A role for calreticulin in the pathogenesis of rheumatoid arthritis

Holoshitz, Joseph; Almeida, Denise E. de; Ling, Song

doi:10.1111/j.1749-6632.2010.05745.x

Cited by 32 publications

(27 citation statements)

References 75 publications

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“…In mammals where the bulk of data has been collected, CRT has been linked to both intracellular and extracellular functions, in health and disease (Holoshitz et al, 2010, Martins et al, 2010, Gold et al, 2010, Wang et al, 2012). The role of CRT in intracellular Ca 2+ homeostasis associates this protein with multiple functions including heart muscle function, adipocyte differentiation and cellular stress responses (Tarr et al, 2010, Van Duyn Graham et al, 2010 Wang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Amblyomma americanum tick calreticulin binds C1q but does not inhibit activation of the classical complement cascade

Kim

Ibelli

Mulenga

2015

Ticks and Tick-borne Diseases

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In this study we characterized Amblyomma americanum (Aam) tick calreticulin (CRT) homolog in tick feeding physiology. In nature, different tick species can be found feeding on the same animal host. This suggests that different tick species found feeding on the same host can modulate the same host anti-tick defense pathways to successfully feed. From this perspective it’s plausible that different tick species can utilize universally conserved proteins such as CRT to regulate and facilitate feeding. CRT is a multi-functional protein found in most taxa that is injected into the vertebrate host during tick feeding. Apart from it’s current use as a biomarker for human tick bites, role(s) of this protein in tick feeding physiology have not been elucidated. Here we show that annotated functional CRT amino acid motifs are well conserved in tick CRT. However our data show that despite high amino acid identity levels to functionally characterized CRT homologs in other organisms, AamCRT is apparently functionally different. Pichia pastoris expressed recombinant (r) AamCRT bound C1q, the first component of the classical complement system, but it did not inhibit activation of this pathway. This contrast with reports of other parasite CRT that inhibited activation of the classical complement pathway through sequestration of C1q. Furthermore rAamCRT did not bind factor Xa in contrast to reports of parasite CRT binding factor Xa, an important protease in the blood clotting system. Consistent with this observation, rAamCRT did not affect plasma clotting or platelet aggregation aggregation. We discuss our findings in the context of tick feeding physiology.

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Section: Introductionmentioning

confidence: 99%

Amblyomma americanum tick calreticulin binds C1q but does not inhibit activation of the classical complement cascade

Kim

Ibelli

Mulenga

2015

Ticks and Tick-borne Diseases

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“…14 We have recently identified the SE as a ligand that binds to cell surface calreticulin and activates pro-osteoclastogenic signalling. [15][16][17][18][19][20][21][22][23][24][25][26][27][28] Using cell-free synthetic ligands expressing the SE motif, we have demonstrated that the SE enhanced Th17 polarisation 24 and directly activated OC differentiation. 26 When administered in vivo to mice with collagen-induced arthritis, the SE ligand enhanced joint inflammation, increased the abundance of tissue and bone marrow OCs, and enhanced bone damage in arthritic joints.…”

Section: Key Questionsmentioning

confidence: 92%

Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-codingHLA-DRB1allele

et al. 2016

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ObjectiveShared epitope (SE)-coding DRB1 alleles are associated with bone erosion in several diseases, including rheumatoid arthritis (RA) and periodontal disease (PD), but the underlying mechanism is unknown. We have recently identified the SE as an osteoclast-activating ligand. To better understand the biological effects of the SE in vivo, here we sought to determine whether it can facilitate spontaneous bone damage in naïve mice.Methods3-month old naïve transgenic mice that carry the human SE-coding allele DRB1*04:01, or a SE-negative allele DRB1*04:02 were studied. Bone tissues were analysed by micro-CT, and the tooth-supporting tissues were studied by histology, immunohistochemistry and immunofluorescence. Serum biomarkers were determined by ELISA.ResultsTransgenic mice expressing the SE-coding DRB1*04:01 allele, but not mice carrying the SE-negative allele DRB1*04:02, showed spontaneous PD associated with interleukin (IL)-17 overabundance and periostin disruption. Mandibular bone volumetric and mineralisation parameters were significantly lower in SE-positive mice, and alveolar bone resorption was significantly increased in these mice. SE-positive mice also had more slender tibiae, and their marrow, cortical and total areas were lower than those of SE-negative mice. Additionally, significantly increased serum IL-17, tumour necrosis factor-α and osteoprotegrin levels were found in SE-positive mice, while their receptor activator of nuclear factor κ-B ligand levels were significantly lower.ConclusionsA human SE-coding allele increases the propensity to spontaneous bone-destructive periodontal inflammation and skeletal bone damage in transgenic mice. These findings provide new insights into the previously documented but poorly understood association of the SE with accelerated bone erosion in RA and several other human diseases.

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“…Calreticulin, despite the lack of a classic secretion peptide or transmembrane domain, plays a role in the clearance of dying cells and has been implicated in autoimmunity. Recent evidence indicates that cell surface calreticulin acts as a signal transducing receptor for the rheumatoid arthritis (RA)-shared epitope (SE) (Holoshitz et al, 2010). However, the biological function of calreticulin and nucleolin in anti-b2GPI antibodies-induced EC activation is not clear.…”

Section: Tlr4 and Apl-induced Cell Activation: In Vitro Studiesmentioning

confidence: 98%

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

et al. 2013

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SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Antiphospholipid antibodies (aPL), particularly against the phospholipid binding protein beta-2 glycoprotein I (b2GPI), play an important role in APS pathological mechanisms. aPL can activate intracellular signal transduction in a b2GPI-dependent manner to induce inflammatory responses, and promote hypercoagulable state and recurrent spontaneous abortion when b2GPI is associated with the cell surface receptor. In vivo and in vitro studies show that Annexin A2 (ANXA2) is the high affinity receptor that connects b2GPI to the target cells. However, ANXA2 is not a transmembrane protein and lacks an intracellular signal transduction pathway. Growing evidences suggest that the transmembrane protein toll-like receptor 4 (TLR4) might act as an 'adaptor' for intracellular signal transduction. This review focuses on the role of TLR4 and its signalling pathway in APS pathological mechanisms which will help us better understand the pathological processes of this syndrome.

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A role for calreticulin in the pathogenesis of rheumatoid arthritis

Cited by 32 publications

References 75 publications

Amblyomma americanum tick calreticulin binds C1q but does not inhibit activation of the classical complement cascade

Amblyomma americanum tick calreticulin binds C1q but does not inhibit activation of the classical complement cascade

Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-codingHLA-DRB1allele

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

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