Helene Leydet-Quilici*Mathieu Luc

Thomas ArmingeatThao Pham

Pierre LafforgueRheumatology Department, Conception Teaching

Hospital, Marseille, France*Corresponding author. Hopital la Conception, Service de

Rhumatologie Sud, 147 boulevard Baille, 13005 Marseille,France. Tel.: þ33 491 383 462; fax: þ33 491 383 887.E-mail address: helene.leydet@wanadoo.fr (H. Leydet-

Quilici)

24 April 2006

Available online 20 February 2007

1297-319X/$ - see front matter � 2007 Elsevier Masson SAS. All rights reserved.

doi:10.1016/j.jbspin.2006.10.005

304 Letters to the editor / Joint Bone Spine 74 (2007) 299e305

Serum IL-17, BMP-7, and bone turnover markers inpatients with ankylosing spondylitis

Keywords: IL-17; BMP-7; Ankylosing spondylitis; Bone remodeling

Ankylosing spondylitis (AS) is associated with a decreasein bone mineral density (BMD) [1], which is due to increasedbone resorption and correlates with laboratory evidence of in-flammation [2]. Bone loss develops early in the course of AS,and osteoporosis may be more common in patients with thanwithout syndesmophytes [3]. IL-17, a proinflammatory cyto-kine similar to TNFa [4,5], may be involved in bone turnover[5] and inflammatory subchondral erosions [6]. Ossification atsites of enthesitis may depend, at least in part, on bone mor-phogenetic proteins (BMPs) [7], which also exert anaboliceffects on bone. Furthermore, in some cell lines, BMP-7increases the expression of mRNA for IL-17 [8].

The objectives of this study were to measure serum IL-17and BMP-7 levels in patients with AS comparatively to con-trols and to look for correlations linking these two factors toclinical and laboratory markers for disease activity and tobone turnover markers.

1. Methods

We included patients who met modified New York criteriafor AS and who were not receiving immunomodulating drugsor drugs known to affect bone metabolism. Age- and sex-matched controls were selected among untreated individualswho had no inflammatory or bone disease.

The following data were collected in each patient: diseaseduration, Bath Ankylosing Spondylitis Disease Activity Index(BASDAI), Bath Ankylosing Spondylitis Functional Index(BASFI), Bath Ankylosing Spondylitis Global score (BAS-G), serum IL-17 level (Quantikine ELISA, R & D,Lille,France), serum BMP-7 level (Human BMP-7 Duoset ELISA,

R & D, Lille, France), laboratory markers for inflammation(erythrocyte sedimentation rate (ESR), C-reactive protein(CRP), and IgA), markers for bone formation (osteocalcinand bone-specific alkaline phosphatase (BAP, Metra Biosys-tems, Moutin View, CA, USA)), markers for bone resorption(serum C-telopeptide of type 1 collagen (sCTX) and tartrate-resistant acid phosphatase (TRAP, SBA Sciences, Turku, Fin-land)), and osteoprotegerin.

The statistical evaluation included t-tests for group compar-isons and ANOVA for identifying correlations. P valuessmaller than 0.05 were considered statistically significant.

2. Results

We included 28 patients with AS (22 men and 6 women),whose mean age was 42 years and mean disease duration14 years. Mean values of disease-related variables were asfollows: BASDAI, 42.0 mm; BASFI, 35.5 mm; BAS-G,49.6 mm; ESR, 32.7 mm; CRP, 21.7 mg/L; and IgA, 2.79 g/L.Table 1 lists the main results. Serum IL-17 levels were signifi-cantly higher in the patients than the controls. No distinctive fea-tures were identified in the patients with the highest IL-17 levels.Non-significant serum BMP-7 elevation was found in the pa-tients compared to the controls. Patients had lower BALP levelsand higher TRAP levels, compared to controls.

The ESR value correlated with the sCTX level (P ¼ 0.02)and the CRP level with the osteocalcin level (P ¼ 0.03).Neither IL-17 nor BMP-7 correlated with any of the disease-related clinical variables (BASDAI, BASFI, and BAS-G),disease-related laboratory variables (ESR, CRP, and IgA),or bone turnover variables (osteocalcin, BALP, sCTX, andosteoprotegerin). Serum IL-17 showed a weak correlation(P ¼ 0.05) with TRAP. None of the other correlations weresignificant.

