol
1 g thrice daily (standard therapy prescribed in the
Department of Rheumatology, KGMU), whereas 75
patients were taking paracetamol 1 g thrice daily alone
as standard therapy for OA.7
Serum COMP was measured at baseline, at 2 months
and at the end of study, that is 1 year. Serum COMP
was measured by sandwich enzyme-linked immunosor-
bent assay (ELISA) technique, utilizing two monoclonal
antibodies directed against separate antigenic determi-
nants on the human COMP molecule (Nordic Bio-
sciences, Herlev, Denmark).
Statistical analysis
Statistical analysis was performed for the patients com-
pleting at least 2 months of treatment. This was done
so that a second sample was available for each study
patient. The serum COMP observations for 2 months
were carried forward for the end of study if the patient
was absent for final assessment. The serum COMP
levels between baseline, 2 months and the end of the
study were compared using repeated measures analysis
of variance (repeated measures ANOVA). For pair-wise
comparison F-test was used. The analysis was per-
formed using Statistical Package for the Social Sciences
(SPSS) software version 21.0 (SPSS Inc., Chicago, IL,
USA).
RESULTS
A total of 150 patients were enrolled and 75 received
paracetamol plus colchicine and 75 received paraceta-
mol alone. Two patients in the colchicine plus paraceta-
mol group and seven in the paracetamol alone group
were excluded from the study as they were found to be
outliers. Further, 16 and 11 patient were excluded from
International Journal of Rheumatic Diseases 2018; 21: 114–117
Colchicine prevents degradation in osteoarthritis
the study from each group as samples could not be
collected at week 8, thus 57 patients in the colchicine
group and 57 patients in the placebo group were
analyzed.
Comparison of serum COMP between visits
A one-way repeated measures ANOVA was performed for
each group separately, as one of the main assumptions
of two-way repeated ANOVA, interaction among the visits
and groups, was not satisfied. In the colchicine group
the repeated measures ANOVA showed no significant
change in serum COMP. In the placebo group a signifi-
cant increase (at 10% level of significance) was recorded
in serum COMP (P = 0.089). The pair-wise comparison
showed that a significant increase (P = 0.015) in serum
COMP was obtained from 2 months to 1 year.
(Tables 1,2 and Fig. 1).
DISCUSSION
Soluble biomarkers have been used to predict or evalu-
ate severity of OA or its occurrence or progression.
However, these studies show contradictory results.8,9
These contradictions stem from the complexities of the
disease and its progression. The biomarkers are prod-
ucts which are released from tissues of joints when
these products are formed and released either during
the synthesis or degradation of these tissues. In OA
there is progressive damage to different tissues. How-
ever, there is a simultaneous repair process going on. A
patient with early OA and minimal cartilage damage
may have highly active degeneration and regeneration
going on simultaneously, resulting in high levels of
degeneration and regeneration markers, where as a
patient with marked cartilage loss but having a quies-
cent disease may not have active degeneration and
regeneration going on with resultant low biomarker
levels. Also the rate of degeneration and regeneration
may vary from time to time, further complicating the
situation. Apart from the diseased joints, normal bones
and cartilage are present in other joints as well, and
have effects on biomarker levels. As a result, degenera-
tion and regeneration markers of bone and cartilage
have inconsistent results when viewed in respect to clin-
ical signs, cartilage thickness and progression. In a dif-
ferent strategy, Gineyts et al.10 used biomarkers to
assess effectiveness of ibuprofen in patients with OA,
suggesting that biomarkers can be used to assess
responses in patients. Here, we report serum COMP
levels as a marker of active disease to assess the mecha-
nism of action of colchicine.
115
R. Srivastava et al.

