Retention of cartilage oligomeric matrix protein (COMP) and cell death in redifferentiated pseudoachondroplasia chondrocytes

Hecht, Jacqueline; Montufar-Solis, Dina; Decker, Glen; Lawler, Jack; Daniels, Karla J.; Duke, P. J.

doi:10.1016/s0945-053x(98)90113-5

Cited by 89 publications

(99 citation statements)

References 16 publications

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“…In addition, such cells expressing mutated COMP exhibited marked apoptosis at higher frequency than cells expressing wild-type COMP (Figure 7). These new findings were compatible with the in vitro finding of reduced survival of cells obtained from PSACH patients 55 and with the in vivo observation of narrowed and irregular columns in the proliferating or hypertrophic zone and reduced numbers of chondrocytes in the growth plates of PSACH patients. 56,57 Since the present experiments were mainly performed with cultured COS7 cells, we could not simply extend our conclusion to in vivo effects of the mutation.…”

Section: Discussionsupporting

confidence: 89%

Mutation (D472Y) in the Type 3 Repeat Domain of Cartilage Oligomeric Matrix Protein Affects Its Early Vesicle Trafficking in Endoplasmic Reticulum and Induces Apoptosis

Hashimoto

Tomiyama

Yamano

et al. 2003

The American Journal of Pathology

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Cartilage oligomeric matrix protein (COMP) is a large pentameric extracellular glycoprotein found in cartilage, tendon, and synovium, and plays structural roles in cartilage as the fifth member of the thrombospondin family. Familial mutations in type 3 repeats of COMP are known to cause pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). Although such mutations induce enlarged rough endoplasmic reticulum (rER) as a morphological change, the metabolic trafficking of mutated COMP remains unclear. In transfected COS7 cells, wild-type COMP was rapidly secreted into culture medium, while the great majority of COMP with the type 3 repeats mutation (D472Y) remained in the cells and a small portion of mutated COMP was secreted. This finding was followed up with a confocal study with an antibody specific to COMP, which demonstrated mutated COMP tightly associated with abnormally enlarged rER. Phosphorylated eIF2␣, an ER stress protein, was expressed as a pathological reaction in virtually all COS7 cells expressing mutated but not wild-type COMP. Moreover, COS7 cells expressing mutated COMP exhibited significantly more apoptotic reaction than those expressing wild-type COMP. Pathological accumulation of COMP in rER and apoptosis in COS7 cells that were induced by the mutation (D472Y) in COMP imply that COMP mutations play a role in the pathogenesis of PSACH. (Am J

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Section: Discussionsupporting

confidence: 89%

Mutation (D472Y) in the Type 3 Repeat Domain of Cartilage Oligomeric Matrix Protein Affects Its Early Vesicle Trafficking in Endoplasmic Reticulum and Induces Apoptosis

Hashimoto

Tomiyama

Yamano

et al. 2003

The American Journal of Pathology

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“…4). One proposed mechanism by which these mutations cause disease is accumulation of unstable protein intracellularly (47)(48)(49). The E3CaG2 expression strategy, which allows production of large amounts of functional protein at 27°C, and knowledge of the sequential disulfide connectivity of the region should facilitate well controlled studies of the effects of mutations inside and outside the Ca 2ϩ -binding repeats on protein structure and function at physiological temperatures.…”

Section: Discussionmentioning

confidence: 99%

Disulfide Connectivity of Recombinant C-terminal Region of Human Thrombospondin 2

Misenheimer

Hahr

Harms

et al. 2001

Journal of Biological Chemistry

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The thrombospondin (TSP) family of extracellular glycoproteins consists of five members in vertebrates, TSP1 to -4 and TSP5/cartilage oligomeric matrix protein, and a single member in Drosophila. TSPs are modular multimeric proteins. The C-terminal end of a monomer consists of 3-6 EGF-like modules; seven tandem 23-, 36-, or 38-residue aspartate-rich, Ca 2؉ -binding repeats; and an ϳ230-residue C-terminal sequence. The Ca 2؉ -binding repeats and C-terminal sequence are spaced almost exactly the same in different TSPs and share many blocks of identical residues. We studied the C-terminal portion of human TSP2 from the third EGF-like module through the end of the protein (E3CaG2). E3CaG2, CaG2 lacking the EGF module, and Ca2 composed of only the Ca 2؉ -binding repeats were expressed using recombinant baculoviruses and purified from conditioned media of insect cells. As previously described for intact TSP1, E3CaG2 bound Ca 2؉ in a cooperative manner as assessed by equilibrium dialysis, and its circular dichroism spectrum was sensitive to the presence of Ca 2؉ . Mass spectrometry of the recombinant proteins digested with endoproteinase Asp-N revealed that disulfide pairing of the 18 cysteines in the Ca 2؉ -binding repeats and C-terminal sequence is sequential, i.e. a 1-2, 3-4, 5-6, etc., pattern.

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“…Retention of COMP is gradual and requires or is at least enhanced by expression of other extracellular matrix proteins in the rER of differentiated chondrocytes (36,37). This suggests the possibility of specific interactions between mutated COMP and other extracellular proteins that are being processed in the rER.…”

Section: Selection Of Recombinant Proteins-thementioning

confidence: 99%

Disease-causing Mutations in Cartilage Oligomeric Matrix Protein Cause an Unstructured Ca2+ Binding Domain

Kleerekoper¹,

Hecht²,

Putkey³

2002

Journal of Biological Chemistry

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Retention of cartilage oligomeric matrix protein (COMP) and cell death in redifferentiated pseudoachondroplasia chondrocytes

Cited by 89 publications

References 16 publications

Mutation (D472Y) in the Type 3 Repeat Domain of Cartilage Oligomeric Matrix Protein Affects Its Early Vesicle Trafficking in Endoplasmic Reticulum and Induces Apoptosis

Mutation (D472Y) in the Type 3 Repeat Domain of Cartilage Oligomeric Matrix Protein Affects Its Early Vesicle Trafficking in Endoplasmic Reticulum and Induces Apoptosis

Disulfide Connectivity of Recombinant C-terminal Region of Human Thrombospondin 2

Disease-causing Mutations in Cartilage Oligomeric Matrix Protein Cause an Unstructured Ca2+ Binding Domain

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