Chop (Ddit3) Is Essential for D469del-COMP Retention and Cell Death in Chondrocytes in an Inducible Transgenic Mouse Model of Pseudoachondroplasia

Posey, Karen L.; Coustry, Françoise; Veerisetty, Alka C.; Liu, Peiman; Alcorn, Joseph L.; Hecht, Jacqueline

doi:10.1016/j.ajpath.2011.10.035

Cited by 37 publications

(142 citation statements)

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“…To circumvent this problem, we generated the mutant (MT)-COMP mouse with the common D469del PSACH mutation that expresses human MT-COMP in chondrocytes in the presence of the inducing agent doxycycline (DOX). [16][17][18][19] MT-COMP mice recapitulate the PSACH clinical findings of reduced growth and cellular abnormalities, including massive intracellular retention of COMP and other ECM proteins. 16,17,19 The intracellular retention of MT-COMP activates the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm of the unfolded protein response, which is the cellular response mechanism that is activated by misfolded proteins.…”

Section: Introductionmentioning

confidence: 83%

“…(B-D) Intracellular retention of MT-COMP is present in untreated MT-COMP (MT-COMP/COMP +/+ ) mice, as shown previously. 16,17,19 (E-J) There is marked decreased MT-COMP intracellular retention with ASO1 treatment. ASO2 did not substantially reduce MT-COMP retention (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…[16][17][18][19] COMP pentamers often include both wild-type and misfolded mutant subunits, with an estimated 97% of the protein stalling and getting trapped in the ER. 21,30 This suggests that, in the presence of MT-COMP, wild-type (WT) COMP subunits may contribute to the cytotoxic intracellular retention.…”

Section: Loss Of Endogenous Mouse Comp Decreases Mt-comp Chondrocyte mentioning

confidence: 99%

“…21,30,47,48 Misfolded COMP causes massive retention of COMP and other extracellular proteins in the ER, which forms an inappropriate intracellular matrix eliciting oxidative and inflammatory stress, which is cytotoxic to the chondrocyte. 3,5,14,[16][17][18]43,49 We have shown that treatments that target inflammation (aspirin), oxidative stress (resveratrol), and ER stress (absence of C/EBP homologous protein [CHOP] in MT-COMP mice, valproate) reduce the MT-COMP chondrocyte pathology. 16,17 Moreover, we have shown that shRNAs in vitro reduce COMP expression, ER stress, and intracellular retention.…”

mentioning

confidence: 99%

“…3,5,14,[16][17][18]43,49 We have shown that treatments that target inflammation (aspirin), oxidative stress (resveratrol), and ER stress (absence of C/EBP homologous protein [CHOP] in MT-COMP mice, valproate) reduce the MT-COMP chondrocyte pathology. 16,17 Moreover, we have shown that shRNAs in vitro reduce COMP expression, ER stress, and intracellular retention. 29 Therefore, treatment(s) aimed at the origin of the pathology should have a therapeutic benefit.…”

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confidence: 99%

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Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

