Abstract
OBJECTIVES:
New bone formation is one of the hallmark characteristics of ankylosing spondylitis, which is thereby associated with syndesmophytes. Fetuin-A is a molecule that is abundantly found in calcified tissues and it shows high affinity for calcium phosphate minerals and related compounds. Considering the role of fetuin-A in the regulation of calcified matrix metabolism, we compared the fetuin-A levels in ankylosing spondylitis patients with syndesmophytes with those in patients without syndesmophytes and in healthy controls. We also studied other biomarkers that are thought to be related to syndesmophytes.
METHODS:
Ninety-four patients (49 patients without syndesmophytes, 67.3% male, 40.7±8.7 years; 45 patients with syndesmophytes, 71.1% M, 43.9±9.9 years) and 68 healthy controls (44.2±10.6 years and 70.6% male) were included in this study. Syndesmophytes were assessed on the lateral radiographs of the cervical and lumbar spine. The serum levels of fetuin-A, dickkopf-1, sclerostin, IL-6, high-sensitivity C-reactive protein and bone morphogenetic protein-7 were measured with an enzyme-linked immunosorbent assay.
RESULTS:
Patients with syndesmophytes had significantly higher levels of fetuin-A compared with patients without syndesmophytes and controls (1.16±0.13, 1.05±0.09 and 1.08±0.13 mg/ml, respectively). However, fetuin-A was not different between the patients without syndesmophytes and controls. Bone morphogenetic protein-7 was significantly lower; dickkopf-1 was significantly higher in patients with ankylosing spondylitis compared with controls. The sclerostin concentrations were not different between the groups. In regression analysis, fetuin-A was an independent, significant predictor of syndesmophytes.
CONCLUSION:
Our results suggest that fetuin-A may a role in the pathogenesis of bony proliferation in ankylosing spondylitis.
Ankylosing Spondylitis; Bone Formation; Fetuin-A; Dickkopf-1 Protein Human; Sclerostin Protein Human; Bone Morphogenetic Protein 7
INTRODUCTION
Ankylosing spondylitis (AS) is a chronic inflammatory disorder that mainly affects
the sacroiliac joints and lumbar spine. New bone formation is one of the hallmark
characteristics of the disease, which is thereby associated with syndesmophytes and
ankylosis (11. Poddubnyy D, Sieper J. Radiographic progression in ankylosing
spondylitis/axial spondyloarthritis: how fast and how clinically
meaningful? Curr Opin Rheumatol. 2012;24(4):363-9,
http://dx.doi.org/10.1097/BOR.0b013e328352b7bd.
http://dx.doi.org/10.1097/BOR.0b013e3283...
). Structural damage in the spine
is associated with reduced spinal mobility and disability and conventional X-rays of
the spine are used for the standard assessment of these changes (22. Baraliakos X, Listing J, Rudwaleit M, Haibel H, Brandt J, Sieper
J, et al. Progression of radiographic damage in patients with ankylosing
spondylitis: defining the central role of syndesmophytes. Ann Rheum Dis.
2007;66(7):910-5, http://dx.doi.org/10.1136/ard.2006.066415.
http://dx.doi.org/10.1136/ard.2006.06641...
,33. Schett G, Rudwaleit M. Can we stop progression of ankylosing
spondylitis? Best Pract Res Clin Rheumatol. 2010;24(3):363-71,
http://dx.doi.org/10.1016/j.berh.2010.01.005.
http://dx.doi.org/10.1016/j.berh.2010.01...
). In
recent years, there has been considerable interest in the prediction and
pathogenesis of syndesmophyte formation. Therefore, several studies have been
conducted to identify the factors affecting this process. Today, biomarkers have
become a very important field of research in spondyloarthropathy. In this regard,
various biomarkers have been used to understand the underlying factors responsible
for syndesmophyte formation. However, available data on this subject are still
limited and additional information is required to clarify the underlying mechanisms
of new bone formation in AS. In a recent study, we reported increased serum fetuin-A
levels compared with controls (44. Sari I, Kebapcilar L, Taylan A, Bilgir O, Kozaci DL, Yildiz Y, et
al. Fetuin-A and interleukin-18 levels in ankylosing spondylitis.
Int J Rheum Dis. 2010;13(1):75-81.).
Considering the role of fetuin-A in the regulation of calcified matrix metabolism
(55. Mori K, Emoto M, Inaba M. Fetuin-A: a multifunctional protein.
