Hypoxia-Inducible Factor-2α Is an Essential Catabolic Regulator of Inflammatory Rheumatoid Arthritis

Ryu, Je‐Hwang; Chae, Chang-Suk; Kwak, Ji-Sun; Oh, Han; Shin, Younghak; Huh, Yun Hyun; Lee, Choong-Gu; Park, Yong-Wook; Chun, Churl Hong; Kim, Young‐Myeong; Im, Sungbin; Chun, Jang‐Soo

doi:10.1371/journal.pbio.1001881

Cited by 71 publications

(116 citation statements)

References 34 publications

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“…4G). Interestingly, we found that the expression of Il6, Cxcl2, Nos2, and Il1b mRNAs, which are produced in macrophages and fibroblasts (37)(38)(39)(40), was strongly upregulated in inflammatory joints from Il1r2 2/2 mice (Fig. 4H).…”

Section: Il1r2mentioning

confidence: 90%

IL-1 Receptor Type 2 Suppresses Collagen-Induced Arthritis by Inhibiting IL-1 Signal on Macrophages

Shimizu

Nakajima

Sudo

et al. 2015

The Journal of Immunology

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IL-1α and IL-1β (in this article referred to as IL-1) play important roles in host defense against infection and inflammatory diseases. IL-1R1 is the receptor for IL-1, and IL-1R2 is suggested to be a decoy receptor, because it lacks the signal-transducing TIR domain in the cytoplasmic part. However, the roles of IL-1R2 in health and disease remain largely unknown. In this study, we generated EGFP-knock-in Il1r2−/− mice and showed that they were highly susceptible to collagen-induced arthritis, an animal model for rheumatoid arthritis in which the expression of IL-1R2 is augmented in inflammatory joints. Il1r2 was highly expressed in neutrophils but had only low expression in other cells, including monocytes and macrophages. Ab production and T cell responses against type II collagen were normal in Il1r2−/− mice. Despite the high expression in neutrophils, no effects of Il1r2 deficiency were observed; however, we found that production of inflammatory mediators in response to IL-1 was greatly enhanced in Il1r2−/− macrophages. These results suggest that IL-1R2 is an important regulator of arthritis by acting specifically on macrophages as a decoy receptor for IL-1.

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Section: Il1r2mentioning

confidence: 90%

IL-1 Receptor Type 2 Suppresses Collagen-Induced Arthritis by Inhibiting IL-1 Signal on Macrophages

Shimizu

Nakajima

Sudo

et al. 2015

The Journal of Immunology

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“…Despite the role of HIFs in the cellular adaptations, studies were concluded their deleterious inflammatory effects in tissue under normoxia/hypoxia that resulted in autoimmune disorders like rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and psoriasis The loss of HIF‐1α blunted the inflammatory response in mouse models of cutaneous inflammation and arthritis . The pro‐inflammatory effect was found to be associated with the crosstalk between the NF‐kB signalling and also due to the excess production of nitric oxide .…”

Section: Hypoxia‐inducible Factors In Inflammationmentioning

confidence: 99%

Hypoxia‐inducible factors as neuroprotective agent in Alzheimer's disease

Ashok

Ajith

Sivanesan

2017

Clin Exp Pharma Physio

145

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“…5A). Because NF-κB previously had been shown to induce IL-1β expression in FLS and HIF-2α expression in chondrocytes (11,20,21), we further examined whether LOX-mediated activation of NF-κB is capable of inducing IL-1β and HIF-2α. Neither LOX nor HIF-2α induced IL-1β expression in chondrocytes (Fig.…”

Section: Cellular Lox Promotes Oa Pathogenesis By Modulating Chondrocytementioning

confidence: 99%

Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis

Kim

Lee

Won

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Osteoarthritis (OA) is characterized by impairment of the loadbearing function of articular cartilage. OA cartilage matrix undergoes extensive biophysical remodeling characterized by decreased compliance. In this study, we elucidate the mechanistic origin of matrix remodeling and the downstream mechanotransduction pathway and further demonstrate an active role of this mechanism in OA pathogenesis. Aging and mechanical stress, the two major risk factors of OA, promote cartilage matrix stiffening through the accumulation of advanced glycation end-products and up-regulation of the collagen cross-linking enzyme lysyl oxidase, respectively. Increasing matrix stiffness substantially disrupts the homeostatic balance between chondrocyte catabolism and anabolism via the Rho-Rho kinase-myosin light chain axis, consequently eliciting OA pathogenesis in mice. Experimental enhancement of nonenzymatic or enzymatic matrix cross-linking augments surgically induced OA pathogenesis in mice, and suppressing these events effectively inhibits OA with concomitant modulation of matrix degrading enzymes. Based on these findings, we propose a central role of matrix-mediated mechanotransduction in OA pathogenesis. Various pathological conditions in human diseases are associated with aberrant ECM remodeling and consequent deviation from intrinsic ECM material properties (2). Mechanical perturbation of ECM affects the ways in which cells respond to externally applied mechanical forces and generate internal traction forces through cell-matrix interactions (3). Therefore, elucidation of the functional relationships between ECM mechanics and cellular transduction pathways is of critical importance.Articular cartilage ECM consisting of a collagenous network and highly charged proteoglycans confers the unique load-bearing function to joints. The dense aggregates of negatively charged proteoglycans provide resistance to compressive loading by promoting osmotic swelling, which is counterbalanced by cross-linked collagen fibrils that confer tissue tensile strength. Disruption of this delicate balance leads to structural damage and functional failure of articular cartilage and, consequently, to development of osteoarthritis (OA), the most common arthropathy (4, 5). OA cartilage ECM undergoes extensive remodeling, characterized by a decrease in matrix compliance (6, 7). These changes occur at the level of individual collagen fibrils, although the precise mechanisms regulating matrix remodeling remain elusive. Notably, matrix remodeling precedes cartilage destruction (6, 7), suggesting that monitoring the mechanical properties of cartilage matrix could serve as an innovative diagnostic approach for early detection of OA. Significant influence of matrix stiffness on mesenchymal lineage specification has been documented, and data have been obtained on the optimal ranges of substrate rigidity promoting osteogenesis. This regulatory process requires nonmuscle myosin II activity, with concomitant effects on adhesion and actin cytoskeleton structures (8).I...

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Hypoxia-Inducible Factor-2α Is an Essential Catabolic Regulator of Inflammatory Rheumatoid Arthritis

Abstract: Hypoxia-inducible factor-2α (HIF-2α) is sufficient to cause experimental rheumatoid arthritis and acts to regulate the functions of fibroblast-like cells from tissue surrounding joints, independent of HIF-1α.

Cited by 71 publications

References 34 publications

IL-1 Receptor Type 2 Suppresses Collagen-Induced Arthritis by Inhibiting IL-1 Signal on Macrophages

IL-1 Receptor Type 2 Suppresses Collagen-Induced Arthritis by Inhibiting IL-1 Signal on Macrophages

Hypoxia‐inducible factors as neuroprotective agent in Alzheimer's disease

Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis

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