XBP1S Associates with RUNX2 and Regulates Chondrocyte Hypertrophy

Liu, Yanna; Zhou, Jia; Zhao, Wenjun; Li, Xiangzhu; Jiang, Rong; Liu, Chuanju; Guo, Fengjin

doi:10.1074/jbc.m112.385922

Cited by 30 publications

(30 citation statements)

References 53 publications

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“…On the opposite way, in our model the role of T3 seems to promote chondrogenesis with no hypertrophy, T3 treatment did not increase, even reduce MMP13, COLX, and ALP signal by immunohistochemistry analysis in spheroid after 14 days ( Fig. 5A and B) as expected as referred by studies published by Mueller and Tuan [2008] and Liu et al [2012]. Our results might be explained because of few days in culture and the source from our MSCs was different from used for those authors and the most important was that the T3 dose used in this work was physiological and very low in front of dose used for those authors.…”

Section: Discussionsupporting

confidence: 86%

“…It is possible that combination of TGF-b withdrawal, a reduction in the level of dexamethasone, and the addition of T3 was essential for hypertrophy induction in the Muellerś work. Also Runx2 gene expression was evaluated by RT-PCR to check hypertrophy or increase of osteogenesis at genetic level as made Liu et al [2012] in their paper and it was not hypertrophy increased in our work when T3 was added to CM (Fig. 5C).…”

Section: Results Of a Previous Study Published Bymentioning

confidence: 71%

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3, 3′, 5‐triiodo‐L‐thyronine Increases In Vitro Chondrogenesis of Mesenchymal Stem Cells From Human Umbilical Cord Stroma Through SRC2

Fernández-Pernas

Fafián-Labora

Lesende-Rodríguez

et al. 2016

J of Cellular Biochemistry

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Our group focuses on the study of mesenchymal stem cells (MSCs) from human umbilical cord stroma or Warthońs jelly and their directed differentiation toward chondrocyte-like cells capable of regenerating damaged cartilage when transplanted into an injured joint. This study aimed to determine whether lactogenic hormone prolactin (PRL) or 3, 3', 5-triiodo-L-thyronine (T3), the active thyroid hormone, modulates chondrogenesis in our in vitro model of directed chondrogenic differentiation, and whether Wnt signalling is involved in this modulation. MSCs from human umbilical cord stroma underwent directed differentiation toward chondrocyte-like cells by spheroid formation. The addition of T3 to the chondrogenic medium increased the expression of genes linked to chondrogenesis like collagen type 2, integrin alpha 10 beta 1, and Sox9 measured by quantitative real time polymerase chain reaction (qRT-PCR) analysis. Levels of collagen type 2 and aggrecane analyzed by immunohistochemistry, and staining by Safranin O were increased after 14 days in spheroid culture with T3 compared to those without T3 or only with PRL. B-catenin, Frizzled, and GSK-3β gene expressions were significantly higher in spheroids cultured with chondrogenic medium (CM) plus T3 compared to CM alone after 14 days in culture. The increase of chondrogenic differentiation was inhibited when the cells were treated with T3 plus ML151, an inhibitor of the T3 steroid receptor. This work demonstrates, for first time, that T3 promotes differentiation towards chondrocytes-like cells in our in vitro model, that this differentiation is mediated by steroid receptor co-activator 2 (SRC2) and does not induce hypertrophy. J. Cell. Biochem. 117: 2097-2108, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 86%

Section: Results Of a Previous Study Published Bymentioning

confidence: 71%

3, 3′, 5‐triiodo‐L‐thyronine Increases In Vitro Chondrogenesis of Mesenchymal Stem Cells From Human Umbilical Cord Stroma Through SRC2

Fernández-Pernas

Fafián-Labora

Lesende-Rodríguez

et al. 2016

J of Cellular Biochemistry

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“…Moreover, findings predominately related to the terminal effectors of the PERK and IRE1 pathways (CHOP and XBP1, respectively) have demonstrated increased UPR activation in OA articular chondrocytes (86,95–97). Alternatively spliced, transcriptionally activated XBP1 (XBP1s), the generation of which is UPR-specific, promotes chondrocyte maturation to hypertrophic differentiation through its association with the transcription factor RUNX2, and by modulation of IHH (Indian hedgehog) and parathyroid hormone-related peptide signalling (98). Notably, XBP1 expression is induced by activated ATF6 (97)(Figure 3), one of the modes of cross-talk between UPR cascades in chondrocyte biology.…”