Recent Pat Endocr Metab Immune Drug Discov. 2011;5(2):124-46,
http://dx.doi.org/10.2174/187221411799015372.
http://dx.doi.org/10.2174/18722141179901...
), we designed this study with the
primary objective of comparing the fetuin-A levels in AS patients with and without
syndesmophytes versus healthy controls. Additionally, we studied
other biomarkers that are suggested to be related to the development of
syndesmophytes in AS patients.
METHODS
Study population and clinical assessment
The sample size was calculated with the results of previous studies that
investigated the levels of fetuin-A (44. Sari I, Kebapcilar L, Taylan A, Bilgir O, Kozaci DL, Yildiz Y, et
al. Fetuin-A and interleukin-18 levels in ankylosing spondylitis.
Int J Rheum Dis. 2010;13(1):75-81.),
dickkopf-1 (DKK-1) (66. Heiland GR, Zwerina K, Baum W, Kireva T, Distler JH, Grisanti M,
et al. Neutralisation of Dkk-1 protects from systemic bone loss during
inflammation and reduces sclerostin expression. Ann Rheum Dis.
2010;69(12):2152-9, http://dx.doi.org/10.1136/ard.2010.132852.
http://dx.doi.org/10.1136/ard.2010.13285...
) and bone
morphogenetic protein-7 (BMP-7) (77. Park MC, Park YB, Lee SK. Relationship of bone morphogenetic
proteins to disease activity and radiographic damage in patients with ankylosing
spondylitis. Scand J Rheumatol. 2008;37(3):200-4.) based
on α = 0.05 and a power of 80%. At least 39 patients were
required per group. We excluded subjects with renal impairment (serum
creatinine>1.4 mg/dl) and patients who were treated with glucocorticoids
during the previous four weeks. We consecutively enrolled 45 AS patients with
syndesmophytes and 49 AS patients without syndesmophytes. All patients met the
1984 modified New York criteria for AS (88. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic
criteria for ankylosing spondylitis. A proposal for modification of the New
York criteria. Arthritis and rheumatism. 1984;27(4):361-8,
http://dx.doi.org/10.1002/art.1780270401.
http://dx.doi.org/10.1002/art.1780270401...
). To assess the disease activity, functional ability and spinal
mobility, we used the Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI) (99. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P,
Calin A. A new approach to defining disease status in ankylosing spondylitis:
the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol.
1994;21(12):2286-91.), Functional Index (BASFI)
(1010. Calin A, Garrett S, Whitelock H, Kennedy LG, O′Hea J,
Mallorie P, et al. A new approach to defining functional ability in ankylosing
spondylitis: the development of the Bath Ankylosing Spondylitis Functional
Index. J Rheumatol. 1994;21(12):2281-5.) and Metrology Index (BASMI)
(1111. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL,
Calin A. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS
Metrology Index. J Rheumatol. 1994;21(9):1694-8.), respectively. There were 68
healthy subjects who served as a control group. The controls were the relatives
of the health professionals and blood donors without inflammatory back pain.
Data regarding cardiovascular risk factors, such as smoking status (defined as
ever/never smokers), hypertension (HT) and diabetes mellitus (DM) were
collected. The symptom duration and past or current treatment for AS were also
recorded. Local ethical committee approval was obtained and all patients signed
informed consent forms.
Radiological evaluations
Lateral plain radiographs of the cervical and lumbar spine were used to detect syndesmophytes. The anterior sites of the lower and upper portion of each vertebra were randomly and blindly assessed by two experienced rheumatologists. In discordant cases, radiographs were re-evaluated by both readers together and consensus was reached. The overall kappa value for the inter-examiner agreement for the presence/absence of syndesmophytes was 0.706. The intra-rater agreement for observers 1 and 2 were 0.77 and 0.85, respectively.
Laboratory measurements
Following an overnight fast, venous blood samples for laboratory tests were collected between 8:00 and 9:00 AM. Serum samples were preserved at −80°C until assayed. The following enzyme-linked immunosorbent assay (ELISA) kits were applied according to the manufacturers' instructions:
High-sensitivity C-reactive protein (hs-CRP; BioCheck, USA, Cat No: BC-1119): The sensitivity of hs-CRP was 0.1 mg/L. The intra-assay and inter-assay coefficients of variation were 4.44% and 3.28%, respectively.
