T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice

Doody, Karen M.; Bussières-Marmen, Stéphanie; Li, Ailian; Paquet, Marilène; Henderson, Janet E.; Tremblay, Michel L.

doi:10.1002/art.33399

Cited by 18 publications

(17 citation statements)

References 30 publications

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“…Previous work had demonstrated a cell-autonomous function of TC-PTP in hematopoietic cell differentiation (42,43). Mice lacking TC-PTP globally exhibit an increase in osteoclast density and bone resorption (15). The current work expands the importance of TC-PTP by showing that it is able to regulate differentiation cell nonautonomously.…”

Section: Discussionsupporting

confidence: 57%

T-Cell Protein Tyrosine Phosphatase Regulates Bone Resorption and Whole-Body Insulin Sensitivity through Its Expression in Osteoblasts

Zee

Settembre

Levine

et al. 2012

Molecular and Cellular Biology

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bInsulin signaling in osteoblasts contributes to whole-body glucose homeostasis in the mouse and in humans by increasing the activity of osteocalcin. The osteoblast insulin signaling cascade is negatively regulated by ESP, a tyrosine phosphatase dephosphorylating the insulin receptor. Esp is one of many tyrosine phosphatases expressed in osteoblasts, and this observation suggests that other protein tyrosine phosphatases (PTPs) may contribute to the attenuation of insulin receptor phosphorylation in this cell type. In this study, we sought to identify an additional PTP(s) that, like ESP, would function in the osteoblast to regulate insulin signaling and thus affect activity of the insulin-sensitizing hormone osteocalcin. For that purpose, we used as criteria expression in osteoblasts, regulation by isoproterenol, and ability to trap the insulin receptor in a substrate-trapping assay. Here we show that the T-cell protein tyrosine phosphatase (TC-PTP) regulates insulin receptor phosphorylation in the osteoblast, thus compromising bone resorption and bioactivity of osteocalcin. Accordingly, osteoblast-specific deletion of TC-PTP promotes insulin sensitivity in an osteocalcin-dependent manner. This study increases the number of genes involved in the bone regulation of glucose homeostasis. The tenuous cross talk existing between bone remodeling and energy metabolism was first demonstrated in vivo through the realization that leptin, an adipocyte-derived hormone, inhibits both appetite (23,25,44) and bone mass accrual (16). The existence of this cross talk was then further substantiated by the observation that, in turn, osteoblasts regulate whole-body glucose metabolism through secretion of the hormone osteocalcin, which favors insulin secretion and insulin sensitivity and increases energy expenditure (20,33,37).Like other peptide hormones, osteocalcin undergoes significant posttranslational modification before being released into general circulation (29, 45). Specifically, osteocalcin, which is secreted by osteoblasts as a ␥-carboxylated protein, must be decarboxylated to become activated and able to fulfill its endocrine functions (33). This activation of osteocalcin has been shown to occur outside the osteoblast, in the bone resorption lacunae (21). As the only mechanism known for decarboxylating proteins outside the cell is incubating them at an acidic pH, the passage of osteocalcin through the acidic microenvironment of the resorption lacunae allows it to become decarboxylated and thus activated (18, 21). In effect, the resorbing function of osteoclasts favors glucose homeostasis by activating osteocalcin (21).In addition to being an endocrine cell, the osteoblast receives many endocrine signals, one of them being insulin. Among other functions, insulin signaling in osteoblast inhibits the expression of Opg, a gene encoding a decoy receptor for the RANKL osteoclast differentiation factor. As a consequence, insulin signals to the osteoblast to promote bone resorption and osteocalcin bioactivity, and thereby its own...

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Section: Discussionsupporting

confidence: 57%

T-Cell Protein Tyrosine Phosphatase Regulates Bone Resorption and Whole-Body Insulin Sensitivity through Its Expression in Osteoblasts

Zee

Settembre

Levine

et al. 2012

Molecular and Cellular Biology

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“…Other protein tyrosine phosphatases were reported to play a regulatory role in inflammation (20). For example, loss of T cell protein tyrosine phosphatase expression results in synovitis, with several hallmarks of inflammatory arthritis, within mouse femurs (21). In the current study, we demonstrated that PTPRO is a critical regulator in both human and mouse FH.…”

Section: Discussionsupporting

confidence: 60%

Survival and Inflammation Promotion Effect of PTPRO in Fulminant Hepatitis Is Associated with NF-κB Activation

