Discoidin domain receptor 2 is involved in the activation of bone marrow-derived dendritic cells caused by type I collagen

Lee, Jieun; Kang, Chon-Sik; Guan, Xiu-Ying; Kim, Beom‐Tae; Kim, Sang-Hyun; Lee, Young-Mi; Moon, Woo-Sung; Kim, Dae‐Ki

doi:10.1016/j.bbrc.2006.11.010

Cited by 32 publications

(20 citation statements)

References 33 publications

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“…74,75 Less is known about the function of DDR2; however, DDR2 was upregulated on mature bone marrow-derived dendritic cells, and promoted antigen uptake and presentation, and cytokine secretion. 76 Taken together, these studies support a role for collagen signaling through DDRs as a key mediator of macrophage and dendritic cell biology.…”

Section: Leukocyte Collagen Receptorsmentioning

confidence: 68%

Collagens in the progression and complications of atherosclerosis

et al. 2009

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Collagens constitute a major portion of the extracellular matrix in the atherosclerotic plaque, where they contribute to the strength and integrity of the fibrous cap, and also modulate cellular responses via specific receptors and signaling pathways. This review focuses on the diverse roles that collagens play in atherosclerosis; regulating the infiltration and differentiation of smooth muscle cells and macrophages; controlling matrix remodeling through feedback signaling to proteinases; and influencing the development of atherosclerotic complications such as plaque rupture, aneurysm formation and calcification. Expanding our understanding of the pathways involved in cell-matrix interactions will provide new therapeutic targets and strategies for the diagnosis and treatment of atherosclerosis.

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Section: Leukocyte Collagen Receptorsmentioning

confidence: 68%

Collagens in the progression and complications of atherosclerosis

et al. 2009

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“…Over the past decade, different groups have identified several target genes downstream of DDR2 activation in various types of cells, including distinct MMPs, interlukin 6 (IL-6), and IL-12. (22,25,(27)(28)(29)(30)54,55) However, the detailed signaling pathways mediating DDR2 regulation of target-gene transcription remain ill-understood. Our study on DDR2 modulation of osteoblastic and chondroblastic gene expression enriches the target-gene list of DDR2.…”

Section: Discussionmentioning

confidence: 99%

An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation

Zhang

et al. 2010

Journal of Bone and Mineral Research

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Discoidin domain receptor 2 (DDR2) belongs to receptor tyrosine kinase (RTK) family and is activated by collagen binding. Although the bone defects in Ddr2 null mice have been reported for a decade, the molecular mechanism remains unclear. This study sought to investigate the function and detailed mechanism of DDR2 in osteogenic and chondrogenic differentiation. Herein we found that in preosteoblastic cells, DDR2 activation was enhanced by osteogenic induction but was not paralleled with the alteration of DDR2 expression. Under differentiated condition, downregulation of endogenous DDR2 through specific shRNA dramatically repressed osteoblastic marker gene expression and osteogenic differentiation. Enforced expression of constitutively activated DDR2 increased the expression of bone markers in both undifferentiated and differentiated osteoblasts. Importantly, molecular evidence showed that DDR2 regulated the transactivity of Runx2, a master transcription factor involved in skeletal development, by modulating its phosphorylation. Analysis of candidate protein kinases indicated that extracellular signal-regulated kinase (ERK) activation is responsive to DDR2 signaling and involved in DDR2 regulation of Runx2 phosphorylation and transcriptional activity. Notably, a gain-of-function mutant of Runx2 with enhanced ERK-independent phosphorylation rescued the impaired osteogenic phenotypes observed in Ddr2-silenced cells, whereas a Runx2 mutant devoid of phosphorylation regulation by ERK inhibited DDR2 induction of osteogenesis. In addition, DDR2 facilitated Runx2 transactivation and type X collagen expression in hypertrophic chondrocytes. Thus this study reveals for the first time that DDR2 plays an essential role in osteoblast and chondrocyte differentiation. The mechanism disclosure may provide therapeutic targets for human genetic disorders caused by DDR2 deficiency. ß

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“…22 Innate immunity or INF response may be stimulated by siRNA. 22,23 In this study, we measured serum INF-␥ levels after applying DDR2 siRNA. The serum INF-␥ levels were similar between siRNA-treated animal and control animals.…”

Section: Discussionmentioning

confidence: 99%

RNA Interference for Discoidin Domain Receptor 2 Attenuates Neointimal Formation in Balloon Injured Rat Carotid Artery

Shyu¹,

Wang

Kuan

et al. 2008

ATVB

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Objectives-Discoidin domain receptor 2 (DDR2) plays potential roles in the regulation of collagen turnover mediated by smooth muscle cells (SMCs) in atherosclerosis. Little is known about the function of DDR2 in vascular system. We investigated whether inhibition of DDR2 by small interfering RNA (siRNA) can reduce neointimal formation after arterial injury. Key Words: discoidin domain receptor 2 Ⅲ smooth muscle cell Ⅲ RNA interference Ⅲ vascular injury D evelopment of neointimal thickening is the major cause of atherosclerosis and restensois. Smooth muscle cells (SMCs) are the predominant cell types in the media of blood vessel walls and contribute to neointimal formation after arterial injury. After arterial injury, SMCs synthesize collagens, 1,2 which act as important signaling molecule regulating SMC responses to arterial repair. 3 Discoidin domain receptor 1 (DDR1) and DDR2 have recently emerged as nonintegrintype receptors for collagen. 4 DDR1 is mainly expressed in epithelial cells, whereas DDR2 is found in mesenchymal cells. 5 DDR1 and DDR2 play potential roles in the regulation of collagen turnover mediated by vascular smooth muscle cells (VSMCs) in obstructive diseases of blood vessel. 6 Both DDRs were found to be highly expressed by SMCs within the fibrous cap. 6 DDR1 has been found to play an important role in mediating intimal thickening after arterial injury 3 ; however, little is known about the function of DDR2 in the vascular system. We have previously demonstrated that stretching of VSMCs in vitro resulted in upregulation of DDR2 expression. 7 In this study we hypothesize that DDR2 plays an important role in vascular injury in vivo. Methods and Results-SMCsRNA interference mediated by small interfering RNA (siRNA) can knock down gene expression at a translational level through interactions with its target messenger RNA 8 and shows great promise for therapeutic applications. 9 Here, we applied RNA interference to study the role of DDR2 in atherosclerosis in vitro and in vivo. Methods siRNA DesignedThe siRNA duplexes targeting the mouse DDR2 mRNA (GenBank accession no. NM_022563) were designed. For the initial screening of the most effective siRNA duplexes, the 21-nucleotide RNAs were synthesized by in vitro transcription (Dharmacon Inc). Further experiments were performed with the most efficient siRNA-duplex. The most efficient siRNA-duplex does have 1 mismatch to the rat sequence NM_031764. The mismatch 1 is located at the 6th base of the duplex, U for mouse and C for rat. No significant similarities to any genes other than DDR2 were found using BLAST against the rat reference sequence database. Vascular Smooth Muscle Cell CulturePrimary cultures of VSMCs were grown by the explant technique from the thoracic aorta of 220-to 260-g male Wistar rats, as Original

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Discoidin domain receptor 2 is involved in the activation of bone marrow-derived dendritic cells caused by type I collagen

Cited by 32 publications

References 33 publications

Collagens in the progression and complications of atherosclerosis

Collagens in the progression and complications of atherosclerosis

An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation

RNA Interference for Discoidin Domain Receptor 2 Attenuates Neointimal Formation in Balloon Injured Rat Carotid Artery

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