The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis.

Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage-bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years.

Regulation of hERG and hEAG channels by Src and by SHP-1 tyrosine phosphatase via an ITIM region in the cyclic nucleotide binding domain.

Members of the EAG K(+) channel superfamily (EAG/Kv10.x, ERG/Kv11.x, ELK/Kv12.

Serum levels of novel noggin and sclerostin-immune complexes are elevated in ankylosing spondylitis.

Background: Unravelling the basis of joint inflammation and ankylosis represents a major challenge in ankylosing spondylitis (AS) research. As noggin (NOG) and sclerostin (SOST) have recently been associated with the disease process in mouse and human studies, respectively, we explored the immune responses to these two molecules in AS.

Methods: Immune complexes (IC) composed of IgG autoantibodies to NOG and SOST were detected by immunoprecipitation and Western blot analyses.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) exhibits functionally significant interaction with HLA-B27 and relates to subtype specificity in ankylosing spondylitis.

Objectives: The functional interaction of endoplasmic reticulum aminopeptidase 1 (ERAP1) with human leucocyte antigen (HLA)-B*27 could be important in the pathogenesis of ankylosing spondylitis (AS). AS is associated with B*27:04 and B*27:05, but not with B*27:06 and B*27:09. The authors studied the surface expression of peptide-HLA(pHLA)-B27 complexes and HLA class-I free heavy chains (FHCs) on peripheral blood mononuclear cells of patients with AS with different ERAP1 single nucleotide polymorphisms.

Aberrant chondrocyte hypertrophy and activation of β-catenin signaling precede joint ankylosis in ank/ank mice.

Objective: We assessed the role of Ank in the maintenance of postnatal articular cartilage using the ank/ank mouse (mice homozygous for progressive ankylosis).

Methods: We analyzed ank/ank mice and wild-type littermates (8, 12, and 18 weeks old). Sections from decalcified, paraffin-embedded joints were stained with hematoxylin and eosin.

Notochordal cells protect nucleus pulposus cells from degradation and apoptosis: implications for the mechanisms of intervertebral disc degeneration.

Introduction: The relative resistance of non-chondrodystrophic (NCD) canines to degenerative disc disease (DDD) may be due to a combination of anabolic and anti-catabolic factors secreted by notochordal cells within the intervertebral disc (IVD) nucleus pulposus (NP). Factors known to induce DDD include interleukin-1 beta (IL-1ß) and/or Fas-Ligand (Fas-L). Therefore we evaluated the ability of notochordal cell conditioned medium (NCCM) to protect NP cells from IL-1ß and IL-1ß +FasL-mediated cell death and degeneration.

Genetics and mechanisms of crystal deposition in calcium pyrophosphate deposition disease.

Calcium pyrophosphate deposition (CPPD) disease (common in older adults) can be asymptomatic, associated with osteoarthritis, or can present as acute/chronic inflammatory arthritis. Due to the phenotypic complexity of CPPD, the European League Against Rheumatism (EULAR) recently made recommendations on terminology, diagnosis, and management based on available research evidence and expert consensus. There are no disease-modifying treatments for CPPD disease, and therapy remains nonspecific with the use of anti-inflammatory and analgesic drugs.

Radiographic severity of ankylosing spondylitis is associated with polymorphism of the large multifunctional peptidase 2 gene in the Spondyloarthritis Research Consortium of Canada cohort.

Objective: There are limited data on genetic predictors of radiographic progression. The aim of this study was to examine polymorphisms in genes involved in antigen presentation and their effect on radiographic severity and progression.

Methods: Caucasian patients with ankylosing spondylitis (AS) (diagnosed according to the modified New York criteria) from 2 Canadian centers were enrolled.

Aberrant axial mineralization precedes spinal ankylosis: a molecular imaging study in ank/ank mice.

