title: In vivo inhibition of osteoblastic metalloproteinases leads to increased trabecular bone mass.
abstract: Mice specifically overexpressing TIMP-1 in osteoblasts have been generated to investigate the role of MMPs in bone in vivo. These mice displayed increased trabecular bone volume and decreased bone turnover. This model provides evidence of the role played by the MMPs in bone remodeling and balance.
  
  
  BACKGROUND
  Although it has been suggested that the matrix metalloproteinases (MMPs) may play a role in initiating the bone resorption process in vitro, there is no evidence that they play any role in in vivo bone maintenance.
  
  
  METHODS
  We used an artificial promoter specifically driving cells of the osteoblastic lineage to overexpress the tissue inhibitor of MMPs (TIMP-1) cDNA in mice. Densitometric analysis, using DXA and pQCT, and static and dynamic histomorphometry were used to evaluate the bone phenotype both in male and female transgenic mice. We evaluated osteoblastic differentiation using a primary osteoblast culture and osteoclast activity using an ex vivo organ culture.
  
  
  CONCLUSIONS
  We showed that at 1 and 2.5 months of age, only the female mice exhibited a bone phenotype. These mice displayed specific increases in the BMD and bone volume of trabecular bone. This increase was accompanied by decreased trabecular separation, suggesting a decrease in bone resorption. Using an ex vivo resorption assay, we demonstrated that parathyroid hormone (PTH)-stimulated bone resorption was reduced in these mice. Evaluation of the bone histomorphometric dynamic parameters showed that the mineralizing surfaces and bone formation rate were both reduced. There was no change in the mineralization lag time or number of osteocyte lacunae. Using primary osteoblast culture and molecular analysis, we showed that the differentiation and function of osteoblasts from transgenic mice were normal, but that the ex vivo formation of mineralized nodules was delayed. This model is the first to show that in vivo MMPs play a role in bone remodeling and bone balance. Moreover, our data suggest that MMP activity could be involved in the hormonal regulation of bone resorption by osteoblasts.
authors.affiliation: INSERM U349, Hôpital Lariboisière, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Geoffroy
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty-Morieux
authors.forename: Nathalie
authors.initials: N
authors.lastname: Le Goupil
authors.forename: Phillippe
authors.initials: P
authors.lastname: Clement-Lacroix
authors.forename: Catherine
authors.initials: C
authors.lastname: Terraz
authors.forename: Monique
authors.initials: M
authors.lastname: Frain
authors.forename: Sophie
authors.initials: S
authors.lastname: Roux
authors.forename: Jérome
authors.initials: J
authors.lastname: Rossert
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: de Vernejoul
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D005260:Female; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011480:Protease Inhibitors / Q000378:metabolism; D011859:Radiography; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D000469:Alkaline Phosphatase; D045726:Metalloproteases