3. Discussion

In a group of patients with established AS and evidence ofactive inflammation (ESR � 30 mm, CRP � 20 mg/L, andBASDAI � 40), the bone formation marker BALP was de-creased and the bone resorption marker TRAP was increasedcompared to controls. In the patients, sCTX correlated with

Table 1

Mean (� SD) values of laboratory variables measured in patients with anky-

losing spondylitis and in controls

Variable AS Controls P value

IL-17 (pg/ml) 11.33 � 10.45 <7 0.006

BMP-7 (pg/ml) 704.5 � 1 220 279.7 � 288.4 0.11

BAP (mg/ml) 10.57 � 3.80 20.03 � 6.64 <0.05

TRAP (U/l) 1.66 � 0.27 0.99 � 0.70 <0.05

OC (ng/ml) 6.04 � 2.89 7.14 � 3.07 NS

sCTX (ng/ml) 0.45 � 0.27 0.50 � 0.20 NS

OPG (pg/ml) 2.72 � 2.19 2.98 � 1.50 NS

IL-17, interleukin-17; BMP-7, bone morphogenetic protein-7; BAP, bone alka-

line phosphatase; TRAP, tartrate-resistant acid phosphatase; OC, osteocalcin;

sCTX, serum C-telopeptide of type 1 collagen; OPG, osteoprotegerin.

305Letters to the editor / Joint Bone Spine 74 (2007) 299e305

ESR. These findings are consistent with earlier data and withthe occurrence of bone loss in some AS patients [1,2].

Serum IL-17 levels were significantly higher in AS pa-tients than in controls. They failed to correlate with labora-tory markers for inflammation. A weak correlation betweenserum IL-17 and TRAP was noted, in keeping with theknown ability of IL-17 to stimulate the expression ofRANK-Ligand, which induces osteoclast activation [5].Thus, IL-17 may contribute to the mechanisms that lead tobone loss in patients with AS.

Although serum BMP-7 levels were higher in the patientswith AS, the difference with the controls was not statisticallysignificant. Several BMPs (BMP-2, BMP-4, and BMP-7) areexpressed at sites of ossifying enthesitis in male DBA/1mice (an animal model of arthritis and ossifying enthesitis),as well as in biopsies of early-stage Achilles tendon enthesop-athy in humans. Transfer of the gene for the BMP antagonistnoggin inhibits the progression of spontaneous arthritis inDBA/1 mice and prevents endochondral ossification at sitesof enthesitis [7]. At the level of the skeleton, BMPs promoteosteoblast differentiation and bone formation; BMP inhibitionby transfer of the noggin gene results in severe osteoporosis ina mouse model [9].

Park et al. [10] measured serum levels of BMP-2, BMP-4,and BMP-7 in 30 patients with AS, 30 patients with rheuma-toid arthritis (RA), and 20 controls. BMP-7 elevation wasmore marked in the AS group than in the RA group, andBMP-7 levels correlated with the BASRI (which takes syndes-mophytes into account). BMP-7 variations over a meanfollow-up of more than 50 months correlated with BASRIvariations (P < 0.05).

These data suggest closer involvement of BMP-7 in enthesealossification than in systemic bone turnover in patients with AS.

References

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Daniel Wendling*Jean-Pierre Cedoz

Rheumatology Department,University Teaching Hospital, Besancon, France

*Corresponding author. Service de Rhumatologie, CHUMinjoz, 25 030 Besancon, France. Tel.: þ33 3 81 66 82 41;

fax: þ33 3 81 66 86 86.E-mail address: daniel.wendling@ufc-chu.univ-fcomte.fr

(D. Wendling)

Evelyne RacadotFrench blood establishment, Boulevard Fleming,

Besancon, France

Gilles DumoulinMetabolic and Renal Function Testing, University Teaching

Hospital,Besancon, France

12 August 2006

Available online 20 February 2007

1297-319X/$ - see front matter � 2007 Elsevier Masson SAS. All rights reserved.

doi:10.1016/j.jbspin.2006.11.005