title: Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice.
abstract: OBJECTIVE
  Fibroblast growth factor (FGF) family members are involved in the regulation of articular cartilage homeostasis. The aim of this study was to investigate the function of FGF receptor 1 (FGFR-1) in the development of osteoarthritis (OA) and its underlying mechanisms.
  
  
  METHODS
  FGFR-1 was deleted from the articular chondrocytes of adult mice in a cartilage-specific and tamoxifen-inducible manner. Two OA models (aging-associated spontaneous OA, and destabilization-induced OA), as well as an antigen-induced arthritis (AIA) model, were established and tested in Fgfr1-deficient and wild-type (WT) mice. Alterations in cartilage structure and the loss of proteoglycan were assessed in the knee joints of mice of either genotype, using these 3 arthritis models. Primary chondrocytes were isolated and the expression of key regulatory molecules was assessed quantitatively. In addition, the effect of an FGFR-1 inhibitor on human articular chondrocytes was examined.
  
  
  RESULTS
  The gross morphologic features of Fgfr1-deficient mice were comparable with those of WT mice at both the postnatal and adult stages. The articular cartilage of 12-month-old Fgfr1-deficient mice displayed greater aggrecan staining compared to 12-month-old WT mice. Fgfr1 deficiency conferred resistance to the proteoglycan loss induced by AIA and attenuated the development of cartilage destruction after surgically induced destabilization of the knee joint. The chondroprotective effect of FGFR-1 inhibition was largely associated with decreased expression of matrix metalloproteinase 13 (MMP-13) and up-regulation of FGFR-3 in mouse and human articular chondrocytes.
  
  
  CONCLUSIONS
  Disruption of FGFR-1 in adult mouse articular chondrocytes inhibits the progression of cartilage degeneration. Down-regulation of MMP-13 expression and up-regulation of FGFR-3 levels may contribute to the phenotypic changes observed in Fgfr1-deficient mice.
authors: Daping Hospital and Research Institute of Surgery of the Third Military Medical University, Chongqing, China.
authors: Tujun
authors: T
authors: Weng
authors: Lingxian
authors: L
authors: Yi
authors: Junlan
authors: J
authors: Huang
authors: Fengtao
authors: F
authors: Luo
authors: Xuan
authors: X
authors: Wen
authors: Xiaolan
authors: X
authors: Du
authors: Qian
authors: Q
authors: Chen
authors: Chuxia
authors: C
authors: Deng
authors: Di
authors: D
authors: Chen
authors: Lin
authors: L
authors: Chen
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000009:adverse effects; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D007719:Knee Joint / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020370:Osteoarthritis, Knee / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D011509:Proteoglycans / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism; D013629:Tamoxifen / Q000009:adverse effects
chemical_list: D053674:Aggrecans; D000941:Antigens; D011509:Proteoglycans; D013629:Tamoxifen; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; C496366:Fgfr3 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3; D053509:Matrix Metalloproteinase 13