The cardiac calsequestrin gene (<i>CASQ2</i>) is up‐regulated in the thyroid in patients with Graves’ ophthalmopathy – support for a role of autoimmunity against calsequestrin as the triggering event

Wescombe, Leon; Lahooti, Hooshang; Gopinath, Bamini; Wall, Jack R.

doi:10.1111/j.1365-2265.2009.03753.x

Cited by 25 publications

(18 citation statements)

References 24 publications

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“…This suggests functional differences in terms of Ca 2+ storage and turnover in EOM. Moreover, Casq2 has been suggested as target in autoimmune thyroid disease with eye involvement (Wescombe, et al, 2009). In fast EOM fibers Casq2 may also be present and may be co-expressed with the fast fiber isoform Casq1 in at least some EOM fiber-types.…”

Section: Discussionmentioning

confidence: 99%

Superior calcium homeostasis of extraocular muscles

Zeiger

Mitchell

Khurana

2010

Experimental Eye Research

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Extraocular muscles (EOMs) are a unique group of skeletal muscles with unusual physiological properties such as being able to undergo rapid twitch contractions over extended periods and escape damage in the presence of excess intracellular calcium (Ca2+) in Duchenne’s muscular dystrophy (DMD). Enhanced Ca2+ buffering has been proposed as a contributory mechanism to explain these properties; however, the mechanisms are not well understood. We investigated mechanisms modulating Ca2+ levels in EOM and tibialis anterior (TA) limb muscles. Using Fura-2 based ratiometric Ca2+ imaging of primary myotubes we found that EOM myotubes reduced elevated Ca2+ ~2-fold faster than TA myotubes, demonstrating more efficient Ca2+ buffering. Quantitative PCR (qPCR) and western blotting revealed higher expression of key components of the Ca2+ regulation system in EOM, such as the cardiac/slow isoforms sarcoplasmic Ca2+-ATPase 2 (Serca2) and calsequestrin 2 (Casq2). Interestingly EOM expressed monomeric rather than multimeric forms of phospholamban (Pln), which was phosphorylated at threonine 17 (Thr17) but not at the serine 16 (Ser16) residue. EOM Pln remained monomeric and unphosphorylated at Ser16 despite protein kinase A (PKA) treatment, suggesting differential signalling and modulation cascades involving Pln-mediated Ca2+ regulation in EOM. Increased expression of Ca2+/SR mRNA, proteins, differential post-translational modification of Pln and superior Ca2+ buffering is consistent with the improved ability of EOM to handle elevated intracellular Ca2+ levels. These characteristics provide mechanistic insight for the potential role of superior Ca2+ buffering in the unusual physiology of EOM and their sparing in DMD.

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Section: Discussionmentioning

confidence: 99%

Superior calcium homeostasis of extraocular muscles

Zeiger

Mitchell

Khurana

2010

Experimental Eye Research

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“…Porter et al [26] showed that CASQ1 is expressed 4.6 times more in extraocular muscles than skeletal muscles elsewhere. In recent micro-array studies in which we compared expression of genes in patients with Graves' hyperthyroidism with and without ophthalmopathy, we found that the gene for CASQ2 was significantly upregulated (2.8-fold) in patients with ophthalmopathy compared to those without eye disease [27]. While the gene for CASQ1 was also upregulated in patients with ophthalmopathy (4.1-fold) this was not statistically significant [27].…”

Section: Introductionmentioning

confidence: 85%

Epitopes, immunoglobulin classes and immunoglobulin G subclasses of calsequestrin antibodies in patients with thyroid eye disease

