Transcriptional Induction of ADAMTS5 Protein by Nuclear Factor-κB (NF-κB) Family Member RelA/p65 in Chondrocytes during Osteoarthritis Development

Kobayashi, Hiroshi; Hirata, Makoto; Saito, Taku; Itoh, Shozo; Chung, Ung‐il; Kawaguchi, Hiroshi

doi:10.1074/jbc.m113.452169

Cited by 68 publications

(64 citation statements)

References 53 publications

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“…1 E ). We have previously reported that this mutation influences the response of chondrocytes to cytokines by regulating NF-κB signaling, itself a proposed regulator of aggrecanase transcription (8); however, as reported (38), there is no constitutive pathway activation. Similarly, here we found no constitutive JNK pathway activity (Fig.…”

Section: Resultsmentioning

confidence: 75%

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

et al. 2018

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Matrix protease activity is fundamental to developmental tissue patterning and remains influential in adult homeostasis. In cartilage, the principal matrix proteoglycan is aggrecan, the protease-mediated catabolism of which defines arthritis; however, the pathophysiologic mechanisms that drive aberrant aggrecanolytic activity remain unclear. Human ciliopathies exhibit altered matrix, which has been proposed to be the result of dysregulated hedgehog signaling that is tuned within the primary cilium. Here, we report that disruption of intraflagellar transport protein 88 (IFT88), a core ciliary trafficking protein, increases chondrocyte aggrecanase activity in vitro. We find that the receptor for protease endocytosis in chondrocytes, LDL receptor–related protein 1 (LRP-1), is unevenly distributed over the cell membrane, often concentrated at the site of cilia assembly. Hypomorphic mutation of IFT88 disturbs this apparent hot spot for protease uptake, increases receptor shedding, and results in a reduced rate of protease clearance from the extracellular space. We propose that IFT88 and/or the cilium regulates the extracellular remodeling of matrix—independently of Hedgehog regulation—by enabling rapid LRP-1–mediated endocytosis of proteases, potentially by supporting the creation of a ciliary pocket. This result highlights new roles for the cilium’s machinery in matrix turnover and LRP-1 function, with potential relevance in a range of diseases.—Coveney, C. R., Collins, I., Mc Fie, M., Chanalaris, A., Yamamoto, K., Wann, A. K. T. Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP-1–mediated endocytosis.

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Section: Resultsmentioning

confidence: 75%

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

et al. 2018

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“…NF-jB transcription also plays an important role in the production of ADAMTSs and MMPs [28][29][30]. The NF-jB pathway is known to be activated upon stimulation by various factors including mechanical stress or some cytokines [17,31].…”

Section: Discussionmentioning

confidence: 99%

“…It is also known that NF-jB induces IL-1 production, and that IL-1 also induces NF-jB [32]. Both IL-1 and NF-jB are known to lead ADAMTS-5 upregulation [28,33].…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan suppresses mechanical stress-induced expression of catabolic enzymes by human chondrocytes via inhibition of IL-1β production and subsequent NF-κB activation

et al. 2015

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“…Indeed, both HSF1 and NF-κB are implicated in inflammatory arthritis, and their activation by proinflammatory cytokines is well documented (25,26). Moreover, NF-κB is a known direct transactivator of ADAMTS5 (27) and HIF-2α (11,20); the latter directly regulates the expression of MMP targets (11). In addition to regulating catabolic factors, NF-κB is a potent suppressor of the anabolic master regulator SOX9 (28).…”

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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Transcriptional Induction of ADAMTS5 Protein by Nuclear Factor-κB (NF-κB) Family Member RelA/p65 in Chondrocytes during Osteoarthritis Development

Cited by 68 publications

References 53 publications

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

Hyaluronan suppresses mechanical stress-induced expression of catabolic enzymes by human chondrocytes via inhibition of IL-1β production and subsequent NF-κB activation

Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis

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