title: Association of cartilage-specific deletion of peroxisome proliferator-activated receptor γ with abnormal endochondral ossification and impaired cartilage growth and development in a murine model.
abstract: OBJECTIVE
  Long bones develop through the strictly regulated process of endochondral ossification within the growth plate, resulting in the replacement of cartilage by bone. Defects in this process can result in skeletal abnormalities and a predisposition to degenerative joint diseases such as osteoarthritis (OA). Studies suggest that activation of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is an important therapeutic target in OA. To devise PPARγ-related therapies in OA, it is critical to identify the role of this transcription factor in cartilage biology. Therefore, this study sought to determine the in vivo role of PPARγ in endochondral ossification and cartilage development, using cartilage-specific PPARγ-knockout (KO) mice.
  
  
  METHODS
  Cartilage-specific PPARγ-KO mice were generated using the Cre/loxP system. Histomorphometric and immunohistochemical analyses were performed to assess the patterns of ossification, proliferation, differentiation, and hypertrophy of chondrocytes, skeletal organization, bone density, and calcium deposition in the KO mice.
  
  
  RESULTS
  PPARγ-KO mice exhibited reductions in body length, body weight, length of the long bones, skeletal growth, cellularity, bone density, calcium deposition, and trabecular bone thickness, abnormal organization of the growth plate, loss of columnar organization, shorter hypertrophic zones, and delayed primary and secondary ossification. Immunohistochemical analyses for Sox9, 5-bromo-2'-deoxyuridine, p57, type X collagen, and platelet endothelial cell adhesion molecule 1 revealed reductions in the differentiation, proliferation, and hypertrophy of chondrocytes and in vascularization of the growth plate in mutant mice. Isolated chondrocytes and cartilage explants from mutant mice showed aberrant expression of Sox9 and extracellular matrix markers, including aggrecan, type II collagen, and matrix metalloproteinase 13. In addition, chondrocytes from mutant mice exhibited enhanced phosphorylation of p38 and decreased expression of Indian hedgehog.
  
  
  CONCLUSIONS
  The presence of PPARγ is required for normal endochondral ossification and cartilage development in vivo.
authors: University of Montreal Hospital Research Centre and University of Montreal, Montreal, Quebec, Canada.
authors: Roxana
authors: R
authors: Monemdjou
authors: Faezeh
authors: F
authors: Vasheghani
authors: Hassan
authors: H
authors: Fahmi
authors: Gemma
authors: G
authors: Perez
authors: Meryem
authors: M
authors: Blati
authors: Noboru
authors: N
authors: Taniguchi
authors: Martin
authors: M
authors: Lotz
authors: René
authors: R
authors: St-Arnaud
authors: Jean-Pierre
authors: JP
authors: Pelletier
authors: Johanne
authors: J
authors: Martel-Pelletier
authors: Frank
authors: F
authors: Beier
authors: Mohit
authors: M
authors: Kapoor
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density; D001846:Bone Development; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002356:Cartilage / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D020219:Chondrogenesis / Q000502:physiology*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism; D006984:Hypertrophy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010012:Osteogenesis / Q000502:physiology*; D047495:PPAR gamma / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053823:Hedgehog Proteins; D047495:PPAR gamma; D048051:p38 Mitogen-Activated Protein Kinases