Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 Axis

Kim, Jin Hong; Jeon, Jimin; Shin, Minhee; Won, Yoonkyung; Lee, Minju; Kwak, Ji-Sun; Lee, Gyuseok; Rhee, Jae-Ho; Ryu, Je‐Hwang; Chun, Churl Hong; Chun, Jang‐Soo

doi:10.1016/j.cell.2014.01.007

Cited by 290 publications

(339 citation statements)

References 42 publications

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“…Consistent with decreased Adamts in embryonic Slc39a8 -/-hearts, SLC39A8 knockdown resulted in decreased ADAMTS1 expression in HUVECs (-49%, P < 0.001) ( Figure 4C). It has been reported that ZIP8 regulates Adamts expression by modulating cellular Zn uptake and subsequently Mtf1 transcriptional activity during osteoarthritis (25). Consistent with this model and the in vivo observation of reduced Zn in Slc39a8…”

Section: Figure 2 Slc39a8 Deletion Results In Lvnc (A) Hande Stainingsupporting

confidence: 74%

“…These findings were further verified by qRT-PCR analysis, which showed a 31% decrease of Adamts1 (P = 0.001), 50% decrease lated by 10 Zn exporters and 14 Zn importers (23). Solute carrier family 39 member 8 (Slc39a8, which encodes a protein historically termed ZIP8) is a cellular Zn importer (24) and has been shown to play a causal role in the pathogenesis of osteoarthritis by promoting cellular Zn uptake, resulting in increased metal-regulatory transcription factor 1 (Mtf1) activity, increased Adamts expression, and ECM degradation (25). Here, we found that Slc39a8-null mice exhibit typical ventricular noncompaction phenotypes associated with reduced Adamts transcription and reduced cardiac jelly degradation.…”

Section: Slc39a8mentioning

confidence: 99%

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Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

Wen¹,

Li²,

Cheng³

et al. 2018

Journal of Clinical Investigation

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Section: Figure 2 Slc39a8 Deletion Results In Lvnc (A) Hande Stainingsupporting

confidence: 74%

Section: Slc39a8mentioning

confidence: 99%

Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

Wen¹,

Li²,

Cheng³

et al. 2018

Journal of Clinical Investigation

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“…LOX overexpression was induced in mouse knee joint tissue via IA injection of Ad-Lox. Consistent with previous demonstrations of effective local gene delivery by adenoviral systems (11,16), AdLox injection triggered LOX overexpression in cartilage, meniscus, and synovium (Fig. S5A).…”

Section: Lysyl Oxidase Up-regulated In Degenerating Cartilage Drives supporting

confidence: 73%

“…Several key cellular pathways regulating these catabolic and anabolic processes have been identified, including the HIF-2α transcriptional network (11,20), the zinc-ZIP8-MTF1 axis (16), and complement pathways (22). In contrast, molecular changes occurring in the ECM during OA pathogenesis have been relatively underexplored to date.…”

Section: Discussionmentioning

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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“…The most common form of arthritis is osteoarthritis (OA), which is characterized by cartilage matrix loss, synovitis, and other pathological changes of joint tissues. [1][2][3] Yet, there are few treatment options for OA due to the limited understanding of OA development and heterogeneity in its pathology. 4 Local inflammation is widely considered to be associated with OA development and cartilage degradation.…”

Section: Introductionmentioning

confidence: 99%

The Chondroprotective Role of Erythromycin in a Murine Joint Destruction Model

et al. 2016

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Objective. Inflammation is a major player in the joint destruction process. Macrolide antibiotics have recently been found to have a novel anti-inflammatory function, but their effects on the joint are unknown. Our objective was to investigate the effect of macrolide antibiotic erythromycin on cartilage gene expression under inflammatory conditions as well as on joint pathology in an in vivo inflammatory joint destruction model. Design. In our in vivo studies, mouse knee joints were injected with monosodium iodoacetate (MIA), a chemical that inhibits glycolysis and causes joint inflammation and matrix loss. Erythromycin was administered by daily intraperitoneal injection. Changes in joint cartilage and synovium were evaluated by histological analysis. In our in vitro studies, primary bovine articular chondrocytes were treated with erythromycin in the presence of pro-inflammatory cytokine IL-1β or lipopolysaccharide (LPS), and cartilage gene expression analysis was performed. Results. Regional differences in cartilage matrix destruction along the medial-lateral axis were observed in joints of MIA-injected mice. Erythromycin treatment inhibited cartilage matrix loss and synovitis in these joints. In addition, erythromycin inhibited IL-1β and LPS-induced expression of MMPs and iNOS, as well as the positive regulatory loop between IL-1β and Toll-like receptor 4 (TLR4) in articular chondrocytes. Furthermore, erythromycin prevented LPSinduced NF-κB activation, a key mediator of TLR4-mediated cartilage destruction process. Conclusions. Erythromycin has the ability to inhibit catabolic gene expression mediated by IL-1β and TLR4 in chondrocytes in vitro and maintains cartilage matrix levels in experimental inflammatory joint destruction in vivo, suggesting that it possesses a chondroprotective activity.

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Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 Axis

Cited by 290 publications

References 42 publications

Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis

The Chondroprotective Role of Erythromycin in a Murine Joint Destruction Model

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