Interleukin-6 (IL-6; Assay Pro, USA, Cat No: EI1006-1): The minimum detectable dose of IL-6 is ∼0.008 ng/ml. The intra-assay and inter-assay coefficients of variation were 4.9% and 7.5%, respectively.
DKK-1 (Adipo Bioscience, USA, Cat No: SK00312-01): The sensitivity of the assay was 62.5 pg/mL. The intra-assay and inter-assay coefficients of variation were 4-6% and 8-10%, respectively.
BMP-7 (Adipo Bioscience, USA, Cat No: SK00019-01): The sensitivity of the assay was 31.25 pg/mL. The intra-assay and inter-assay coefficients of variation were 4-6% and 8-10%, respectively.
Sclerostin (Biomedica Gruppe, Vienna, Austria, Cat. No.: BI-20492): The sensitivity of the assay was 62.5 pg/mL. The intra-assay and inter-assay coefficients of variation were 4-6% and 8-10%, respectively.
Fetuin-A (Assay Pro, USA, Cat No:EG3501-1): The minimum detectable dose of alpha-2-HS-Glycoprotein is ∼3 ng/ml. The intra-assay and inter-assay coefficients of variation were 5.0% and 7.0%, respectively.
Statistical analysis
The statistical analysis was performed using Statistical Package for the Social Sciences (SPSS), version 16.0 (Chicago, IL, USA). The Kolmogorov-Smirnov normality test was used to determine the distribution pattern of the variables. Most of the parameters, including fetuin-A, DKK-1, sclerostin and hs-CRP, showed a normal distribution and we used parametric tests for the statistical analysis. Data were expressed as the mean ± standard deviation for continuous variables or as percentages of the total for categorical variables. Student's t-test was used for comparisons between two groups of continuous variables. The Pearson χ2 or Fisher's exact test was performed to compare categorical variables. The relationships between different variables were analyzed by the Pearson correlation test. Binary logistical regression analysis was used to identify the factors associated with the presence of syndesmophytes. A one-way ANOVA was used to test for differences among the three group means (patients with and without syndesmophytes and healthy controls). Kappa statistics were used to assess the agreement of the observers. A double-tailed p value of <0.05 was considered statistically significant.
RESULTS
There were 94 patients (49 without syndesmophyte, 67.3% male [M], 40.7±8.7 years; 45 with syndesmophyte, 71.1% M, 43.9±9.9 years) and 68 healthy control subjects (44.2±10.6 years and 70.6% M) in the study group. The age, sex distributions, number of patients with HT, DM and smoking status were similar between the three groups (p>0.05). The demographical and clinical characteristics of the groups are summarized in Table 1.
Comparison of the syndesmophyte-positive and -negative patients and healthy control groups
Fetuin-A was significantly higher in the AS patients with syndesmophytes compared with patients without syndesmophytes and healthy controls (Figure 1, p<0.05; 1.16±0.13, 1.05±0.09 and 1.08±0.13 mg/ml, respectively). The concentrations of DKK-1 were significantly higher in both the syndesmophyte-positive and -negative patient groups compared with controls (p<0.05; 1911±1344, 1727±1083 and 672±592 pg/ml, respectively). The BMP-7 levels were significantly down-regulated in the patients with and without syndesmophytes compared with healthy controls (p<0.05; 9.4±15.6, 10.7±16.4 and 75.8±110 pg/ml, respectively). Both IL-6 and hs-CRP were significantly higher in the patient group than in controls (p<0.05, Table 2). By contrast, the sclerostin levels were similar between the groups (p>0.05). Post hoc comparisons between the groups for each biomarker are summarized in Table 2.
Box plot of the mean fetuin-A levels for two groups of patients (with and without syndesmophytes) and healthy controls.
Comparison of the syndesmophyte-positive and -negative patients
The disease duration and BASFI and BASDAI values were comparable between the AS patients with and without syndesmophytes (p>0.05); however, the BASMI values were significantly lower in patients with syndesmophytes (p<0.0001, 3.2±1.5 vs. 4.9±1.9). The proportion of patients receiving biological agents, non-steroid anti-inflammatory drugs (NSAIDs) and sulfasalazine (SSZ) were not different between the patients with and without syndesmophytes (p>0.05). The percentages of patients receiving NSAIDs on a continuous or on-demand basis were also similar between the two groups (p>0.05). The fetuin-A levels were significantly higher in patients with syndesmophytes (p = 0.01; 1.16±0.13 vs. 1.05±0.09 mg/ml, respectively) than in those without. The levels of other soluble biomarkers, including DKK-1, sclerostin, BMP-7, IL-6 and hs-CRP, were not different between the two groups (p>0.05).
