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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.



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.


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.


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.


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.


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    Arthritis and rheumatism 64:8 2012 Aug pg 2644-54


    Animals, Newborn
    Bone Density
    Bone and Bones
    Cartilage Oligomeric Matrix Protein
    Extracellular Matrix Proteins
    Matrilin Proteins
    Mice, Inbred C57BL
    Mice, Knockout
    Models, Animal
    Tissue Inhibitor of Metalloproteinase-3

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't



    PubMed ID