Overexpression of Human Matrix Metalloproteinase-12 Enhances the Development of Inflammatory Arthritis in Transgenic Rabbits

Wang, Xiaofei; Liang, Jingyan; Koike, Tomonari; Sun, Huijun; Ichikawa, Tomonaga; Kitajima, Shuji; Morimoto, Masatoshi; Shikama, Hisataka; Watanabe, Teruo; Sasaguri, Yasuyuki; Fan, Jianglin

doi:10.1016/s0002-9440(10)63395-0

Cited by 82 publications

(65 citation statements)

References 34 publications

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“…These results demonstrate that an increased proteolytic activity of MMP-12 magnifies the degradation of the articular connective tissue and cartilage, thus playing a critical role in the development of an inflammatory joint disease (Wang et al, 2004c). Association of MMP-12 genotype with functional disability in rheumatoid arthritis patients was further demonstrated (Ye et al, 2007).…”

Section: Spinal Cord Injury (Sci)mentioning

confidence: 60%

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Sbardella

Fasciglione

Gioia

et al. 2012

Molecular Aspects of Medicine

208

212

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a b s t r a c tHuman matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn 2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes.

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Section: Spinal Cord Injury (Sci)mentioning

confidence: 60%

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Sbardella

Fasciglione

Gioia

et al. 2012

Molecular Aspects of Medicine

208

212

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“…Total RNA was reverse-transcriptase into cDNA by using Invitrogen reverse transcription reagents and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) (DNA Engine Option; MJ Research, Tokyo, Japan) was performed using a DyNAmo SYBR Green qPCR kit (Finnzymes) according to the manufacturer's instructions. 19 The specific primer for hVEGF was: 5 0 -GGC AGA ATC ATC ACG AAG-3 0 and 5 0 -CAG GAT GGC TTG AAG ATG-3 0 .…”

Section: Generation Of Tg Rabbitsmentioning

confidence: 99%

“…Rabbits were selected for this undertaking because of their usefulness in the study of atherosclerosis, 17 diabetes mellitus 18 and arthritis, 19 and also because our laboratory has been using Tg rabbits to investigate these diseases. In addition, the large size of the eyeballs of rabbits may facilitate retinal studies, such as studies of diabetic retinopathy.…”

mentioning

confidence: 99%

Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: a new model for Kasabach–Merritt syndrome

Kitajima

Liu

Morimoto

et al. 2005

Laboratory Investigation

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Clinical studies have provided ample evidence that high (either systemic or local) levels of vascular endothelial growth factor (VEGF) are associated with several pathophysiological disorders, including hemangiomas. To investigate whether elevated VEGF expression could directly affect these disorders, we created a transgenic (Tg) rabbit model with increased hepatic expression of the human VEGF 165 transgene under the control of the human a-antitrypsin promoter. Tg rabbits exhibited marked hepatomegaly, with livers 2.5-fold heavier than those of control rabbits. Histological analysis revealed that the livers of Tg rabbits showed prominent dilation of the sinusoids and formed various-sized blood vessel networks, a feature of diffuse hemangiomas. Immunohistochemical staining revealed that the hepatocytes produced VEGF 165 , whereas plasma VEGF 165 was not detected. Furthermore, Tg rabbits suffered from hemolytic anemia, thrombocytopenia and splenomegaly, which was associated with marked extramedullary hematopoiesis. The manifestations of Tg rabbits mimic many of the features of hemangiomatous disorders in humans such as the Kasabach-Merritt syndrome, and therefore this model may be potentially useful for the study of the pathogenesis and complications of hemangiomas as well as the investigation of angiogenesis inhibitors.

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“…MMP-12 has emerged as a drug target for atherosclerosis because specific inhibition of it is expected to stabilize atherosclerotic plaques and prevent ruptures that precipitate heart attack and stroke (23,25,26). This protease also exacerbates inflammatory arthritis (27) where collagenolysis is well known. The active form of MMP-12 (also called macrophage metalloelastase) observed in situ consists of its catalytic domain apparently after autolytic loss of the C-terminal hemopexin domain (28).…”

mentioning

confidence: 99%

MMP-12 Catalytic Domain Recognizes Triple Helical Peptide Models of Collagen V with Exosites and High Activity

Bhaskaran

Palmier

Lauer‐Fields

et al. 2008

Journal of Biological Chemistry

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Collagens are principal constituents of connective tissues. They are hydrolyzed during development, wound repair, and remodeling of the extracellular matrix. Dysregulated collagenolysis is active in inflammatory diseases such as atherosclerosis, cancer, rheumatoid arthritis, periodontitis, and liver and kidney pathologies. Matrix metalloproteinases (MMPs) 3 play key roles in these processes (1-3). Mutagenesis has established the importance of the V-B loop (joining ␤-strand V and helix B) in collagenolysis by MMP-1 (4). Residues at the C-terminal end of this loop in MMP-8 were also implicated in collagenolysis (5) and triple helical peptidase activity (6).Binding of an inactivated MMP-1 to an intact collagen fibril likely unwinds the triple helix at the cleavage site to provide access for an active MMP-1 catalytic domain to hydrolyze individual chains (7). The direction of collagen triple helices at the active site is unknown, but the orientation can be hypothesized to be the same as in linear peptide substrates that run antiparallel to ␤-strand IV (8, 9). Single chain peptides from the ␣1 chain of type I/III collagens were soaked into crystals of MMP-12 and MMP-8 catalytic domains, and snapshots of bound hydrolysis products were obtained (8).However, neither crystallography nor NMR data representative of interactions with collagen have been reported because of technical limitations. More generally, structural studies of complexes of enzymes with their substrates have been rare presumably because of catalytic turnover and affinities lower than those for transition state analogues. Several biologically active, self-assembling triple helical peptide (THP) mimics of collagens have been developed. These THPs have facilitated numerous biochemical and cell biological studies otherwise infeasible with insoluble, intact collagen fibrils. THPs are successful in reproducing the cleavage sites of MMPs in collagens I, II, III, V, and XI and in reproducing rate dependences on intact triple helical structure (10, 11). Fluorogenic labeling of THPs has facilitated quantitative comparisons of the triple helical peptidase activities of a variety of MMPs in solution and in cell culture assay (6,11,12). The affinities of MMP catalytic domains for triple helices range from 1 to 80 M (6, 11-13). Collagenolysis involves several MMP functions that include initial nonspecific binding and orientation of collagen fibrils (14, 15), manipulation of collagen fibrils with the C-terminal hemopexin domain (16) and catalytic domain (7), unwinding of triple helices within fibrils, and ensuing hydrolysis of single chains from the melted triple helix (7). THPs are not suitable for modeling the initial binding, orientation, and manipulation of full-length collagen assembled into large, insoluble fibrils (6, 11). They are too small to participate in these higher order events (7). Nonetheless THPs have proven themselves to be outstanding substrates for detailed characterization of the triple helical peptidase activities of MMPs and other metalloprotein...

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Overexpression of Human Matrix Metalloproteinase-12 Enhances the Development of Inflammatory Arthritis in Transgenic Rabbits

Cited by 82 publications

References 34 publications

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: a new model for Kasabach–Merritt syndrome

MMP-12 Catalytic Domain Recognizes Triple Helical Peptide Models of Collagen V with Exosites and High Activity

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