ABSTRACT
El lupus eritematoso sistémico es el prototipo de las enfermedades autoinmunes no órgano-específicas, con un curso fluctuante entre periodos de remisión y crisis. La complejidad de sus mecanismos fisiopatológicos mantiene la necesidad de desarrollar nuevos tópicos de investigación que faciliten su entendimiento y generen potenciales blancos terapéuticos. La vía de señalización Wnt y su principal inhibidor la protema Dickkopf-1 tienen un rol trascendental en fenómenos biológicos como la homeostasis ósea. Sin embargo, estudios recientes en lupus eritematoso sistémico han permitido reconocer otros procesos extraóseos regulados por la proteína Dickkopf-1. Entre ellos: la preservación de la integridad de las membranas glomerulares a nivel renal, reversión de rasgos de senescencia de células mesenquimales de interés en la optimización de los planes de trasplante como medida terapéutica; y la homeostasis articular. Alrededor de estos resultados han de suscitarse nuevas investigaciones sobre la proteína Dickkopf-1 y lupus eritematoso sistémico, que consoliden la información obtenida dado el gran potencial clínico y terapéutico que implica.
Systemic lupus erythematosus is the prototype of non-organ specific autoimmune diseases, with a fluctuating course between remission and crisis. The complexity of pathophysiological mechanisms opens up the possibility to develop multiple research topics to facilitate their understanding and generate potential therapeutic targets. The Wnt signalling pathway and its main inhibitor, Dickkopf-1 protein, have a major role in biological phenomena, such as bone homeostasis. However, recent studies have enabled other extra-osseous processes regulated by Dickkopf-1 to be recognised. These include: preserving the integrity of kidney glomerular membranes, senescence reversal characteristics of mesenchymal cells of interest in optimising transplantation plans as a therapeutic measure, and joint homeostasis. Some of these results have led to further research into Dickkopf-1 and systemic lupus erythematosus, in order to consolidate the information obtained given the great clinical and therapeutic potential involved.
Subject(s)
Humans , Autoimmune Diseases , Lupus Erythematosus, SystemicABSTRACT
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. .
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Ossification, Heterotopic/metabolism , Spondylitis, Ankylosing/metabolism , /analysis , Analysis of Variance , Biomarkers/blood , /blood , Bone Morphogenetic Proteins/blood , C-Reactive Protein/analysis , Case-Control Studies , Cervical Vertebrae/metabolism , Cervical Vertebrae , Enzyme-Linked Immunosorbent Assay , Genetic Markers , Intercellular Signaling Peptides and Proteins/blood , /blood , Lumbar Vertebrae/metabolism , Lumbar Vertebrae , Ossification, Heterotopic/pathology , Reference Values , Statistics, Nonparametric , Spondylitis, Ankylosing/pathology , /metabolismABSTRACT
Los agentes biológicos inhibidores del factor de necrosis tumoral alfa (anti-TNF) se constituyen en un avance muy significativo en el tratamiento de los pacientes con espondilitis anquilosante (EA), demostrando una notable mejoría de sus síntomas, de su función y de su calidad de vida. Sumado a esta excelente respuesta clínica, se ha demostrado igualmente mejoría de la inflamación, demostrada mediante pruebas de laboratorio y estudios de resonancia nuclear magnética. A pesar de esta clara evidencia, la conexión entre actividad inflamatoria y progresión estructural no está tan claramente establecida como en artritis reumatoide (AR), y la evidencia de la eficacia de los anti-TNF en la prevención de la progresión del daño radiológico crónico en EA es deficiente. Se revisan las evidencias y las teorías actuales respecto a este crucial tema y se hace mención del importante papel de la proteína DKK-1, inhibidora de la vía Wnt. Esta proteína ha emergido recientemente como un regulador fundamental en la biología ósea y se constituye en una conexión clave entre inflamación, osteoporosis y remodelación articular.
The anti-TNF biological agents constitute a major advance in the treatment of patients with ankylosing spondylitis (AS) showing a remarkable improvement in symptoms of patients, their function and quality of life. In addition to this excellent clinical response, it has also been clearly demonstrated improvement of inflammation as evidenced by laboratory tests and MRI studies. Despite this clear evidence, the connection between inflammatory activity and structural progression is not as clearly established as in rheumatoid arthritis, and the evidence of anti-TNF therapy to prevent chronic EA radiological damage is poor. We review the evidence and current theories about this crucial issue and mention the important role of DKK-1 protein, an inhibitor of the Wnt pathway. This protein has recently emerged as a key regulator in bone biology and constitutes a key link between inflammation, osteoporosis and joint remodeling.
Subject(s)
Humans , Spondylitis, Ankylosing , Quality of Life , Radiographic Magnification , Tumor Necrosis Factor-alpha , Wnt Signaling PathwayABSTRACT
Objective To investigate the effects of the Wnt antagonist Dickkopf-1(Dkk-1) on epithelial mesenchymal transdifferentiation in human proximal tubular epithelial cells induced by transforming growth factor-β1 (TGF-β1). Methods Human proximal tubular epithelial cells (HKC) were cultured in vitro and divided into three groups as follows: control group, TGF-β1 group, and TGF-β1+Dkk-1 group. The cells in the control group underwent routine culture with medium containing 10% fetal calf serum. For the TGF-β1 group, TGF-β1 (final concentration 20ng/ml) was added into the routine culture medium. For TGF- β1+Dkk-1 group, TGF-β1 (final concentration 20ng/ml) and Dkk-1(final concentration 100ng/ml) were added at the same time. After cultured for 48h, we performed morphologic observation using an inverted contrast microscope. RT-PCR and Western blotting were adopted to detect the expressions of Wnt4, β-catenin, E-cadherin, and α-SMA mRNA. E-cadherin and α-SMA expressions were detected by cell immunofluorescence. Results Compared with control group, the mRNA expression of Wnt4 and the protein expression of Wnt4 were significantly increased in TGF-β1 and TGF-β1+Dkk-1 groups (P0.05). There was no obvious difference between each group in mRNA expression of β-catenin (P>0.05). The β-catenin protein exhibited low expression in control group, whereas the expression significantly increased in TGF-β1 group. The expression of β-catenin in TGF-β1+Dkk-1 group was lower than that in TGF-β1 group (P0.05). The mRNA and protein expression of E-cadherin were high in control group, but were significantly decreased in TGF-β1 group. Their expressions in the TGF-β1+Dkk-1 group were increased compared with that in TGF-β1 group (P0.05). The mRNA and protein expression of α-SMA were decreased in control and TGF-β1+Dkk-1 groups, compared with TGF-β1 group (P<0.05). Immune fluorescent staining showed that the expression of E-cadherin and α-SMA were consistent with the results of RT-PCR and Western blotting. Conclusion Wnt antagonist Dickkopf-1(Dkk-1) can inhibit epithelial mesenchymal transdifferentiation induced by TGF-β1.