Correlation analysis
Correlation analysis showed that the presence of syndesmophytes was significantly and positively correlated with the BASMI and fetuin-A levels (p<0.05, r = 0.5 and 0.3, respectively). However, there were no correlations between the presence of syndesmophytes and IL-6, hs-CRP, DKK-1, sclerostin, and BMP-7 levels (p>0.05). Additionally, no correlation was observed for the disease duration, BASDAI, BASFI, anti-tumor necrosis factor alpha (TNF-α) or NSAID therapy, smoking status, presence of HT or DM. Correlations with other variables are given in Table 3.
Regression analysis
We performed binary logistic regression analysis to identify the factors that were the independent predictors of syndesmophytes. In the model, we included the age, sex, disease duration, BASDAI, BASFI, BASMI, hs-CRP, IL-6, DKK-1, BMP-7 and fetuin-A. When all predictor variables are considered together, they significantly predict syndesmophytes, X2 = 46.42, df = 12, n = 80 and p<0.001. In the model, increased fetuin-A (odds ratio [OR], and 95% confidence interval [CI] = 422.7, and 4.8-37201, respectively), BASMI (OR, and 95%CI = 3.2, and 1.8-5.9, respectively) and BASDAI (OR, and 95%CI = 0.64, and 0.46-0.89, respectively) significantly and independently predicted syndesmophytes.
DISCUSSION
In this study, we detected higher fetuin-A levels in AS patients with syndesmophytes
compared with patients without syndesmophytes and healthy controls, which was the
primary focus of the study. Moreover, fetuin-A was an independent, significant
predictor of the presence of syndesmophytes. The results of this study are
inconsistent with our previous study, which showed significantly higher levels of
fetuin-A in 45 AS patients compared with 29 healthy subjects (44. Sari I, Kebapcilar L, Taylan A, Bilgir O, Kozaci DL, Yildiz Y, et
al. Fetuin-A and interleukin-18 levels in ankylosing spondylitis.
Int J Rheum Dis. 2010;13(1):75-81.). However, that study did not include a radiographic
assessment. In the current study, we excluded subjects with renal failure and
patients receiving corticosteroids to avoid the negative effect of these variables
on the molecule (1212. Sato H, Kazama JJ, Wada Y, Kuroda T, Narita I, Gejyo F, et al.
Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A
(AHSG) in patients with rheumatoid arthritis. Intern Med. 2007;46(20):1685-91,
http://dx.doi.org/10.2169/internalmedicine.46.6269.
http://dx.doi.org/10.2169/internalmedici...
). The age, sex
distributions and disease durations as well as the prevalence of hypertension and
diabetes mellitus, which may affect the serum fetuin-A levels (1313. Laughlin GA, Cummins KM, Wassel CL, Daniels LB, Ix JH. The
association of fetuin-A with cardiovascular disease mortality in older
community-dwelling adults: the Rancho Bernardo study. J Am Coll Cardiol.
2012;59(19):1688-96,
http://dx.doi.org/10.1016/j.jacc.2012.01.038.
http://dx.doi.org/10.1016/j.jacc.2012.01...
), were similar in the two patient groups. Fetuin-A has also
been evaluated in several other inflammatory rheumatic diseases, including
rheumatoid arthritis, which revealed decreased levels of this molecule in this group
of patients compared with healthy subjects (1212. Sato H, Kazama JJ, Wada Y, Kuroda T, Narita I, Gejyo F, et al.
Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A
(AHSG) in patients with rheumatoid arthritis. Intern Med. 2007;46(20):1685-91,
http://dx.doi.org/10.2169/internalmedicine.46.6269.
http://dx.doi.org/10.2169/internalmedici...
). This finding may only be a reflection of the negative acute-phase
reactant nature of fetuin-A (1414. van Oss CJ, Bronson PM, Border JR. Changes in the serum alpha
glycoprotein distribution in trauma patients. J Trauma.
1975;15(5):451-5.).