et al. 2010

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A number of serum autoantibodies are associated with thyroid eye disease (TED), including those reactive against the calcium binding protein calsequestrin (CASQ). There are two isoforms of CASQ namely; CASQ1, found in skeletal, including extra ocular, muscle, and CASQ2, found in cardiac muscle. We determined (i) the reactivity profiles of CASQ1 and CASQ2 antibodies and (ii) the immunoglobulin (Ig) classes and IgG subclasses of CASQ1 antibodies, using enzyme-linked immunosorbent assay. Of the 20 patients with TED tested, 35% were positive for CASQ1 antibodies, 25% for CASQ2 antibodies and two patients (10%) were positive for both antibodies. Of the 12 patients with Hashimoto's thyroiditis and ophthalmopathy tested, 25% were positive for CASQ1 antibodies, 42% for CASQ2 antibodies and two patients (17%) were positive for both antibodies. CASQ1 antibodies were mainly of the IgG class and IgG1 and IgG3 subclasses. These results suggest that CASQ1 and CASQ2 do not share major epitopes. Because antibodies of the IgG1 and IgG3 subclasses are cytotoxic, CASQ1 antibodies may contribute to the eye muscle damage in patients with TED. Because CASQ1 antibodies were positive in only a third of patients with active TED we are unable to draw conclusions about their role in its pathogenesis. On the other hand, a possible role of CASQ2 antibodies in the aetiology of the cardiac complications of Graves' disease is a new avenue for research and appears worthy of further investigation.

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“…Bostwick et al [36] found elevated levels of IGFBP5 when investigating the fibroblasts in fibrotic lung tissue, and that the expression of IGFBP5 was increased in liver fibrosis. However, IGFBP5 was downregulated in GO thyroid tissue [37]. IGFBP5 has different functions, which are dependent on the cell and tissue type [38,39].…”

Section: Characterization Of Eom-mpcs From Go Patientsmentioning

confidence: 92%

Isolation and Characterization of Extraocular Muscle-Derived Muscle Progenitor Cells from Normal and Graves' Orbitopathy Patients

Park

Nepali

Lew

2020

Stem Cells and Development

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Mesenchymal stem cells (MSCs) are useful for various purposes, including tissue engineering, regeneration, and gene therapy. MSCs isolated from extraocular muscles (EOMs) can be easily expanded in vitro, and can undergo multilineage differentiations involving adipogenesis, chondrogenesis, osteogenesis, and even neuronal or myogenic differentiation. This study aimed to isolate, characterize, and compare extraocular muscle-derived muscle progenitor cells (EOM-MPCs) from normal subjects and patients with Graves' orbitopathy (GO). EOM was obtained during strabismus surgery. Flow cytometry was conducted to identify CD surface antigens such as CD34, CD45, CD44, CD59, CD73, and CD90. We quantitated various cytokines secreted from MSCs, including interleukin (IL)-1a, IL-2, IL-6, IL-8, IL-10, IL-12, IL17A, tumor necrosis factor (TNF)-a, and interferon (IFN)-g, using a multi-analysis enzyme-linked immunosorbent assay array kit. We performed Oil Red O staining for adipogenesis, Alzarin Red staining for osteogenesis, Alcian blue staining for chondrogenesis, and polymerase chain reaction to measure messenger RNA expression during myogenesis. Our results show that EOM-MPCs from normal subjects and GO patients had similar levels of surface antigen expression and cytokine secretion. There was also no significant difference in the multilineage differentiation of adipocytes, chondrocytes, osteocytes, and myoblasts from EOM-MPCs taken from normal subjects and GO patients. However, hyaluronic acid synthetase 2 expression was higher after induction with tafluprost in EOM-MPCs from GO patients when compared with normal subjects. Together, these results show that EOM-MPCs derived from normal subjects are a good source for stem cell-based therapy for various disorders.

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The cardiac calsequestrin gene (CASQ2) is up‐regulated in the thyroid in patients with Graves’ ophthalmopathy – support for a role of autoimmunity against calsequestrin as the triggering event

Cited by 25 publications

References 24 publications

Superior calcium homeostasis of extraocular muscles

Superior calcium homeostasis of extraocular muscles

Epitopes, immunoglobulin classes and immunoglobulin G subclasses of calsequestrin antibodies in patients with thyroid eye disease

Isolation and Characterization of Extraocular Muscle-Derived Muscle Progenitor Cells from Normal and Graves' Orbitopathy Patients

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