Introduction: The diagnosis of ankylosing spondylitis is made from a combination of clinical features and the presence of radiographic evidence that may be detected only after many years of inflammatory back pain. It is not uncommon to have a diagnosis confirmed 5 to 10 years after the initial onset of symptoms. Development of a more-sensitive molecular imaging technology to detect structural changes in the joints would lead to earlier diagnosis and quantitative tracking of ankylosis progression.

Serum cytokine receptors in ankylosing spondylitis: relationship to inflammatory markers and endoplasmic reticulum aminopeptidase polymorphisms.

Objective: Endoplasmic reticulum aminopeptidase (ERAP)1 is associated with ankylosing spondylitis (AS) and is known to be involved in the clipping of the cytokine receptors interleukin 1 receptor II (IL-1RII), IL-6Ralpha, and tumor necrosis factor receptor I (TNFRI). We studied the relationship of these serum cytokine receptors and their corresponding cytokines to markers of inflammation and polymorphisms in ERAP1 and ERAP2 in patients with AS.

Methods: Sera from patients with AS were assayed for TNF-alpha, IL-1, IL-6, sTNFRI, sIL-1RII, and sIL-6Ralpha by ELISA.

Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis.

Objectives: To assess whether there is excess transmission of alleles from the ERAP1 ERAP2 locus in families with ankylosing spondylitis (AS).

Methods: 199 multiplex families with AS with four non-synonymous single nucleotide polymorphisms (SNPs), three in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene (rs27044, rs10050860 and rs30187) and one in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene (rs2549782), were genotyped and family-based association analyses were performed.

Results: Family-based association testing (FBAT -e; empirical variance option) analysis showed that ERAP1 rs30187[T] was associated with AS (additive model: p=0.

The CPPDD-associated ANKH M48T mutation interrupts the interaction of ANKH with the sodium/phosphate cotransporter PiT-1.

Objective: Numerous dominant human homolog of progressive ankylosis (ANKH) mutations have been identified in familial calcium pyrophosphate dihydrate crystal deposition disease (CPPDD). Due to the dominant nature of these mutations, we investigated whether ANKH interacts with other proteins; and if so, whether any CPPDD-associated ANKH mutation might disrupt such protein interactions.

Methods: Stable ATDC5 ANKH wt- and ANKH M48T-transfectants were generated.

The ANKH ΔE490Mutation in Calcium Pyrophosphate Dihydrate Crystal Deposition Disease (CPPDD) affects tissue non-specific Alkaline Phosphatase (TNAP) activities.

ANKH (human homolog of progressive ankylosis) regulates inorganic pyrophosphate (PPi) transport. Dominant ANKH mutations were detected in at least five multiplex families with calcium pyrophosphate dihydrate crystal deposition disease (CPPPD). The objective of this study is to assess the functional consequences of one CPPDD-associated ANKH mutation (ΔE490) in chondrogenic ATDC5 cells.

Toll-like receptor 2 variants are associated with acute reactive arthritis.

Objective: We previously reported a recent outbreak of salmonellosis in which some individuals developed complications of the enteric infection. The objective of this study was to identify genetic variants that might predispose infected individuals to develop articular and/or extraarticular sequelae after Salmonella enteritidis infection.

Methods: The entire exposed cohort was invited to participate in the study by sending a saliva sample for DNA analysis.

Symptomatic acute reactive arthritis after an outbreak of salmonella.

Objective: In 2005, 592 individuals in Ontario developed acute gastroenteritis, predominantly after consuming bean sprouts contaminated with Salmonella enteritidis. Salmonella is a known trigger of reactive arthritis (ReA). We describe the population affected by the Salmonella outbreak in terms of clinical presentation of self-reported arthritic symptoms and HLA-B27 genotyping.

Retinol (vitamin A) and retinol-binding protein levels are decreased in ankylosing spondylitis: clinical and genetic analysis.

Objective: Retinol (vitamin A) plays an important role in bone structure and function. Treatment with retinoids has been associated with bone abnormalities mimicking spondyloarthropathy and diffuse idiopathic skeletal hyperostosis. To determine whether retinol concentrations are altered in patients with ankylosing spondylitis (AS), we examined serum retinol levels in patients with AS and healthy controls.

