Related Experiment Videos

Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis

Rowan Hardy, Maria Juarez, Amy Naylor

    Arthritis Research & Therapy
    |October 20, 2012
    PubMed
    Abstract

    Insights

    In inflammatory arthritis, glucocorticoids directly regulate dickkopf-1 (DKK1) in synovial fibroblasts, influencing bone remodelling. This regulation is indirect when mediated by inflammatory cytokines, highlighting the role of local glucocorticoid activation.

    Area of Science:

    • Rheumatology
    • Endocrinology
    • Cell Biology

    Background:

    • Inflammatory arthritis causes abnormal bone remodeling, with dickkopf-1 (DKK1) implicated in regulating bone formation and resorption.
    • Synovial fibroblasts in inflamed joints produce DKK1 and increased local glucocorticoids, suggesting a link between these factors and bone changes.

    Purpose of the Study:

    • To investigate how local glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis.
    • To elucidate the role of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in mediating cytokine effects on DKK1 production.

    Main Methods:

    • Primary human synovial fibroblasts from inflammatory arthritis patients were cultured.
    • Real-time PCR and ELISA measured DKK1 mRNA and protein levels in response to TNFα, IL-1β, and glucocorticoids.
    • Wnt signaling pathway gene expression was analyzed using a custom array.

    Main Results:

    • Glucocorticoids directly regulated DKK1 expression in synovial fibroblasts, while TNFα and IL-1β did not.
    • Glucocorticoids modulated Wnt signaling components, favoring inhibition.
    • TNFα and IL-1β indirectly increased DKK1 production by upregulating 11β-HSD1, enhancing local glucocorticoid activation.

    Conclusions:

    • DKK1 expression in rheumatoid arthritis synovial fibroblasts is directly controlled by glucocorticoids, not inflammatory cytokines like TNFα.
    • The connection between synovial inflammation, Wnt signaling, and bone remodeling is mediated by local glucocorticoid activation, not solely by direct cytokine effects.

    Related Concept Videos

    The JAK-STAT Signaling Pathway01:20

    The JAK-STAT Signaling Pathway

    Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
    Acute Inflammation III: Local and Systemic Effects01:25

    Acute Inflammation III: Local and Systemic Effects

    Acute inflammation produces a coordinated set of local and systemic changes that limit injury, eliminate pathogens, and initiate repair. These responses arise within minutes of infection, trauma, or chemical insult and are driven by vascular alterations and leukocyte-derived mediators. When the stimulus resolves, the reaction typically abates within days.Local EffectsAt the site of injury, arteriolar vasodilation increases blood flow, resulting in redness and warmth. Simultaneously, increased...
    Inflammatory Response01:28

    Inflammatory Response

    An inflammatory response is a localized, nonspecific immune reaction that occurs when a tissue is injured. It is characterized by redness, swelling, heat, and pain, which are commonly called the cardinal signs and symptoms of inflammation. Inflammation can sometimes result in a loss of function.
    Inflammation can be triggered by various stimuli, such as impact, abrasion, chemical irritation, infections, and extreme hot or cold temperatures. These can damage cells and connective tissue fibers,...
    Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids01:21

    Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids

    Glucocorticoids, a class of anti-inflammatory drugs, are pivotal in treating moderate to severe Crohn's disease by inducing remission. They exhibit their anti-inflammatory action by inhibiting the production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and chemokines like IL-8. In addition, they reduce the expression of inflammatory cell adhesion molecules and inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2 (COX-2),...
    T Cell Types and Functions01:24

    T Cell Types and Functions

    When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
    Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
    Inflammatory Bowel Disease III: Crohn's Disease01:25

    Inflammatory Bowel Disease III: Crohn's Disease

    Crohn’s disease is a chronic, relapsing form of inflammatory bowel disease characterized by segmental, transmural inflammation that can affect any part of the gastrointestinal tract. Its pathogenesis arises from a combination of genetic susceptibility, environmental exposures, epithelial barrier dysfunction, and immune dysregulation. Together, these factors lead to an exaggerated immune response against components of the gut microbiome.Genetic and Environmental InfluencesMultiple genetic...