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.

CONCLUSION:

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: Tujun Weng, Lingxian Yi, Junlan Huang, Fengtao Luo, Xuan Wen, Xiaolan Du, Qian Chen, Chuxia Deng, Di Chen, Lin Chen
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 64 Issue 12 Pg. 3982-92 (Dec 2012) ISSN: 1529-0131 [Electronic] United States
• PMID: 22833219 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 by the American College of Rheumatology.

Chemical References

• Aggrecans
• Antigens
• Proteoglycans
• Tamoxifen
• FGFR1 protein, human
• Fgfr1 protein, mouse
• Fgfr3 protein, mouse
• Receptor, Fibroblast Growth Factor, Type 1
• Receptor, Fibroblast Growth Factor, Type 3
• Matrix Metalloproteinase 13

Topics

• Aggrecans (metabolism)
• Animals
• Antigens (adverse effects)
• Cartilage, Articular (metabolism, pathology)
• Cells, Cultured
• Chondrocytes (metabolism, pathology)
• Disease Models, Animal
• Gene Deletion
• Humans
• Knee Joint (metabolism, pathology)
• Male
• Matrix Metalloproteinase 13 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Osteoarthritis, Knee (chemically induced, metabolism, prevention & control)
• Proteoglycans (metabolism)
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors, genetics, metabolism)
• Receptor, Fibroblast Growth Factor, Type 3 (metabolism)
• Tamoxifen (adverse effects)