Transgenic mice expressing D469Δ mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations

Schmitz, Markus; Niehoff, Anja; Miosge, Nicolai; Smyth, Neil; Paulsson, Mats; Zaucke, Frank

doi:10.1016/j.matbio.2007.08.001

Cited by 43 publications

(69 citation statements)

References 61 publications

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“…In these individuals and in cell culture models expressing selected mutant variants, the retention of misfolded COMP leads to coretention of other ECM components, including collagens (types II, IX and XI) (Hecht et al, 2005;Maddox et al, 1997;Vranka et al, 2001). Most of these mutations have been shown to induce improperly folded COMP that, along with its bound interaction partners, is not secreted (Coustry et al, 2012;Posey et al, 2009;Schmitz et al, 2006Schmitz et al, , 2008. It remains to be determined for each mutation individually whether the extent of co-retention is caused by different binding affinities to collagens or by a complete absence of functional COMP.…”

Section: Discussionmentioning

confidence: 99%

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

Schulz

Nüchel

Niehoff

et al. 2016

Journal of Cell Science

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Cartilage oligomeric matrix protein (COMP) is an abundant component in the extracellular matrix (ECM) of load-bearing tissues such as tendons and cartilage. It provides adaptor functions by bridging different ECM structures. We have previously shown that COMP is also a constitutive component of healthy human skin and is strongly induced in fibrosis. It binds directly and with high affinity to collagen I and to collagen XII that decorates the surface of collagen I fibrils. We demonstrate here that lack of COMP-collagen interaction in the extracellular space leads to changes in collagen fibril morphology and density, resulting in altered skin biomechanical properties. Surprisingly, COMP also fulfills an important intracellular function in assisting efficient secretion of collagens, which were retained in the endoplasmic reticulum of COMP-null fibroblasts. Accordingly, COMPnull mice showed severely attenuated fibrotic responses in skin. Collagen secretion was fully restored by introducing wild-type COMP. Hence, our work unravels a new, non-structural and intracellular function of the ECM protein COMP in controlling collagen secretion.

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Section: Discussionmentioning

confidence: 99%

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

Schulz

Nüchel

Niehoff

et al. 2016

Journal of Cell Science

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“…In contrast to patients with pseudoachondroplasia, transgenic mice expressing a moderate level of p.469delD COMP protein showed only a very mild dwarfism (Schmitz et al, 2008). When bred onto a COMP-deficient background, the dwarfism became more severe, which correlated with increased intracellular retention of mutant proteins and apoptosis in chondrocytes (Schmitz et al, 2008).…”

Section: Adaptation To Er Stress In Vivomentioning

confidence: 95%

“…When bred onto a COMP-deficient background, the dwarfism became more severe, which correlated with increased intracellular retention of mutant proteins and apoptosis in chondrocytes (Schmitz et al, 2008). The authors suggested that the wild-type COMP protein modulated the phenotype by facilitating the secretion of mutant COMP proteins as heteropentamers, whereas the mutant COMP protein alone could not form secretable homopentamers.…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

“…In cultured chondrocytes or transfected cells, a moderately severe mutation (p.469delD) in cartilage oligomeric matrix protein (COMP) (Briggs et al, 1995), which is associated with the disorder pseudoachondroplasia, causes reduced cell viability in a dosedependent manner. Affected cells retained other ECM proteins in the ER in addition to the mutant COMP protein, showed expansion of ER cisternae and induction of ER stress markers, and were unable to make a proper ECM (Dinser et al, 2002).In contrast to patients with pseudoachondroplasia, transgenic mice expressing a moderate level of p.469delD COMP protein showed only a very mild dwarfism (Schmitz et al, 2008). When bred onto a COMP-deficient background, the dwarfism became more severe, which correlated with increased intracellular retention of mutant proteins and apoptosis in chondrocytes (Schmitz et al, 2008).…”

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In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

