Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis

Echtermeyer, Frank; Bertrand, Jessica; Dreier, Rita; Meinecke, Ingmar; Neugebauer, Katja; Fuerst, Martin; Lee, Yun Jong; Song, Yeong Wook; Herzog, Christine; Theilmeier, Gregor; Pap, Thomas

doi:10.1038/nm.1998

Cited by 292 publications

(282 citation statements)

References 28 publications

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“…For instance, the complement cascade has been shown to play an active role in OA by promoting the expression of catabolic proteases (2). Similarly, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) has been identified as a critical aggrecanase that breaks down cartilage matrix in OA, and further advances demonstrate that this protease is highly regulated, for example, via syndecan 4-mediated inhibition (3)(4)(5). Despite these advances, less is understood regarding the transcriptional regulation of OA gene expression programs.…”

mentioning

confidence: 99%

NFATc1 and NFATc2 repress spontaneous osteoarthritis

Greenblatt

Ritter²,

Wright

et al. 2013

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

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Osteoarthritis (OA) was once viewed originally as a mechanical disease of "wear and tear," but advances made during the past two decades suggest that abnormal biomechanics contribute to active dysregulation of chondrocyte biology, leading to catabolism of the cartilage matrix. A number of signaling and transcriptional mechanisms have been studied in relation to the regulation of this catabolic program, but how they specifically regulate the initiation or progression of the disease is poorly understood. Here, we demonstrate that cartilage-specific ablation of Nuclear factor of activated T cells c1 (Nfatc1) in Nfatc2 −/− mice leads to early onset, aggressive OA affecting multiple joints. This model recapitulates features of human OA, including loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and eventual progression to cartilage effacement and joint instability. Consistent with the notion that NFATC1 is an OA-suppressor gene, NFATC1 expression was significantly down-regulated in paired lesional vs. macroscopically normal cartilage samples from OA patients. The highly penetrant, early onset, and severe nature of this model make it an attractive platform for the preclinical development of treatments to alter the course of OA. Furthermore, these findings indicate that NFATs are key suppressors of OA, and regulating NFATs or their transcriptional targets in chondrocytes may lead to novel disease-modifying OA therapies.

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mentioning

confidence: 99%

NFATc1 and NFATc2 repress spontaneous osteoarthritis

Greenblatt

Ritter²,

Wright

et al. 2013

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

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“…This finding indicates the possibility of a progressive sequence that could lead to the activation of ERK phosphorylations, because both Rho and Rac are part of the integrin mechanotransduction pathway as well. In addition, syndecans are present in a variety of tissues, including mesenchymal and arterial tissues, and have been demonstrated to be essential in a diversity of physiologically relevant areas such as wound healing, neointima formation, liver disease, and cancer (22,23). The ability to control the surface interactions of cells with their interface (e.g., polymer membrane surface) is critical for investigating mechanotransduction related to types of transmembrane proteins.…”

mentioning

confidence: 99%

Defining the role of syndecan-4 in mechanotransduction using surface-modification approaches

