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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Cologne, Cologne, Germany.
authors.forename: Gergely
authors.initials: G
authors.lastname: Groma
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.forename: Ivan
authors.initials: I
authors.lastname: Grskovic
authors.forename: Anja
authors.initials: A
authors.lastname: Niehoff
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
authors.forename: Mats
authors.initials: M
authors.lastname: Paulsson
authors.forename: Frank
authors.initials: F
authors.lastname: Zaucke
mesh_terms: D053674:Aggrecans / Q000378:metabolism*; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism*; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D064235:Matrilin Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010641:Phenotype; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; C577546:Matn3 protein, mouse; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3