transforming-growth-factor-beta and Spondylarthropathies

Dickkopf-1 (Dkk-1) is a soluble inhibitor of the canonical Wnt pathway, which plays critical roles in embryonic development. Evidence suggests that this molecule regulates several aspects of both bone biology and fibrosis.. To provide an overview of our current knowledge of the role of Dkk-1 in joint remodeling and fibrosis.. We performed an electronic search (Medline) using the following key words: Dickkopf-1 (or Dkk-1), new bone formation, joint remodeling, ankylosing spondylitis, systemic sclerosis (or scleroderma), and fibrosis, supplemented by a manual search of references from retrieved articles.. Dkk-1 is a master regulator of joint remodeling in animal models of arthritis shifting the balance toward new bone formation when its expression is decreased and toward erosion/joint destruction when its expression is increased. In humans, evidence suggests that Dkk-1 may be dysfunctional in patients with ankylosing spondylitis, a prototype bone forming disease. Moreover, data from animal models indicate that Dkk-1 has a protective role against fibrosis in several organs. Recent data suggest that inhibiting the canonical Wnt pathway by overexpression of Dkk-1 could be a way to target TGF-β signaling in fibrotic diseases. Finally, B-cell depletion therapy in systemic sclerosis may exert its effects through TGF-β dependent upregulation of Dkk-1.. Dkk-1 appears to play a crucial role in both joint remodeling/ectopic ossification and fibrosis, and may be a prospective therapeutic modality for fibrotic diseases or diseases characterized by pathologic joint remodeling.

Topics: Animals; B-Lymphocytes; Bone Remodeling; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Scleroderma, Systemic; Spondylarthropathies; Spondylitis, Ankylosing; Transforming Growth Factor beta; Wnt Signaling Pathway

We and others have previously shown that IL-17 is elevated in the synovial fluid of patients with reactive arthritis (ReA)/undifferentiated spondyloarthropathy (uSpA) having acute synovitis. Major source for IL-17 is Th17 cells, which differentiate from Th0 cells under the influence of TGF-β and IL-6, IL1-β and are maintained by IL-21 and 23. There is a paucity of data on these cytokines in ReA/uSpA. Thus, we measured the levels of Th-17 differentiating and maintaining cytokines in synovial fluid of patients with ReA and uSpA. Fifty patients with ReA/uSpA (ReA 24, uSpA 26), 19 patients with rheumatoid arthritis (RA) and 11 patients with osteoarthritis (OA) were included in the study. Synovial fluid (SF) were collected from knee joint and stored at -80°C until analysis. Cytokines were assayed using ELISA in SF specimens. The median IL-17A levels were significantly elevated in ReA (48.3 pg/ml) and uSpA (32.5 pg/ml) as compared to non-inflammatory OA controls (<7.8 pg/ml; p < 0.0001), while comparable to RA (57.9 pg/ml). Further, IL-6 median values were higher in ReA (25.2 ng/ml) and uSpA (13.6 ng/ml) as compared to OA (0.76 ng/ml; p < 0.0001), and comparable to RA (15.8 ng/ml). The median levels of IL-1β, IL-21 levels were elevated in ReA, uSpA and RA as compared to OA but were not statistically significant. TGF-β levels in ReA and uSpA were similar to OA but lower than in RA (4340 pg/ml; p < 0.05). IL-23 was not detectable in any synovial fluid sample. However, levels of these cytokines did not correlate with disease activity parameters. Significant positive correlation was observed between IL-17 and IL-1β (r = 0.38, p < 0.005), IL-17 and IL-6 (r = 0.659, p < 0.0001), and IL-1β and IL-6 (r = 0.391, p < 0.0001) in ReA and uSpA group. Inflammatory synovitis in ReA/uSpA is mediated by pro-inflammatory cytokines like IL-17, IL-6, IL-1β, and IL-21. However, IL-23 was not detectable in SF. Good correlation between IL-17, IL-6, and IL 1β suggest that either they are co-regulated or they regulate each other.

Topics: Adult; Arthritis, Reactive; Arthritis, Rheumatoid; Case-Control Studies; Female; Humans; Interleukin-17; Interleukin-1beta; Interleukin-23; Interleukin-6; Interleukins; Male; Osteoarthritis; Prohibitins; Retrospective Studies; Spondylarthropathies; Synovial Fluid; Synovitis; Th17 Cells; Transforming Growth Factor beta

Data on synovial fluid (SF) cytokine concentrations in patients with reactive arthritis (ReA) or undifferentiated spondyloarthropathy (uSpA) are limited and contradictory. We measured levels of several proinflammatory and immunoregulatory cytokines in SF and sera from patients with ReA/uSpA.. Interleukin 17 (IL-17), IL-6, interferon-g (IFN-g), and IL-12p40, and immunoregulatory cytokines IL-10 and transforming growth factor-beta (TGF-beta) were assayed using ELISA in SF specimens from 51 patients with ReA/uSpA (ReA 21, uSpA 30), 40 patients with rheumatoid arthritis (RA), and 11 patients with osteoarthritis (OA). IL-17, IL-6, IFN-g, and IL-10 levels were also measured in paired sera samples from patients with ReA/uSpA.. SF concentrations of IL-17, IL-6, TGF-beta, and IFN-g were significantly higher in patients with ReA/uSpA as compared to RA patients (for IL-17 median 46 pg/ml, range < 7.8-220 vs median < 7.8 pg/ml, range < 7.8-136, p < 0.05; for TGF-beta median 4.2 ng/ml, range 1.32-12 vs median 3.01 ng/ml, range 0.6-9.6, p < 0.01; for IL-6 median 58 ng/ml, range 2-540 vs median 34.5 ng/ml, range < 0.009-220, p < 0.05; for IFN-g median 290 pg/ml, range < 9.4-1600 vs median 100 pg/ml, range < 9.4-490, p < 0.05). SF levels of IL-10 were comparable but the ratio of IFN-g/IL-10 was significantly higher in ReA/uSpA patients than RA patients (median 3.18, range 0.06-200 for ReA/uSpA vs median 1.0, range 0.03-26.9 for RA; p < 0.05). IL-17, IL-6, IL-10, and IFN-g SF levels were significantly higher than paired serum levels in ReA/uSpA patients (p < 0.01 for IL-17, p < 0.0001 for IL-6, p < 0.0001 for IL-10, and p < 0.001 for IFN-g).. Increased IL-17, IL-6, TGF-beta, and IFN-g concentrations in ReA/uSpA than in RA suggest that Th1 and Th17 cells could be the major agents in inflammation in ReA/uSpA.

Topics: Adolescent; Adult; Arthritis, Reactive; Arthritis, Rheumatoid; Cytokines; Female; Humans; Interferon-gamma; Interleukin-12 Subunit p40; Interleukin-17; Interleukin-6; Male; Middle Aged; Osteoarthritis; Prohibitins; Spondylarthropathies; Synovial Fluid; Transforming Growth Factor beta