Bellin

Kubicek

Frigault

et al. 2009

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

116

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The ability of cells to respond to external mechanical stimulation is a complex and robust process involving a diversity of molecular interactions. Although mechanotransduction has been heavily studied, many questions remain regarding the link between physical stimulation and biochemical response. Of significant interest has been the contribution of the transmembrane proteins involved, and integrins in particular, because of their connectivity to both the extracellular matrix and the cytoskeleton. Here, we demonstrate the existence of a mechanically based initiation molecule, syndecan-4. We first demonstrate the ability of syndecan-4 molecules to support cell attachment and spreading without the direct extracellular binding of integrins. We also examine the distribution of focal adhesion-associated proteins through controlling surface interactions of beads with molecular specificity in binding to living cells. Furthermore, after adhering cells to elastomeric membranes via syndecan-4-specific attachments we mechanically strained the cells via our mechanical stimulation and polymer surface chemical modification approach. We found ERK phosphorylation similar to that shown for mechanotransductive response for integrin-based cell attachments through our elastomeric membrane-based approach and optical magnetic twisting cytometry for syndecan-4. Finally, through the use of cytoskeletal disruption agents, this mechanical signaling was shown to be actin cytoskeleton dependent. We believe that these results will be of interest to a wide range of fields, including mechanotransduction, syndecan biology, and cell-material interactions.T he biochemical response of cells to external mechanical stimulation has generated tremendous interest over the past decade. Of particular interest are the causative contributions of mechanotransductive transmembrane integrin molecules that link the extracellular matrix (ECM) to the cell interior and play a role in physiological response and molecular signaling within the cell. Recently, numerous exciting discoveries have evolved from these studies including the role of mechanotransduction in vascular physiology and atherogenesis, Src activation (Src phosphorylation/ activation under local mechanical stimulation), and the effect of matrix stiffness on stem cell differentiation (1-3). Mechanical stimulation has been shown to produce a wide range of cellular responses including the proteomic activation of the mitogenactivated protein kinase (MAPK) pathways in extracellular signalregulated kinases (ERKs), alterations of genomic expression profiles, and control of cell morphology, differentiation, and proliferation (4, 5). However, such research has focused primarily on the integrins as the mechanical signal initiator/transmembrane protein. Although other strain-sensitive proteins, such as mechanosensitive ion channels and protein kinase C, are known to be altered by mechanical stimulation, these responses are thought to occur downstream or be directly linked to the transmembrane proteininitiating...

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“…To further investigate the significance of our findings in SDC4 À / À mice (on C57BL/6 background), we inhibited SDC4 function in OVA-immunized BALB/c mice (a more Th2-dominant mouse strain) by using a polyclonal antibody that has been shown to inhibit SDC4 signalling effectively 14 . Anti-SDC4 Ab was applied on day 0 and on day 13, 1 day before OVA immunization, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…AHR was measured at day 24 and mice were killed on day 25. To inhibit SDC4 function, we used a polyclonal antibody against SDC4 ectodomain (200 mg) 14 or nonspecific IgG Abs were applied into BALB/c mice i.p. on days 0 and 13 one day before OVA immunization, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Previous animal studies have shown a pivotal role for SDC4 in protecting against kidney injury 12 , limiting endotoxin shock 7 and promoting wound healing 13 . However, an inhibition of SDC4 by a specific antibody protected mice from cartilage damage in a murine model of osteoarthritis 14 . Moreover, the depletion of SDC4 þ T cells markedly suppressed contact hypersensitivity (CHS) responses in hapten-sensitized mice 4 .…”

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confidence: 99%

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Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation

et al. 2015

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Syndecan-4 (SDC4), expressed on dendritic cells (DCs) and activated T cells, plays a crucial role in DC motility and has been shown as a potential target for activated T-cell-driven diseases. In the present study, we investigate the role of SDC4 in the development of T-helper 2 cell-mediated allergic asthma. Using SDC4-deficient mice or an anti-SDC4 antibody we show that the absence or blocking of SDC4 signalling in ovalbumin-sensitized mice results in a reduced asthma phenotype compared with control animals. Most importantly, even established asthma is significantly decreased using the anti-SDC4 antibody. The disturbed SDC4 signalling leads to an impaired motility and directional migration of antigen-presenting DCs and therefore, to a modified sensitization leading to diminished airway inflammation. Our results demonstrate that SDC4 plays an important role in asthma induction and indicate SDC4 as possible target for therapeutic intervention in this disease.

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Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis

Cited by 292 publications

References 28 publications

NFATc1 and NFATc2 repress spontaneous osteoarthritis

NFATc1 and NFATc2 repress spontaneous osteoarthritis

Defining the role of syndecan-4 in mechanotransduction using surface-modification approaches

Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation

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