Tsang

Chan

Bateman

et al. 2010

Journal of Cell Science

116

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SummaryDisturbances to the balance of protein synthesis, folding and secretion in the endoplasmic reticulum (ER) induce stress and thereby the ER stress signaling (ERSS) response, which alleviates this stress. In this Commentary, we review the emerging idea that ER stress caused by abnormal physiological conditions and/or mutations in genes that encode client proteins of the ER is a key factor underlying different developmental processes and the pathology of diverse diseases, including diabetes, neurodegeneration and skeletal dysplasias. Recent studies in mouse models indicate that the effect of ERSS in vivo and the nature of the cellular strategies induced to ameliorate pathological ER stress are crucial factors in determining cell fate and clinical disease features. Importantly, ERSS can affect cellular proliferation and the differentiation program; cells that survive the stress can become 'reprogrammed' or dysfunctional. These cellautonomous adaptation strategies can generate a spectrum of context-dependent cellular consequences, ranging from recovery to death. Secondary effects can include altered cell-extracellular-matrix interactions and non-cell-autonomous alteration of paracrine signaling, which contribute to the final phenotypic outcome. Recent reports showing that ER stress can be alleviated by chemical compounds suggest the potential for novel therapeutic approaches. (1) Physiological ER stress during development is mild and controllable. The cell can recover from and/or adapt to the protein-folding stress; it can also differentiate into a specialized cell type in a manner that depends on components of ERSS and appropriate developmental signals. (2) In severe pathological ER stress, ERSS is initially an adaptive response, but, if stress remains unresolved, perhaps because of continuous and/or cyclical expression of mutant protein, it can lead to interference with developmental signals and disruption of cellular gene expression patterns. The cell can then display altered proliferation and differentiation status, and become dysfunctional. (3) Under conditions of extreme stress, an apoptotic signal is triggered and becomes dominant, leading to cell death. This can occur through excessive production of reactive oxygen species (ROS) caused by enhanced protein-folding activity, which relates to levels of CHOP, GADD34 and ERO1 expression. Journal of Cell Science Attenuation of translationOne of the early responses to ER stress is the modulation of translation, a highly conserved adaptation mechanism (Yamasaki and Anderson, 2008). Phosphorylation of eukaryotic initiation factor 2 (eIF2) by PERK reduces protein translation and shifts the translation machinery to favor alternative modes of initiation, including selective translation of activating transcription factor 4 (ATF4) . Phosphorylated eIF2 also activates the conversion of microtubule-associated protein 1 light chain 3 (LC3-I), an essential protein for autophagy, to LC3-II and hence promotes autophagosome formation Kouroku et al., 2007), as well as t...

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“…Transgenic mouse models expressing mutant COMP demonstrate a mild PSACH phenotype (Pirog-Garcia et al 2007;Schmitz et al 2007;Posey et al 2008). In contrast, COMP knockout mice develop normally, suggesting that COMP may not be necessary or has a redundant function in cartilage formation, bone growth, and extracellular cartilage matrix (ECM) development (Svensson et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Ribozyme-mediated reduction of wild-type and mutant cartilage oligomeric matrix protein (COMP) mRNA and protein

Alcorn¹,

Merritt

Farach-Carson

et al. 2009

RNA

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Dominant-negative mutations in the homopentameric extracellular matrix glycoprotein cartilage oligomeric matrix protein (COMP) result in inappropriate intracellular retention of misfolded COMP in the rough endoplasmic reticulum of chondrocytes, causing chondrocyte cell death, which leads to two skeletal dysplasias: pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). COMP null mice show no adverse effects on normal bone development and growth, suggesting a possible therapy involving removal of COMP mRNA. The goal of this study was to assess the ability of a hammerhead ribozyme (Ribo56, designed against the D469del mutation) to reduce COMP mRNA expression. In COS7 cells transfected with plasmids that overexpress wild-type or mutant COMP mRNA and Ribo56, the ribozyme reduced overexpressed normal COMP mRNA by 46% and mutant COMP mRNA by 56% in a dose-dependent manner. Surprisingly, the use of recombinant adenoviruses to deliver wild-type or mutant COMP mRNA and Ribo56 simultaneously into COS7 cells proved problematic for the activity of the ribozyme to reduce COMP expression. However, in normal human costochondral cells (hCCCs) infected only with adenoviruses expressing Ribo56, expression of endogenous wild-type COMP mRNA was reduced in a dose-dependent manner by 50%. In chondrocytes that contain heterozygous COMP mutations (D469del, G427E and D511Y) that cause PSACH, Ribo56 was more effective at reducing COMP mRNA (up to 70%). These results indicate that Ribo56 is effective at reducing mutant and wild-type COMP levels in cells and suggests a possible mode of therapy to reduce the mutant protein load.

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Transgenic mice expressing D469Δ mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations

Cited by 43 publications

References 61 publications

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

Ribozyme-mediated reduction of wild-type and mutant cartilage oligomeric matrix protein (COMP) mRNA and protein

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