An Inducible Cartilage Oligomeric Matrix Protein Mouse Model Recapitulates Human Pseudoachondroplasia Phenotype

Posey, Karen L.; Veerisetty, Alka C.; Liu, Pieman; Wang, Huiqiu R.; Poindexter, Brian J.; Bick, Roger J.; Alcorn, Joseph L.; Hecht, Jacqueline

doi:10.2353/ajpath.2009.090184

Cited by 60 publications

(154 citation statements)

References 59 publications

(56 reference statements)

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“…[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. 20,21 By 3 weeks of age, all murine MT-COMP growth plate chondrocytes have mutant COMP in the ER, causing chronic ER stress, inflammation, oxidative stress, and DNA damage that drives the chondrocytes to necroptosis.…”

Section: Introductionmentioning

confidence: 83%

“…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%

“…28 C57BL/6 mice were used as controls because the WT-COMP mice showed no phenotypic differences in our previous studies. 19 …”

Section: Mt-comp and Mt-comp/comp -/-Micementioning

confidence: 99%

“…19 Briefly, the limbs were fixed in 95% v/v ethanol for immunostaining for human-specific COMP (Thermo Fisher Scientific, ab11056-rat, 1:100), YM1/eosinophil chemotactic factor-L protein (ECF-L; STEMCELL Technologies, 01404, 1:100), IL-16 (Santa Cruz Biotechnology, SC-7902, 1:100), Ki67 M19 (Santa Cruz, SC-7846 1:200), or Ionis ASO DNA backbone Ect3 antibody (Ionis Pharmaceuticals, proprietary, 1:20,000). Sections immunostained with Ionis ASO DNA backbone antibody were quenched (endogenous peroxide) with 3% hydrogen peroxide incubation for 10-15 min, followed by two rinses in PBS with tween (PBST) for 5 min each.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

“…(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).…”

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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: Introductionmentioning

confidence: 83%

“…28 C57BL/6 mice were used as controls because the WT-COMP mice showed no phenotypic differences in our previous studies. 19 …”

Section: Mt-comp and Mt-comp/comp -/-Micementioning

confidence: 99%

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

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Genetic Disorders of the Extracellular Matrix

Lamandé

Bateman

2019

The Anatomical Record

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Mutations in the genes for extracellular matrix (ECM) components cause a wide range of genetic connective tissues disorders throughout the body. The elucidation of mutations and their correlation with pathology has been instrumental in understanding the roles of many ECM components. The pathological consequences of ECM protein mutations depend on its tissue distribution, tissue function, and on the nature of the mutation. The prevalent paradigm for the molecular pathology has been that there are two global mechanisms. First, mutations that reduce the production of ECM proteins impair matrix integrity largely due to quantitative ECM defects. Second, mutations altering protein structure may reduce protein secretion but also introduce dominant negative effects in ECM formation, structure and/or stability. Recent studies show that endoplasmic reticulum (ER) stress, caused by mutant misfolded ECM proteins, makes a significant contribution to the pathophysiology. This suggests that targeting ER-stress may offer a new therapeutic strategy in a range of ECM disorders caused by protein misfolding mutations. Anat Rec,

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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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An Inducible Cartilage Oligomeric Matrix Protein Mouse Model Recapitulates Human Pseudoachondroplasia Phenotype

Cited by 60 publications

References 59 publications

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

Genetic Disorders of the Extracellular Matrix

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

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