New bone formation that develops in both the upper and lower endplates of the
vertebra is a hallmark feature of AS. It becomes visible on radiographs as a
syndesmophyte, which is the most typical finding of structural damage (11. Poddubnyy D, Sieper J. Radiographic progression in ankylosing
spondylitis/axial spondyloarthritis: how fast and how clinically
meaningful? Curr Opin Rheumatol. 2012;24(4):363-9,
http://dx.doi.org/10.1097/BOR.0b013e328352b7bd.
http://dx.doi.org/10.1097/BOR.0b013e3283...
,1515. Maksymowych WP, Chiowchanwisawakit P, Clare T, Pedersen SJ,
Ostergaard M, Lambert RG. Inflammatory lesions of the spine on magnetic
resonance imaging predict the development of new syndesmophytes in ankylosing
spondylitis: evidence of a relationship between inflammation and new bone
formation. Arthritis and rheumatism. 2009;60(1):93-102,
http://dx.doi.org/10.1002/art.24132.
http://dx.doi.org/10.1002/art.24132...
).
Bony spur formation and ankylosis may limit the range of motion of the spine and
eventually compromise function and cause deformity. Therefore, significant research
has focused on understanding the cellular and molecular mechanisms of bone formation
in AS (33. Schett G, Rudwaleit M. Can we stop progression of ankylosing
spondylitis? Best Pract Res Clin Rheumatol. 2010;24(3):363-71,
http://dx.doi.org/10.1016/j.berh.2010.01.005.
http://dx.doi.org/10.1016/j.berh.2010.01...
).
Fetuin-A, formerly known as α2-Heremans-Schmid glycoprotein, is a molecule that
is mainly synthesized in the liver (1212. Sato H, Kazama JJ, Wada Y, Kuroda T, Narita I, Gejyo F, et al.
Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A
(AHSG) in patients with rheumatoid arthritis. Intern Med. 2007;46(20):1685-91,
http://dx.doi.org/10.2169/internalmedicine.46.6269.
http://dx.doi.org/10.2169/internalmedici...
). It
is abundantly found in calcified tissues, including bone and ectopic calcified
lesions (1212. Sato H, Kazama JJ, Wada Y, Kuroda T, Narita I, Gejyo F, et al.
Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A
(AHSG) in patients with rheumatoid arthritis. Intern Med. 2007;46(20):1685-91,
http://dx.doi.org/10.2169/internalmedicine.46.6269.
http://dx.doi.org/10.2169/internalmedici...
,1616. Kazama JJ, Gejyo F, Ei I. The immunohistochemical localization
of alpha2-Heremans-Schmid glycoprotein/fetuin-A (AHSG). Nephrol Dial Transplant.
2005;20(4):851-2, http://dx.doi.org/10.1093/ndt/gfh690.
http://dx.doi.org/10.1093/ndt/gfh690...
) and shows high affinity for calcium phosphate minerals and related
compounds (1717. Jahnen-Dechent W, Heiss A, Schafer C, Ketteler M. Fetuin-A
regulation of calcified matrix metabolism. Circ Res. 2011;108(12):1494-509,
http://dx.doi.org/10.1161/CIRCRESAHA.110.234260.
http://dx.doi.org/10.1161/CIRCRESAHA.110...
). Animal studies have shown
that fetuin-A-deficient mice display calcification of various tissues, suggesting
that it may act as an ectopic calcification inhibitor (1212. Sato H, Kazama JJ, Wada Y, Kuroda T, Narita I, Gejyo F, et al.
Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A
(AHSG) in patients with rheumatoid arthritis. Intern Med. 2007;46(20):1685-91,
http://dx.doi.org/10.2169/internalmedicine.46.6269.
http://dx.doi.org/10.2169/internalmedici...
,1717. Jahnen-Dechent W, Heiss A, Schafer C, Ketteler M. Fetuin-A
regulation of calcified matrix metabolism. Circ Res. 2011;108(12):1494-509,
http://dx.doi.org/10.1161/CIRCRESAHA.110.234260.
http://dx.doi.org/10.1161/CIRCRESAHA.110...
). However, its
abundant presence in bone suggests it may promote bone mineralization. Increased
serum fetuin-A levels have been reported in fetal calves compared with adult cows,
which may reflect a higher rate of bone mineralization in early fetal life (1818. Brown WM, Saunders NR, Mollgard K, Dziegielewska KM. Fetuin-an
old friend revisited. Bioessays. 1992;14(11):749-55,
http://dx.doi.org/10.1002/bies.950141105.
http://dx.doi.org/10.1002/bies.950141105...