Section: Impaired Chondrocyte Bioenergymentioning

confidence: 99%

Emerging regulators of the inflammatory process in osteoarthritis

2014

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Chronic, low-grade inflammation in osteoarthritis (OA) contributes to symptoms and disease progression. Effective disease-modifying medical OA therapies are lacking, but better understanding inflammatory pathophysiology in OA could lead to transformative therapy. Networks of diverse innate inflammatory danger signals, including complement and alarmins, are activated in OA. Through inflammatory mediators, biomechanical cartilage injury and oxidative stress compromise chondrocyte viability and reprogram viable chondrocytes to hypertrophic differentiation and proinflammatory, and procatabolic responses in mechanistically similar ways. Integral to this reprogramming are certain ‘switching’ pathways in transcriptional signals, other than the well-characterized effects of NFκB and mitogen-activated protein kinase signalling. HIF-2α transcriptional signalling and ZIP8-mediated Zn2+ uptake, with downstream MTF1 transcriptional signalling, have been implicated in chondrocyte reprogramming, but further validation is required. Permissive factors in procatabolic reprogramming of OA chondrocytes by inflammatory mediators also have come to light, including impaired bioenergetics, such as altered mitochondrial function and decreased activity of the bioenergy sensors AMPK and SIRT1. These factors interact with molecular inflammatory responses and proteostasis mechanisms that normally resolve cell stress, such as the unfolded protein response and autophagy. Bioenergy-sensing by AMPK and SIRT1 modulates proteostasis and provides ‘stop signals’ for oxidative stress, inflammatory, and matrix catabolic processes in chondrocytes. The complexity of molecular inflammatory processes in OA, and the involvement of multiple inflammatory mediators in tissue repair responses, raises daunting questions about how to therapeutically target inflammatory processes and macroscopic inflammation in OA. Bioenergy sensing might provide a pragmatic ‘entry point’ for novel strategies to limit OA progression.

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“…2), evidenced by increased expression of GRP78 and CHOP, as well as generation of alternatively spliced and transcriptionally activated X-box protein 1 (XBP1) in OA cartilage 62,63 . ATF6 upregulates XBP1 expression in OA chondrocytes by promoting direct binding to XBP1 promoter 64 , and increased XBP1s expression accelerates chondrocyte hypertrophy 65 . XBP1 expression is also increased by IL-1β in chondrocytes 62 .…”

Section: Ampk and Sirt1 In Chondrocyte Stress Resistancementioning

confidence: 99%

Inflammation and intracellular metabolism: new targets in OA

Liu‐Bryan

2015

Osteoarthritis and Cartilage

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SUMMARY Articular cartilage degeneration is hallmark of osteoarthritis (OA). Low-grade chronic inflammation in the joint can promote OA progression. Emerging evidence indicates that bioenergy sensors couple metabolism with inflammation to switch physiological and clinical phenotypes. Changes in cellular bioenergy metabolism can reprogram inflammatory responses, and inflammation can disturb cellular energy balance and increase cell stress. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are two critical bioenergy sensors that regulate energy balance at both cellular and whole-body levels. Dysregulation of AMPK and SIRT1 has been implicated in diverse human diseases and aging. This review reveals recent findings on the role of AMPK and SIRT1 in joint tissue homeostasis and OA, with a focus on how AMPK and SIRT1 in articular chondrocytes modulate intracellular energy metabolism during stress responses (e.g., inflammatory responses) and how these changes dictate specific effector functions, and discusses translational significance of AMPK and SIRT1 as new therapeutic targets for OA.

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XBP1S Associates with RUNX2 and Regulates Chondrocyte Hypertrophy

Cited by 30 publications

References 53 publications

3, 3′, 5‐triiodo‐L‐thyronine Increases In Vitro Chondrogenesis of Mesenchymal Stem Cells From Human Umbilical Cord Stroma Through SRC2

3, 3′, 5‐triiodo‐L‐thyronine Increases In Vitro Chondrogenesis of Mesenchymal Stem Cells From Human Umbilical Cord Stroma Through SRC2

Emerging regulators of the inflammatory process in osteoarthritis

Inflammation and intracellular metabolism: new targets in OA

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