Collagen-induced expression of collagenase-3 by primary chondrocytes is mediated by integrin  1 and discoidin domain receptor 2: a protein kinase C-dependent pathway

Vonk, Luciënne A.; Doulabi, Behrouz Zandieh; Huang, ChunLing; Helder, Marco N.; Everts, Vincent; Bank, Ruud A.

doi:10.1093/rheumatology/keq305

Cited by 29 publications

(22 citation statements)

References 42 publications

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“…9 -11 We found the following: i) increased expression of discoidin domain receptor 2 (DDR2), a cell membrane receptor tyrosine kinase for native collagen type II, was associated with the increased expression of MMP-13 in human OA cartilage and in the articular cartilage of the mouse models of OA; ii) reduced expression of Ddr2 attenuated OA progression in mouse models of OA; and iii) activation of DDR2 through interaction of chondrocytes with native collagen type II induced the expression of MMP-13 in chondrocytes in vitro. Based on the aforementioned results and data obtained from other investigators, 12,13 we proposed a molecular chain of events responsible for articular cartilage degeneration. Our hypothesis was as follows.…”

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confidence: 85%

Intact Pericellular Matrix of Articular Cartilage Is Required for Unactivated Discoidin Domain Receptor 2 in the Mouse Model

Polur

Servais

et al. 2011

The American Journal of Pathology

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Increased expression of the discoidin domain receptor 2 (DDR2) results from its interaction with collagen type II. This induces expression of matrix metalloproteinase (MMP)-13, leading to osteoarthritis (OA). To investigate the impact of the pericellular matrix of chondrocytes on DDR2, we generated a mouse model with inducible overexpression of DDR2 in cartilage. Conditional overexpression of DDR2 in mature mouse articular cartilage was controlled via the cartilage oligomeric matrix protein promoter using the Tet-Off-inducible system. Doxycycline was withdrawn at 1 month of age, and knee joints were examined at 2, 3, and 4 months of age. Microsurgery was performed on 3-month-old transgenic mice overexpressing DDR2 to destabilize the medial meniscus, and serial paraffin sections were examined at 2, 4, 8, and 12 weeks after surgery. DDR2 expression increased in the knee joints of transgenic mice. However, the increased DDR2 did not induce MMP-13 expression. No OA-like changes were observed in the transgenic mice at the age of 4 months. When transgenic mice were subjected to destabilizing of the medial meniscus, we observed accelerated progression to OA, which was associated with DDR2 activation. Therefore, conditionally overexpressing DDR2 in the mature articular cartilage of mouse knee joints requires activation to induce OA, and altered biomechanical stress can accelerate the onset of cartilage loss and progression to OA in transgenic mice.

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confidence: 85%

Intact Pericellular Matrix of Articular Cartilage Is Required for Unactivated Discoidin Domain Receptor 2 in the Mouse Model

Polur

Servais

et al. 2011

The American Journal of Pathology

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“…While most investigations of alterations in cartilage properties in OA focus on the macroscale properties of the ECM, characterization of the morphological, biochemical, and biomechanical changes in the PCM can improve our understanding of the specific contributions of mechanical loading to cartilage degeneration in OA. In this regard, alterations in PCM appear to modify the response of chondrocytes to soluble mediators and matrix proteins (Peters et al, 2011; Vonk et al, 2011; Xu et al, 2011)…”

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confidence: 99%

The structure and function of the pericellular matrix of articular cartilage

2014

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Chondrocytes in articular cartilage are surrounded by a narrow pericellular matrix (PCM) that is both biochemically and biomechanically distinct from the extracellular matrix (ECM) of the tissue. While the PCM was first observed nearly a century ago, its role is still under investigation. In support of early hypotheses regarding its function, increasing evidence indicates that the PCM serves as a transducer of biochemical and biomechanical signals to the chondrocyte. Work over the past two decades has established that the PCM in adult tissue is defined biochemically by several molecular components, including type VI collagen and perlecan. On the other hand, the biomechanical properties of this structure have only recently been measured. Techniques such as micropipette aspiration, in situ imaging, computational modeling, and atomic force microscopy have determined that the PCM exhibits distinct mechanical properties as compared to the ECM, and that these properties are influenced by specific PCM components as well as disease state. Importantly, the unique relationships among the mechanical properties of the chondrocyte, PCM, and ECM in different zones of cartilage suggest that this region significantly influences the stress-strain environment of the chondrocyte. In this review, we discuss recent advances in the measurement of PCM mechanical properties and structure that further increase our understanding of PCM function. Taken together, these studies suggest that the PCM plays a critical role in controlling the mechanical environment and mechanobiology of cells in cartilage and other cartilaginous tissues, such as the meniscus or intervertebral disc.