,1919. Toroian D, Price PA. The essential role of fetuin in the
serum-induced calcification of collagen. Calcif Tissue Int. 2008;82(2):116-26,
http://dx.doi.org/10.1007/s00223-007-9085-2.
http://dx.doi.org/10.1007/s00223-007-908...
).
Moreover, higher fetuin-A levels were associated with higher bone mineral density
among well-functioning community-dwelling elderly women (2020. Ix JH, Wassel CL, Bauer DC, Toroian D, Tylavsky FA, Cauley JA,
et al. Fetuin-A and BMD in older persons: the Health Aging and Body Composition
(Health ABC) study. J Bone Miner Res. 2009;24(3):514-21,
http://dx.doi.org/10.1359/jbmr.081017.
http://dx.doi.org/10.1359/jbmr.081017...
). In line with these observations, fetuin-A was demonstrated
as both necessary and sufficient for calcification of the type I collagen fibril
(2121. Price PA, Toroian D, Lim JE. Mineralization by inhibitor
exclusion: the calcification of collagen with fetuin. J Biol Chem. [In
Vitro];284(25):17092-101.).
DKK-1 is a molecule that has an inhibitory effect on osteoblastic activity by
suppressing the WNT signaling pathway. It has been suggested that decreased or
dysfunctional DKK-1 is associated with increased osteoblastic activity, inducing or
promoting syndesmophytes (2222. Schett G. Bone formation versus bone resorption in ankylosing
spondylitis. Adv Exp Med Biol. 2009;649:114-21,
http://dx.doi.org/10.1007/978-1-4419-0298-6_8.
http://dx.doi.org/10.1007/978-1-4419-029...
,2323. Daoussis D, Andonopoulos AP. The emerging role of Dickkopf-1 in
bone biology: is it the main switch controlling bone and joint remodeling?
Semin Arthritis Rheum. 2011;41(2):170-7,
http://dx.doi.org/10.1016/j.semarthrit.2011.01.006.
http://dx.doi.org/10.1016/j.semarthrit.2...
). Several reports investigated the DKK-1
levels in AS (2424. Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H,
et al. High level of functional dickkopf-1 predicts protection from
syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis.
2012;71(4):572-4,
http://dx.doi.org/10.1136/annrheumdis-2011-200216.
http://dx.doi.org/10.1136/annrheumdis-20...
25. Korkosz M, Gasowski J, Leszczynski P, Pawlak-Bus K, Jeka S,
Kucharska E, et al. High disease activity in ankylosing spondylitis is
associated with increased serum sclerostin level and decreased wingless
protein-3a signaling but is not linked with greater structural damage. BMC
Musculoskelet Disord. 2013;14:99,
http://dx.doi.org/10.1186/1471-2474-14-99.
http://dx.doi.org/10.1186/1471-2474-14-9...
26. Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K,
Karampetsou M, et al. Evidence that Dkk-1 is dysfunctional in ankylosing
spondylitis. Arthritis and rheumatism. 2010;62(1):150-8,
http://dx.doi.org/10.1002/art.27231.
http://dx.doi.org/10.1002/art.27231...
27. Hu Z, Xu M, Li Q, Lin Z, Liao Z, Cao S, et al. Adalimumab
significantly reduces inflammation and serum DKK-1 level but increases fatty
deposition in lumbar spine in active ankylosing spondylitis.
Int J Rheum Dis. 2012;15(4):358-65.
28. Kwon SR, Lim MJ, Suh CH, Park SG, Hong YS, Yoon BY, et al.
Dickkopf-1 level is lower in patients with ankylosing spondylitis than in
healthy people and is not influenced by anti-tumor necrosis factor therapy.
Rheumatol Int. 2012;32(8):2523-7,
http://dx.doi.org/10.1007/s00296-011-1981-0.
http://dx.doi.org/10.1007/s00296-011-198...
-2929. Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, et al.
Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of
patients with ankylosing spondylitis. BMC Musculoskelet Disord. 2012;13:191,
http://dx.doi.org/10.1186/1471-2474-13-191.
http://dx.doi.org/10.1186/1471-2474-13-1...
). However, these studies are inconsistent in their findings.
Some reported increased concentrations of DKK-1 in AS (2626. Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K,
Karampetsou M, et al. Evidence that Dkk-1 is dysfunctional in ankylosing
spondylitis. Arthritis and rheumatism. 2010;62(1):150-8,
http://dx.doi.org/10.1002/art.27231.
http://dx.doi.org/10.1002/art.27231...