Microcytosis in ank/ank mice and the role of ANKH in promoting erythroid differentiation.

Progressive ankylosis (Ank and the human homolog, ANKH) is a transmembrane protein which regulates transport of inorganic pyrophosphate (PPi). ank/ank mice with a mutated ank gene, have calcification and bone ankylosis of the affected joints. In the course of studying these mutant mice, we found that they have microcytosis.

Inhibition of alkaline phosphatase by cysteine: implications for calcium pyrophosphate dihydrate crystal deposition disease.

Objective: Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, a common arthritis affecting the elderly, is characterized by the deposition of CPPD crystals in articular joints. The mechanism underlying disease expression is unknown, but factors contributing to the pathogenesis may involve changes in enzymatic activities involving pyrophosphate and phosphate metabolism. Tissue nonspecific alkaline phosphatase (TNAP) is one of the major enzymes regulating pyrophosphate concentrations in articular joints.

Association of a TNAP haplotype with ankylosing spondylitis.

Objective: To use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS).

Methods: We genotyped 201 multiplex AS families with 1 exonic and 5 intronic single-nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissue-nonspecific alkaline phosphatase, and performed family-based association analyses.

Results: In our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) was significantly associated with AS (P = 0.

Investigations into the regulation and function of the SH2 domain-containing protein-tyrosine phosphatase, SHP-1.

Our laboratory is interested in identifying genes relevant to diseases. Our approach is to use spontaneous mouse mutants with immunological defects and decipher the molecular basis of the phenotypes. In the early 1990s, our attention was focused on the motheaten and viable motheaten mouse mutants.

ANKH variants associated with ankylosing spondylitis: gender differences.

The ank (progressive ankylosis) mutant mouse, which has a nonsense mutation in exon 12 of the inorganic pyrophosphate regulator gene (ank), exhibits aberrant joint ankylosis similar to human ankylosing spondylitis (AS). We previously performed family-based association analyses of 124 Caucasian AS families and showed that novel genetic markers in the 5' flanking region of ANKH (the human homolog of the murine ank gene) are modestly associated with AS. The objective of the present study was to conduct a more extensive evaluation of ANKH variants that are significantly associated with AS and to determine whether the association is gender specific.

Expression of cytokines and receptors in normal, immortalized, and malignant ovarian epithelial cell lines.

Background: Ovarian carcinoma originates from the epithelial cells on the surface of the ovary. This study evaluates cytokine production by these cells.

Materials And Methods: Normal human ovary surface epithelial cells (HOSE cells), immortalized HOSE cells and ovarian cancer cells were used for the study of cytokines.

Novel genetic markers in the 5'-flanking region of ANKH are associated with ankylosing spondylitis.

Objective: To use a candidate gene approach for the identification of genetic markers that are significantly linked to and associated with ankylosing spondylitis (AS).

Methods: We searched for novel polymorphisms in the ANKH gene (human homolog of the murine progressive ankylosis gene) and genotyped 2 polymorphic sites, one in the 5'-noncoding region and the other in the promoter region of ANKH, using DNA from affected (n = 273) and unaffected (n = 112) individuals from 124 AS families. We used these ANKH and other nearby polymorphisms to perform linkage and family-based association analyses.

Modulation of the ERG K+ current by the tyrosine phosphatase, SHP-1.

We reported previously (Cayabyab, F. S., and Schlichter, L.

Differential activation of human and guinea pig complement by pentameric and hexameric IgM.

Human and mouse IgM can be polymerized as a hexamer in addition to a pentamer. Our previous work with mouse IgM measured activation of guinea pig complement by highly enriched preparations of hexamer and pentamer and showed that hexamer is >100-fold more active than pentamer. In this report pentamer and hexamer were compared for their capacity to activate complement in a homogeneic system, i.