et al. 2017

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Mutations in cartilage oligomeric matrix protein cause pseudoachondroplasia, a severe disproportionate short stature disorder. Mutant cartilage oligomeric matrix protein produces massive intracellular retention of cartilage oligomeric matrix protein, stimulating ER and oxidative stresses and inflammation, culminating in post-natal loss of growth plate chondrocytes, which compromises linear bone growth. Treatments for pseudoachondroplasia are limited because cartilage is relatively avascular and considered inaccessible. Here we report successful delivery and treatment using antisense oligonucleotide technology in our transgenic pseudoachondroplasia mouse model. We demonstrate delivery of human cartilage oligomeric matrix protein-specific antisense oligonucleotides to cartilage and reduction of cartilage oligomeric matrix protein expression, which largely alleviates pseudoachondroplasia growth plate chondrocyte pathology. One antisense oligonucleotide reduced steady-state levels of cartilage oligomeric matrix protein mRNA and dampened intracellular retention of mutant cartilage oligomeric matrix protein, leading to a reduction of inflammatory markers and cell death and partial restoration of proliferation. This novel and exciting work demonstrates that antisense-based therapy is a viable approach for treating pseudoachondroplasia and other human cartilage disorders. INTRODUCTIONTreatments of skeletal dysplasia/dwarfing conditions, including pseudoachondroplasia (PSACH), are few and fraught with problems because of the inaccessibility of chondrocytes within the cartilage matrix and the relative avascular nature of the cartilage environment. PSACH is clinically characterized by disproportionate short stature, rhizomelic shortening of the long bones, brachydactyly, and extreme joint laxity. 1,2 Joint pain in childhood and osteoarthritis (OA) in early adulthood are the most debilitating features of PSACH; only symptomatic treatments are available and have limited efficacy. 2,3 The diagnosis is made between 2-3 years of age when linear growth slows and a waddling gait develops. 1,2 Because the diagnosis, in most cases, is made post-natally, treatments aimed at resolving the pathology will have to be started immediately after diagnosis.PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric extracellular matrix (ECM) glycoprotein abundant in musculoskeletal tissues. 4,5 Functionally, COMP facilitates type II collagen fibril assembly, enhances chondrocyte attachment in vitro, and interacts with other ECM proteins, including type II and IX collagens, matrilin 3, and SPARC. [6][7][8][9][10][11][12] In contrast, mutations in COMP cause misfolding of the protein, preventing export from the chondrocyte and resulting in massive retention within the endoplasmic reticulum (ER). 10,[13][14][15] Although this finding has long been appreciated, there was little understanding of the pathologic molecular mechanisms, which are critical to develop mechanism-driven therapeutics. To circumvent this proble...

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Loss Of Endogenous Mouse Comp Decreases Mt-comp Chondrocyte mentioning

confidence: 99%

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Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

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Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues

Dennis

Greenhalgh‐Maychell

Briggs

2020

Developmental Dynamics

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For the vast majority of the 6000 known rare disease the pathogenic mechanisms are poorly defined and there is little treatment, leading to poor quality of life and high healthcare costs. Genetic skeletal diseases (skeletal dysplasias) are archetypal examples of rare diseases that are chronically debilitating, often life-threatening and for which no treatments are currently available. There are more than 450 unique phenotypes that, although individually rare, have an overall prevalence of at least 1 per 4000 children. Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous disorder characterized by disproportionate short stature, joint pain, and early-onset osteoarthritis. MED is caused by mutations in the genes encoding important cartilage extracellular matrix proteins, enzymes, and transporter proteins. Recently, through the use of various cell and mouse models, disease mechanisms underlying this diverse phenotypic spectrum are starting to be elucidated. For example, ER stress induced as a consequence of retained misfolded mutant proteins has emerged as a unifying disease mechanisms for several forms of MED in particular and skeletal dysplasia in general. Moreover, targeting ER stress through drug repurposing has become an attractive therapeutic avenue.

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Mechanisms and models of endoplasmic reticulum stress in chondrodysplasia

Patterson

Dealy

2014

Developmental Dynamics

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Chondrodysplasias are a group of genetic disorders that affect the development and growth of cartilage. These disorders can result in extreme short stature, craniofacial defects, joint malformation, and early osteoarthritis; severely impacting quality of life for affected individuals. Many chondrodysplasias are caused by mutations in genes encoding cartilage extracellular matrix (ECM) proteins. These mutations typically result in synthesis of abnormal proteins that are improperly folded, and hence inappropriately retained within the endoplasmic reticulum (ER) of the cell, activating ER stress and the unfolded protein response (UPR), an adaptive cellular response to minimize production of the mutant protein and/or to enhance protein folding, degradation or export. If prolonged, activation of the UPR causes apoptotic cell death. Many human disorders have an underlying mechanism in UPR activation, and targeting ER stress pathways is showing promise for development of therapeutics for these conditions. Understanding and modeling the UPR in chondrodysplasia will be essential to advance such targeted approaches for the benefit of chondrodysplasia patients. The focus of this review is to compare the mechanistic sequelae of ECM protein mutations in chondrodysplasia that may cause chondrocyte ER stress and UPR activation, and to present current and future directions in chondrodysplasia disease modeling and therapeutic intervention. Developmental Dynamics 243:875-893,

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Chop (Ddit3) Is Essential for D469del-COMP Retention and Cell Death in Chondrocytes in an Inducible Transgenic Mouse Model of Pseudoachondroplasia

Cited by 37 publications

References 60 publications

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues

Mechanisms and models of endoplasmic reticulum stress in chondrodysplasia

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