Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double-deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

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Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double-deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation. / Groma, Gergely; Xin, Wei; Grskovic, Ivan; Niehoff, Anja; Brachvogel, Bent; Paulsson, Mats; Zaucke, Frank.

in: Arthritis and rheumatism, Jahrgang 64, Nr. 8, 01.08.2012, S. 2644-2654.

Publikationen: Beitrag in FachzeitschriftZeitschriftenaufsätzeForschungBegutachtung

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@article{1c388f1fb74d47e6853f72c899664918,
title = "Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double-deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation",
abstract = "OBJECTIVE: Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other.METHODS: To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development.RESULTS: At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)-deficient mice.CONCLUSION: We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 double-deficient and MMP-13-deficient mice.",
keywords = "Aggrecans, Aging, Animals, Animals, Newborn, Bone Density, Bone and Bones, Cartilage Oligomeric Matrix Protein, Extracellular Matrix Proteins, Glycoproteins, Matrilin Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Animal, Phenotype, Tissue Inhibitor of Metalloproteinase-3",
author = "Gergely Groma and Wei Xin and Ivan Grskovic and Anja Niehoff and Bent Brachvogel and Mats Paulsson and Frank Zaucke",
note = "Copyright {\textcopyright} 2012 by the American College of Rheumatology.",
year = "2012",
month = aug,
day = "1",
doi = "10.1002/art.34435",
language = "English",
volume = "64",
pages = "2644--2654",
journal = "Arthritis and rheumatism",
issn = "1529-0131",
publisher = "John Wiley and Sons Inc.",
number = "8",

}

RIS

TY - JOUR

T1 - Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double-deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

AU - Groma, Gergely

AU - Xin, Wei

AU - Grskovic, Ivan

AU - Niehoff, Anja

AU - Brachvogel, Bent

AU - Paulsson, Mats

AU - Zaucke, Frank

N1 - Copyright © 2012 by the American College of Rheumatology.

PY - 2012/8/1

Y1 - 2012/8/1

N2 - OBJECTIVE: Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other.METHODS: To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development.RESULTS: At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)-deficient mice.CONCLUSION: We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 double-deficient and MMP-13-deficient mice.

AB - OBJECTIVE: Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other.METHODS: To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development.RESULTS: At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)-deficient mice.CONCLUSION: We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 double-deficient and MMP-13-deficient mice.

KW - Aggrecans

KW - Aging

KW - Animals

KW - Animals, Newborn

KW - Bone Density

KW - Bone and Bones

KW - Cartilage Oligomeric Matrix Protein

KW - Extracellular Matrix Proteins

KW - Glycoproteins

KW - Matrilin Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Models, Animal

KW - Phenotype

KW - Tissue Inhibitor of Metalloproteinase-3

U2 - 10.1002/art.34435

DO - 10.1002/art.34435

M3 - Journal articles

C2 - 22378539

VL - 64

SP - 2644

EP - 2654

JO - Arthritis and rheumatism

JF - Arthritis and rheumatism

SN - 1529-0131

IS - 8

ER -

ID: 21809