,2727. Hu Z, Xu M, Li Q, Lin Z, Liao Z, Cao S, et al. Adalimumab
significantly reduces inflammation and serum DKK-1 level but increases fatty
deposition in lumbar spine in active ankylosing spondylitis.
Int J Rheum Dis. 2012;15(4):358-65.), whereas others
did not find any differences or showed decreased levels of the molecule (2828. Kwon SR, Lim MJ, Suh CH, Park SG, Hong YS, Yoon BY, et al.
Dickkopf-1 level is lower in patients with ankylosing spondylitis than in
healthy people and is not influenced by anti-tumor necrosis factor therapy.
Rheumatol Int. 2012;32(8):2523-7,
http://dx.doi.org/10.1007/s00296-011-1981-0.
http://dx.doi.org/10.1007/s00296-011-198...
,2929. Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, et al.
Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of
patients with ankylosing spondylitis. BMC Musculoskelet Disord. 2012;13:191,
http://dx.doi.org/10.1186/1471-2474-13-191.
http://dx.doi.org/10.1186/1471-2474-13-1...
).
In the current study, we revealed that both the patients with and without
syndesmophytes had significantly higher levels of DKK-1 compared with healthy
subjects. Sclerostin is a natural inhibitor of the WNT pathway (3030. Beyer C, Schett G. Pharmacotherapy: concepts of pathogenesis and
emerging treatments. Novel targets in bone and cartilage. Best Pract Res Clin
Rheumatol. 2010;24(4):489-96,
http://dx.doi.org/10.1016/j.berh.2010.03.001.
http://dx.doi.org/10.1016/j.berh.2010.03...
). Similar to DKK-1, there are also
contradictory results regarding the association of sclerostin and AS (2525. Korkosz M, Gasowski J, Leszczynski P, Pawlak-Bus K, Jeka S,
Kucharska E, et al. High disease activity in ankylosing spondylitis is
associated with increased serum sclerostin level and decreased wingless
protein-3a signaling but is not linked with greater structural damage. BMC
Musculoskelet Disord. 2013;14:99,
http://dx.doi.org/10.1186/1471-2474-14-99.
http://dx.doi.org/10.1186/1471-2474-14-9...
,2929. Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, et al.
Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of
patients with ankylosing spondylitis. BMC Musculoskelet Disord. 2012;13:191,
http://dx.doi.org/10.1186/1471-2474-13-191.
http://dx.doi.org/10.1186/1471-2474-13-1...
,3131. Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M,
Mueller R, et al. Altered skeletal expression of sclerostin and its link to
radiographic progression in ankylosing spondylitis. Arthritis and rheumatism.
2009;60(11):3257-62, http://dx.doi.org/10.1002/art.24888.
http://dx.doi.org/10.1002/art.24888...
,3232. Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR,
Rodrigues MB, et al. Low sclerostin levels: a predictive marker of persistent
inflammation in ankylosing spondylitis during anti-tumor necrosis factor
therapy? Arthritis Res Ther. 2012;14(5):R216,
http://dx.doi.org/10.1186/ar4055.
http://dx.doi.org/10.1186/ar4055...
). In our study, we found that the sclerostin concentrations
were not different between the study groups. BMPs are members of the transforming
growth factor beta superfamily that play a crucial role in skeletal and joint
morphogenesis (3333. Lories RJ, Derese I, Luyten FP. Modulation of bone morphogenetic
protein signaling inhibits the onset and progression of ankylosing enthesitis.
J Clin Invest. 2005;115(6):1571-9,
http://dx.doi.org/10.1172/JCI23738.
http://dx.doi.org/10.1172/JCI23738...
). They are reported to play
a role in pathologic new bone formation, especially BMP-7 (77. Park MC, Park YB, Lee SK. Relationship of bone morphogenetic
proteins to disease activity and radiographic damage in patients with ankylosing
spondylitis. Scand J Rheumatol. 2008;37(3):200-4.). Because of the association of BMPs with new formation,
several reports studied different BMPs in AS (77. Park MC, Park YB, Lee SK. Relationship of bone morphogenetic
proteins to disease activity and radiographic damage in patients with ankylosing
spondylitis. Scand J Rheumatol. 2008;37(3):200-4.,3434. Chen HA, Chen CH, Lin YJ, Chen PC, Chen WS, Lu CL, et al.
