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G protein-coupled receptor 137b (GPR137b) is an orphan seven-pass transmembrane receptor of unknown function. In mouse, Gpr137b is highly expressed in osteoclasts in vivo and is upregulated during in vitro differentiation. To elucidate the role that GPR137b plays in osteoclasts, we tested the effect of GPR137b deficiency on osteoclast maturation and resorbing activity. We used CRISPR/Cas9 gene editing in mouse-derived ER-Hoxb8 immortalized myeloid progenitors to generate GPR137b-deficient osteoclast precursors. Decreasing Gpr137b in these precursors led to increased osteoclast differentiation and bone resorption activity. To explore the role of GPR137b during skeletal development, we generated zebrafish deficient for the ortholog gpr137ba. Gpr137ba-deficient zebrafish are viable and fertile and do not display overt morphological defects as adults. However, analysis of osteoclast function in gpr137ba-/- mutants demonstrated increased bone resorption. Micro-computed tomography evaluation of vertebral bone mass and morphology demonstrated that gpr137ba-deficiency altered the angle of the neural arch, a skeletal site with high osteoclast activity. Vital staining of gpr137ba-/- fish with calcein and alizarin red indicated that bone formation in the mutants is also increased, suggesting high bone turnover. These results identify GPR137b as a conserved negative regulator of osteoclast activity essential for normal resorption and patterning of the skeleton. Further, these data suggest that coordination of osteoclast and osteoblast activity is a conserved process among vertebrates and may have similar regulation.

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OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

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OBJECTIVES: Among the seven subtypes of juvenile idiopathic arthritis (JIA), oligoarticular JIA (oJIA) and psoriatic JIA (psJIA) display a predilection for onset in early childhood. We examined whether meaningful differences in clinical phenotype justify the distinction between these conditions. METHODS: We performed a chart review to identify children with psoriatic and non-psoriatic oligoarticular-onset JIA. Clinical and demographic features of the two groups of children were compared. RESULTS: Of the 390 children included in the study, 303 met the criteria for oJIA and 87 met the criteria for oligoarticular-onset psJIA. Both groups had a peak age of onset at 2-3 years, though psJIA had appreciable incidence into adolescence. Onset before 5 years of age was observed in 215 (71%) and 38 (44%) children respectively (p<0.001). Within this age category, children with psJIA demonstrated similar gender ratio and anti-nuclear antibody status to those with oJIA but exhibited a distinctive clinical pattern, with a tendency to involve the wrists and small joints of the hands and feet. Conversely, among all children presenting with oligoarthritis in early childhood, those with wrist or small joint involvement were more likely to have nail pits, psoriasis, or a family history of psoriasis than those without (p<0.05), supporting the association of this joint pattern with the psoriatic diathesis. CONCLUSIONS: Even taking into account age of onset and number of joints, oJIA and psJIA remain clinically distinct, though important demographic overlap remains. These findings support separate diagnostic categories but justify further investigation into the similarities as well as differences among these children.

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A pathogenic role for autoantibodies, immune complexes and mast cells has long been hypothesized in rheumatoid arthritis (RA). Recent studies demonstrating novel RA-associated autoantibodies and the efficacy of B cell-directed therapy have led to a renewed interest in the role of humoral immunity in RA. Mouse models of arthritis have provided further support for a direct pathogenic role of autoantibodies in the development of synovial inflammation. Interestingly, in antibody-mediated K/BxN serum transfer arthritis, mast cells have now been identified as a critical cellular mediator of autoantibody-driven joint inflammation. Here, we focus on the role of autoantibodies and mast cells in murine and human inflammatory arthritis.

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