Effect of cartilage oligomeric matrix protein on mesenchymal chondrogenesis in vitro

Kipnes, J.R.; Carlberg, Alyssa L.; Loredo, Grace A.; Lawler, Jack; Tuan, Rocky S.; Hall, D.

doi:10.1016/s1063-4584(03)00055-4

Cited by 55 publications

(49 citation statements)

References 53 publications

(105 reference statements)

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“…Additional studies have indicated that COMP can inhibit cell proliferation while enhancing in vitro chondrogenesis (21). Finally, expression of COMP in the presence of BMP2 stimulation can lead to a late increase in apoptosis (21). This latter finding is consistent with the fact that the mutant COMP proteins in multiple epiphysial dysplasia and PSACH appear to mediate apoptosis of chondrocytes in cartilage in vivo (25)(26)(27).…”

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confidence: 68%

“…Cells-It has been previously demonstrated that expression of COMP, as either a wild type or mutant form, can affect the level of apoptosis both in vivo and in vitro (21,(25)(26)(27). To explore an effect of COMP on apoptosis, we began transient transfection experiments using a COMP expression plasmid in 293 cells.…”

Section: Comp Enhances Cell Survival In 293mentioning

confidence: 99%

“…In cartilage, COMP is expressed in both the developing and mature tissue (7,20,21). In adult cartilage, COMP has been shown to be located primarily in the interterritorial matrix between chondrocytes (22).…”

mentioning

confidence: 99%

“…However, it is not yet known whether COMP plays any role in maintaining the stability of cartilage. Additional studies have indicated that COMP can inhibit cell proliferation while enhancing in vitro chondrogenesis (21). Finally, expression of COMP in the presence of BMP2 stimulation can lead to a late increase in apoptosis (21).…”

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confidence: 99%

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Cartilage Oligomeric Matrix Protein Protects Cells against Death by Elevating Members of the IAP Family of Survival Proteins

Gagarina

Carlberg

Mouriès

et al. 2008

Journal of Biological Chemistry

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Cartilage oligomeric matrix protein (COMP) is a component of cartilage, synovium, ligament, and tendon, yet its normal function is largely unknown. To identify its function we have expressed it in 293 and HeLa cell lines and in primary human chondrocytes. We find that COMP protects these cells against death, either in the presence or absence of tumor necrosis factor ␣ and is able to block activation of caspase 3, a critical effector caspase. This effect appears to be mediated by the IAP (inhibitor of apoptosis protein) family of anti-apoptotic proteins because the levels of XIAP, survivin, cIAP1 and cIAP2 are significantly elevated in the COMP-expressing cells and down-regulation of survivin and XIAP protein levels by small interfering RNAs blocks the ability of COMP to enhance survival. The mRNAs for most of the IAP family members were not increased by COMP, indicating that a translational/post-translational mechanism was involved in their induction. However, in both HeLa cells and chondrocytes, COMP induced survivin mRNA by 5-fold. Thus survivin is the first gene identified to be up-regulated transcriptionally by COMP. The carboxyl-terminal half of the protein comprising the type 3 repeats and the RGD sequence (CaCTD domain) was sufficient to promote survival and to elevate the IAPs. Further, an RGD peptide was able to block the prosurvival effect of COMP and the induction of XIAP and survivin, indicating that survival is likely mediated through integrin signaling. These data point to a new role for COMP in protecting cells against death.

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confidence: 68%

Section: Comp Enhances Cell Survival In 293mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Cartilage Oligomeric Matrix Protein Protects Cells against Death by Elevating Members of the IAP Family of Survival Proteins

Gagarina

Carlberg

Mouriès

et al. 2008

Journal of Biological Chemistry

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“…COMP, the fifth member of the thrombospondin (TSP) gene family, is a multidomain homopentameric protein comprised of an N-terminal pentamerization domain, an epidermal growth factor (EGF)-like domain, a highly conserved type 3 (calcium-binding) repeat domain, and a C-terminal globular region (Fife and Brandt 1984;DiCesare et al 1994;Adams et al 1995;Smith et al 1997;Hecht et al 1998a;Carlson et al 2008). Recent work suggests that COMP is multifunctional and is involved in (1) regulation of collagen fiber assembly/diameter (Rosenberg et al 1998); (2) interaction with other ECM molecules (Holden et al 2001;Thur et al 2001;Mann et al 2004); (3) regulation of chondrocyte proliferation (Kipnes et al 2003;Xu et al 2007); (4) regulation of apoptosis (Duke et al 2003;Hashimoto et al 2003;Hecht et al 2004); and (5) enhancement of cellular attachment (Chen et al 2005).…”

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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Prenatal exposure to environmental factors and congenital limb defects

Alexander

Clark

Tuan

2016

Birth Defects Research Pt C

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Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact. This is limited by the insufficiencies of currently available models. Specifically, in vivo approaches using guideline animal models have inherently deficient predictive power due to genomic and anatomic differences that complicate mechanistic comparisons. On the other hand, in vitro two-dimensional (2D) cell cultures, while accessible for cellular and molecular experimentation, do not reflect the three-dimensional (3D) morphogenetic events in vivo nor systemic influences. More robust and accessible models based on human cells that accurately replicate specific processes of embryonic limb development are needed to enhance limb teratogenesis prediction and to permit mechanistic analysis of the adverse outcome pathways. Recent advances in elucidating mechanisms of normal development will aid in the development of process-specific 3D cell cultures within specialized bioreactors to support multicellular microtissues or organoid constructs that will lead to increased understanding of cell functions, cell-to-cell signaling, pathway networks, and mechanisms of toxicity. The promise is prompting researchers to look to such 3D microphysiological systems to help sort out complex and often subtle interactions relevant to developmental malformations that would not be evident by standard 2D cell culture testing. Birth Defects Research (Part C) 108:243-273, 2016. © 2016 Wiley Periodicals, Inc.

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Effect of cartilage oligomeric matrix protein on mesenchymal chondrogenesis in vitro

Abstract: These data suggest that COMP and BMP-2 signaling converge to regulate the fate of these cells in vitro by affecting both early and late stages of chondrogenesis.

Cited by 55 publications

References 53 publications

Cartilage Oligomeric Matrix Protein Protects Cells against Death by Elevating Members of the IAP Family of Survival Proteins

Cartilage Oligomeric Matrix Protein Protects Cells against Death by Elevating Members of the IAP Family of Survival Proteins

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

Prenatal exposure to environmental factors and congenital limb defects

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