Effects Of Anti-Tumor Necrosis Factor-α Inhibitor On Serum Level Of DKK-1 Expression In Patients With Osteoarticular Disease

Objective:The Wnt/p-catenin signaling pathway is critically important in normal bone homeostasis.DKK-1,an inhibitory molecule that regulates the Wnt pathway,was recently recognized as a key player in animal models of arthritis and joint damage.This study was undertaken to explore the expression of DKK-1 and its potential role in patients with ankylosing spondylitis(AS)、rheumatoid arthritis(RA)and osteoarthritis(OA).To assess the effects of tumor necrosis factor(TNF)a blockers on serum DKK-1 levels and the binding of DKK-1 to its receptor low-density lipoprotein receptor-related protein 6(LRP-6)in patients with AS and RA.In addition to examine serum and synovial fluid DKK-1 levels of patients with knee OA and to investigate their relationship with disease severity.To investigate the Wnt/β-catenin signaling pathway related proteins expression in the articular cartilage of patients with knee OA.This study provides evidence about the role of Wnt/β-catenin signaling in the development of OA.Methods:Serum and synovial fluid DKK-1 levels were measured by sandwich enzyme linked immunosorbent assay(ELISA).Two groups of AS and RA subjects were tested.The first group consisted of patients who have been receiving anti-TNFa treatment more than 12 weeks.In the second group,patients had not been treated with biological agents.These were compared to 30 healthy subjects.A functional ELISA was used to assess the binding of DKK-1 to its receptor(LRP-6)in patients with AS and RA.Meanwhile,serum samples and synovial fluid samples from 30 patients with OA who undergoing total knee arthroplasty were measured.The levels of β-catenin were detected by immunohistochemistry staining.Markers of inflammation(erythrocyte sedimentation rate[ESR]and C-reactive protein[CRP]levels)were measured in all patients and normal subjects.Results:Serum DKK-1 levels were significantly decreased in AS patients who have not been treated with anti-TNFα agents as compared with patients with AS receiving anti-TNFa treatment and normal subjects(P<0.001 respectively).Patients with RA who have not been treated with anti-TNFa showed significantly higher serum DKK-1 levels compared with patients with RA who were receiving such treatment(P<0.01).but were similar compared with normal subjects(P>0.05).Patients with AS receiving anti-TNFα treatment had no different in the binding of DKK-1 to its receptor compared with patients with AS not receiving this treatment(P>0.05),in contrast to patients with RA.who exhibited a dramatic decrease(P<0.01).The BASDAI.ESR and CRP in patients with AS did not correlate with serum DKK-1 levels(P>0.05.respectively).The serum DKK-1 levels in all patients with RA were correlated with levels of DAS28(P<0.05),but did not correlate with ESR and CRP(P>0.05,respectively).Serum DKK-1 levels were significantly decreased in OA patients as compared with normal sub.jects(P<0.001).Serum DKK-1 levels showed a positive correlation with synovial fluid DKK-1 levels(P<0.001).DKK-1 levels in synovial fluid were significantly lower than in paired plasma samples(P<0.01)in knee OA.Furthermore,both plasma and synovial fluid DKK-1 levels were inversely correlated with radiographic severity(P<0.01.respectively).The results of β-catenin immunohistochemistry were significantly increased in OA group than control group(P<0.01).Conclusions:Our results indicated that the levels of serum DKK-1,the circulating bone formation inhibitory factor,were decrease in patients with AS.TNFa blockers could induce the expression of DKK-1 in patients with AS in sharp contrast to patients with RA,who exhibited a dramatic decrease in DKK-1 levels was noticed following anti-TNFα treatment.Despite an increase in circulating DKK-1 levels after anti-TNFa administration in patients with AS,binding of DKK-1 to LRP-6 is not enhanced.This can be at least partially attributed to decreased DKK-1-mediated inhibition in AS.The levels of serum DKK-1 were decrease and β-catenin in articular chondrocytes were overexpression in patients with OA.These were important reasons of the articular cartilage damage and development of OA.DKK-1 levels in serum and synovial fluid are inversely related to the severity of joint damage in knee OA.Therefore,DKK-1 could serve as a biochemical marker for determinin、g disease severitxy and might play a potential role in the pathogenesis of AS RA and OA.