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“…5 A common outcome after DDR activation is the increase in metalloproteinase (MMP) secretion and collagen rearrangement. [6][7][8][9] As a consequence, DDR1 and DDR2 have both been associated with metastasis during tumor progression. 6 Similarly, DDR1 overexpression has been shown to enhance lymphocyte migration.…”

Section: Introductionmentioning

confidence: 99%

Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices

Afonso

McCann

Kapnick

et al. 2013

Blood

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Key Points• DDR2 regulates the directional migration of neutrophils in 3D collagen matrices, but not on 2D surfaces. • DDR2 regulates directionality through increased metalloproteinase secretion and generation of collagen-derived chemotactic peptide gradients.Neutrophils express a variety of collagen receptors at their surface, yet their functional significance remains unclear. Although integrins are essential for neutrophil adhesion and migration on 2-dimensional (2D) surfaces, neutrophils can compensate for the absence of integrins in 3-dimensional (3D) lattices. In contrast, we demonstrate that the inhibition of the tyrosine-kinase collagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migration on 2D surfaces but is an important regulator of neutrophil chemotaxis in 3D collagen matrices. In this context, we show that DDR2 activation specifically regulates the directional migration of neutrophils in chemoattractant gradients. We further demonstrate that DDR2 regulates directionality through its ability to increase secretion of metalloproteinases and local generation of collagen-derived chemotactic peptide gradients. Our findings highlight the importance of collagen-derived extracellular signaling during neutrophil chemotaxis in 3D matrices. (Blood. 2013;121(9):1644-1650) IntroductionNeutrophils exhibit the ability to maintain robust migration under a wide array of distinct environmental conditions. For example, by increasing the rate of actin polymerization, neutrophils lacking integrins are able to retain normal migration speeds in 3D environments. 1,2 We set out to determine the role of another collagen receptor family, the discoidin domain receptors (DDRs), during neutrophil chemotaxis. The DDR family is composed of 2 members, DDR1 and DDR2. DDRs are homodimeric receptor tyrosine kinases that bind to triple-helical collagen fibers through a domain similar to discoidin 1 of the social amoeba Dictyostelium discoideum. 3,4 On binding to collagen, DDRs become activated and serve as docking sites for many signaling pathways. 5 A common outcome after DDR activation is the increase in metalloproteinase (MMP) secretion and collagen rearrangement. [6][7][8][9] As a consequence, DDR1 and DDR2 have both been associated with metastasis during tumor progression. 6 Similarly, DDR1 overexpression has been shown to enhance lymphocyte migration. 10,11 However, the mechanism underlying the enhanced leukocyte migration remains unknown.We show that circulating human primary neutrophils solely express DDR2 and establish that DDR2 regulates the ability of neutrophils to migrate directionally toward chemoattractants in a collagen I matrix. DDR2 activation induces increased MMP secretion, leading to the generation of collagen-derived chemotactic peptides that are poised to form local gradients and enhance neutrophil persistence. Methods Isolation of human blood neutrophilsBlood was collected from anonymous healthy donors enrolled in the National Institutes of Health Blood Bank research prog...

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Collagen-induced expression of collagenase-3 by primary chondrocytes is mediated by integrin 1 and discoidin domain receptor 2: a protein kinase C-dependent pathway

Cited by 29 publications

References 42 publications

Intact Pericellular Matrix of Articular Cartilage Is Required for Unactivated Discoidin Domain Receptor 2 in the Mouse Model

Intact Pericellular Matrix of Articular Cartilage Is Required for Unactivated Discoidin Domain Receptor 2 in the Mouse Model

The structure and function of the pericellular matrix of articular cartilage

Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices

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