Association of bone morphogenetic proteins with spinal fusion in ankylosing
spondylitis. The Journal of rheumatology. 2010;37(10):2126-32,
http://dx.doi.org/10.3899/jrheum.100200.
http://dx.doi.org/10.3899/jrheum.100200...
35. Wendling D, Cedoz JP, Racadot E. Serum levels of MMP-3 and
cathepsin K in patients with ankylosing spondylitis: effect of TNFalpha
antagonist therapy. Joint Bone Spine. 2008;75(5):559-62,
http://dx.doi.org/10.1016/j.jbspin.2008.01.026.
http://dx.doi.org/10.1016/j.jbspin.2008....
-3636. Wendling D, Cedoz JP, Racadot E, Dumoulin G. Serum IL-17, BMP-7,
and bone turnover markers in patients with ankylosing spondylitis. Joint Bone
Spine. 2007;74(3):304-5,
http://dx.doi.org/10.1016/j.jbspin.2006.11.005.
http://dx.doi.org/10.1016/j.jbspin.2006....
). In the current study, we showed that the BMP-7
concentrations were significantly lower in the total AS group compared with healthy
controls. However, in the subgroup analysis, the BMP-7 levels were not different
between the patients with and without syndesmophytes. The main limitations of our
study are its cross-sectional design and the lack of information on the HLAB27
status of the patients.
In conclusion, higher fetuin-A levels in AS patients with syndesmophytes than in those without syndesmophytes and in healthy controls suggest a role for this molecule in the pathogenesis of bony proliferation in AS, which needs to be explored in prospective studies.
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25Korkosz M, Gasowski J, Leszczynski P, Pawlak-Bus K, Jeka S, Kucharska E, et al. High disease activity in ankylosing spondylitis is associated with increased serum sclerostin level and decreased wingless protein-3a signaling but is not linked with greater structural damage. BMC Musculoskelet Disord. 2013;14:99, http://dx.doi.org/10.1186/1471-2474-14-99.
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29Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, et al. Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis. BMC Musculoskelet Disord. 2012;13:191, http://dx.doi.org/10.1186/1471-2474-13-191.
» http://dx.doi.org/10.1186/1471-2474-13-191 -
30Beyer C, Schett G. Pharmacotherapy: concepts of pathogenesis and emerging treatments. Novel targets in bone and cartilage. Best Pract Res Clin Rheumatol. 2010;24(4):489-96, http://dx.doi.org/10.1016/j.berh.2010.03.001.
» http://dx.doi.org/10.1016/j.berh.2010.03.001 -
31Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis and rheumatism. 2009;60(11):3257-62, http://dx.doi.org/10.1002/art.24888.
» http://dx.doi.org/10.1002/art.24888 -
32Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR, Rodrigues MB, et al. Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Ther. 2012;14(5):R216, http://dx.doi.org/10.1186/ar4055.
» http://dx.doi.org/10.1186/ar4055 -
33Lories RJ, Derese I, Luyten FP. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest. 2005;115(6):1571-9, http://dx.doi.org/10.1172/JCI23738.
» http://dx.doi.org/10.1172/JCI23738 -
34Chen HA, Chen CH, Lin YJ, Chen PC, Chen WS, Lu CL, et al. Association of bone morphogenetic proteins with spinal fusion in ankylosing spondylitis. The Journal of rheumatology. 2010;37(10):2126-32, http://dx.doi.org/10.3899/jrheum.100200.
» http://dx.doi.org/10.3899/jrheum.100200 -
35Wendling D, Cedoz JP, Racadot E. Serum levels of MMP-3 and cathepsin K in patients with ankylosing spondylitis: effect of TNFalpha antagonist therapy. Joint Bone Spine. 2008;75(5):559-62, http://dx.doi.org/10.1016/j.jbspin.2008.01.026.
» http://dx.doi.org/10.1016/j.jbspin.2008.01.026 -
36Wendling D, Cedoz JP, Racadot E, Dumoulin G. Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. Joint Bone Spine. 2007;74(3):304-5, http://dx.doi.org/10.1016/j.jbspin.2006.11.005.
» http://dx.doi.org/10.1016/j.jbspin.2006.11.005
-
No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Oct 2014
History
-
Received
4 Apr 2014 -
Reviewed
13 June 2014 -
Accepted
7 July 2014