Chondrocyte cell death and intracellular distribution of COMP and type IX collagen in the pseudoachondroplasia growth plate

Authors

  • Jacqueline T. Hecht,

    Corresponding author
    1. Department of Pediatrics, University of Texas Medical School at Houston, 6431 Fannin St. MSB 3.136, Houston, TX 77030, USA Shriners Hospital for Children, Houston, USA
    2. Division of Genetics and Genomic Biology, The Research Institute, University of Toronto, The Hospital for Sick Children, Toronto, Canada
    Current affiliation:
    1. Department of Pediatrics, University of Texas-Houston Medical School, 6431 Fannin St. MSB 3.136, Houston, TX 77030, USA
    • Department of Pediatrics, University of Texas-Houston Medical School, 6431 Fannin St. MSB 3.136, Houston, TX 77030, USA. Tel.: +1-713-500-5764; fax: +1-713-500-5689
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  • Outi Makitie,

    1. Department of Orthodontics, University of Texas Dental Branch at Houston, Houston, USA
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  • Elizabeth Hayes,

    1. Department of Pediatrics, University of Texas Medical School at Houston, 6431 Fannin St. MSB 3.136, Houston, TX 77030, USA Shriners Hospital for Children, Houston, USA
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  • Richard Haynes,

    1. Division of Genetics and Genomic Biology, The Research Institute, University of Toronto, The Hospital for Sick Children, Toronto, Canada
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  • Miki Susic,

    1. Department of Orthodontics, University of Texas Dental Branch at Houston, Houston, USA
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  • Dina Montufar-Solis,

    1. Department of Orthodontics, University of Texas Dental Branch at Houston. Houston, USA
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  • P. Jackie Duke,

    1. Department of Orthodontics, University of Texas Dental Branch at Houston. Houston, USA
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  • William G. Cole

    1. Department of Orthodontics, University of Texas Dental Branch at Houston, Houston, USA
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Abstract

Cartilage oligomeric matrix protein (COMP) is a large extracellular matrix protein expressed in cartilage, ligament and tendon. Mutations in the COMP gene cause two dominantly inherited skeletal dysplasias, pseudoachondroplasia (PSACH) and Multiple Epiphyseal Dysplasia (MED/EDM1). We report on a novel point mutation D511Y in the seventh calcium-binding repeat of the COMP gene and the resulting iliac crest growth plate pathology. The PSACH iliac crest growth plate is comprised of a large region of resting chondrocytes above a narrow region composed of clusters of disorganized proliferative and hypertrophic chondrocytes. Chondrocytes in all zones show massive intracellular retention of COMP and the surrounding extracellular matrix is deficient in COMP. Moreover, the 511Y COMP mutation selectively affects type IX collagen as little is found in the growth plate matrix whereas type II collagen and aggrecan are abundant in the matrix. Chondrocyte remnants are observed in the chondrocyte clusters and dead cells are found throughout the growth plate. Apoptosis studies demonstrate an unusual pattern of TUNEL staining in the PSACH chondrocytes compared to the control growth plate. These in vivo findings support our previous observation that retention of COMP leads to chondrocyte death. These results also add to the increasing evidence that PSACH and EDM1 are rER storage diseases and that impaired linear growth and joint erosion are caused by the disruptive effect of massive amounts of COMP within the chondrocytes. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

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