Jiang

Chen

Hou

et al. 2014

The Journal of Immunology

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Previous investigations demonstrated that protein tyrosine phosphatase, receptor type, O (PTPRO) acts as a tumor suppressor in liver cancer; however, little is known about its role in liver inflammation. Thus, we investigated the role of PTPRO in fulminant hepatitis (FH) using a Con A–induced mouse model. Significantly more severe liver damage, but attenuated inflammation, was detected in PTPRO-knockout (KO) mice, and PTPRO deficiency could confer this phenotype to wild-type mice in bone marrow transplantation. Moreover, hepatocytes with PTPRO depletion were more sensitive to TNF-α–induced apoptosis, and secretion of cytokines was significantly decreased in both T and NK/NKT cells and led to marked impairment of NF-κB activation. Intriguingly, wild-type and PTPRO-KO cells responded equally to TNF-α in activation of IKK, but NF-κB activation was clearly decreased in PTPRO-KO cells. PTPRO associated with ErbB2, and loss of PTPRO potentiated activation of the ErbB2/Akt/GSK-3β/β-catenin cascade. Increased β-catenin formed a complex with NF-κB and attenuated its nuclear translocation and activation. Importantly, in humans, PTPRO was much decreased in FH, and this was associated with enhanced β-catenin accumulation but reduced IFN-γ secretion. Taken together, our study identified a novel PTPRO/ErbB2/Akt/GSK-3β/β-catenin/NF-κB axis in FH, which suggests that PTPRO may have therapeutic potential in this liver disease.

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“…Our data suggest that balanced nonpathological T helper polarisation requires a highly upregulated expression of SHP1 during the generation of IFN γ producing cells. By contrast, although the polymorphism rs1893217(C) in the PTPN2 gene has been associated with a decrease in the expression levels that promotes autoimmunity [23, 70] and to a reduced response to IL-2 [26], the regulation of the expression levels of this gene does not seem to be necessary during the generation of IFN γ producing cells. Single nucleotide polymorphisms (SNPs) in nonregulated PTPs PTPN22 and PTPRC have been associated with human autoimmune diseases, including multiple sclerosis and autoimmune hepatitis in the case of PTPRC and type I diabetes, rheumatoid arthritis, and systemic lupus erythematosus in the case of PTPN22 [13, 23, 37, 52].…”

Section: Conclusion: Perspective On Autoimmune Diseasesmentioning

confidence: 99%

Gene Expression Profiles of Human Phosphotyrosine Phosphatases Consequent to Th1 Polarisation and Effector Function

Castro-Sánchez¹,

Ramirez-Munoz²,

Roda-Navarro³

2017

Journal of Immunology Research

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Phosphotyrosine phosphatases (PTPs) constitute a complex family of enzymes that control the balance of intracellular phosphorylation levels to allow cell responses while avoiding the development of diseases. Despite the relevance of CD4 T cell polarisation and effector function in human autoimmune diseases, the expression profile of PTPs during T helper polarisation and restimulation at inflammatory sites has not been assessed. Here, a systematic analysis of the expression profile of PTPs has been carried out during Th1-polarising conditions and upon PKC activation and intracellular raise of Ca2+ in effector cells. Changes in gene expression levels suggest a previously nonnoted regulatory role of several PTPs in Th1 polarisation and effector function. A substantial change in the spatial compartmentalisation of ERK during T cell responses is proposed based on changes in the dose of cytoplasmic and nuclear MAPK phosphatases. Our study also suggests a regulatory role of autoimmune-related PTPs in controlling T helper polarisation in humans. We expect that those PTPs that regulate T helper polarisation will constitute potential targets for intervening CD4 T cell immune responses in order to generate new therapies for the treatment of autoimmune diseases.

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T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice

Cited by 18 publications

References 30 publications

T-Cell Protein Tyrosine Phosphatase Regulates Bone Resorption and Whole-Body Insulin Sensitivity through Its Expression in Osteoblasts

T-Cell Protein Tyrosine Phosphatase Regulates Bone Resorption and Whole-Body Insulin Sensitivity through Its Expression in Osteoblasts

Survival and Inflammation Promotion Effect of PTPRO in Fulminant Hepatitis Is Associated with NF-κB Activation

Gene Expression Profiles of Human Phosphotyrosine Phosphatases Consequent to Th1 Polarisation and Effector Function

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