Table 1 Comparison of serum cartilage

Serum COMP Baseline 2 months 1 year F (P-value)
oligomeric matrix protein (COMP)
ng/ml Mean (SD) Mean (SD) Mean (SD)
between various visits for the colchicine
Colchicine plus 12.51 (21.82) 12.47 (20.56) 14.82 (21.26) 0.162 (0.850) and without colchicine groups using
paracetamol repeated measures analysis of variance
Paracetamol alone 17.41 (21.40) 16.51 (24.91) 26.31 (29.76) 2.51 (0.089)

Table 2 Comparison of serum cartilage oligomeric matrix remained untouched in the colchicine group but rose
protein (COMP) between 2 months versus baseline and significantly in the patients only on paracetamol
1 year versus 2 months for the colchicine and non-colchicine between 2 months and 1 year. This could signify rapid
groups using F-test collagen fibril formation, uncoupling of collagen from
aggrecan and active cartilage degeneration in the pla-
Serum COMP 2 month versus 1 year versus
baseline F (P-value) 2 months F
cebo group.
(P-value) Stable serum COMP levels in the colchicine group indi-
cate stability of the cartilage, prevention of uncoupling of
Colchicine plus < 0.001 (0.996) 1.005 (0.323)
collagen from proteoglycans and the possibility that col-
paracetamol
chicine may act as a disease-modifying agent in OA.
Paracetamol 0.031 (0.862) 6.529 (0.015)
alone
Calcium-containing crystals (CPPD as well BCP) and
monosodium urate (MSU) crystals have not been stud-
ied here and this is a drawback of the study. However,
as regards CPPD crystals, most patients with knee OA
35
Colchicine have calcium containing either CPPD or BCP crystals in
Placebo
the joint fluid or in the cartilage,11 hence it is expected
30
that there would be no difference in the presence of
25 CPPD crystals in both groups. All patients had normal
serum uric acid and the prevalence of MSU crystals in
20 such patients is rare.
Biological actions of colchicine on serum COMP
15 levels can only be a matter of conjecture. A Medline
search of colchicine and serum COMP did not show/
10 produce any result. Hence, possibly there is no direct
action of colchicine on serum COMP levels. The postu-
5 lated anti-inflammatory mechanism of action of colchi-
cine in OA and crystal arthritis is via blocking the
0
Base line Week 8 Week 52 inflammasome pathway.12 It has been shown that col-
chicine reduces formation of interleukin (IL)-1b levels
Figure 1 Comparison of serum cartilage oligomeric matrix in crystal arthritis13 and coronary syndrome.14 In turn,
protein (COMP) between the colchicine and non-colchicine IL-1b has been shown to be correlated with serum
groups at baseline, week 8 and week 52 (mean  SE).
COMP levels in OA and Kashin-Beck disease.15,16 Possi-
bly downstream IL-1b-mediated inflammation is
COMP or thrombospondin 5, is a non-collagenous responsible for cartilage degradation/regeneration and
protein present on the surface of collagen and is said to rise in serum COMP levels. By stabilizing the inflamma-
be responsible for rapid collagen fibrilogenesis from some pathway, colchicine may be acting as a disease-
multiple collagen molecules. It has also been shown to modifying agent in OA.
bind to aggrecan and thus would have a key role in nor-
mal cartilage physiology. Increased COMP levels indi-
ACKNOWLEDGEMENTS
cate rapid regeneration that usually follows active
degeneration and possibly uncoupling of collagen from The authors would like to acknowledge Ms Pallavi
aggrecan. However, in this report mean COMP levels Hajela for her technical support. The study was

116 International Journal of Rheumatic Diseases 2018; 21: 114–117


supported by Indian Council of Medical Research grant
no 5/4-5/3/Ortho/06-NCD-I. None of the authors have
any industrial links or affiliations to which there are
any conflicts of interest.
AUTHOR CONTRIBUTIONS
RS collected and assembled data, drafted the article,
analyzed the samples and interpreted the data, criti-
cally revised the article for important intellectual
content and finally approved the article. SKD concep-
tualized and designed the work, obtained funds,
provided study material, critically revised the article for
important intellectual content and finally approved
the article. GG collected and assembled data, finally
approved the article. AA statistically analyzed, critically
revised the article for important intellectual content
and finally approved the article. GGA critically revised
the article for important intellectual content and
finally approved the article.
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