title: Pseudoachondroplasia/COMP - translating from the bench to the bedside.
abstract: Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Karen.Posey@uth.tmc.edu.
authors.forename: Karen LaShea
authors.initials: KL
authors.lastname: Posey
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Alcorn
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA; Shriners Hospital for Children, Houston, TX 77030, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
mesh_terms: D000130:Achondroplasia / Q000235:genetics*; D000818:Animals; D064236:Cartilage Oligomeric Matrix Protein / Q000235:genetics* / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D064236:Cartilage Oligomeric Matrix Protein
keywords: Chondrocyte; Growth plate and COMP; Mouse model; PSACH; Pseudoachondroplasia; TSP-5