Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice

Osteoarthritis (OA) is one of the most prevalent chronic joint diseases and is characterized by progressive cartilage destruction and insufficient extracellular matrix synthesis. Thus far, none of the strategies employed to prevent and treat OA have been effective. The final option for advanced OA is the surgical approach of total joint replacement (1). Studies have shown that changes in growth factor signalings and their downstream target genes may be involved in the development of OA (2–5). However, the pathogenic mechanisms of OA are still largely unknown. Better understanding of the molecular events in OA development would provide important information that could facilitate the identification of novel therapeutic targets for the prevention and treatment of OA. Chondrocytes are the only cell type in adult human articular cartilage in which the main responsibility is the synthesis and degradation of extracellular matrix (6). Numerous molecules and pathways, such as hypoxia-inducible factor 2α, discoidin domain receptor 2, and hedgehog signaling, in the articular chondrocytes have been shown to be involved in cartilage metabolism (7–11). Recently, the role of fibroblast growth factor (FGF) family members in the regulation of cartilage homeostasis has received specific attention (12). FGF-18 is a well-established anabolic growth factor that contributes to the metabolism of articular cartilage (13,14). Although several lines of evidence support the tight association between FGF-2 and articular cartilage metabolism, the role of FGF-2 in cartilage homeostasis is controversial (12,15). Some studies of human articular chondrocytes have demonstrated that FGF-2 stimulates the production of matrix metalloproteinase 13 (MMP-13), which is the main collagenase responsible for collagen degradation (16). Results of other studies have suggested that FGF-2 functions as a chondroprotective factor in cartilage homeostasis (17–19). It has been reported that FGF-2 can suppress interleukin-1 (IL-1)–induced catabolic effects on human cartilage (18). In mice with Fgf2 deficiency, spontaneous OA, as well as instability-induced OA, is accelerated (19). In response to tissue injury or mechanical compression, FGF-2 can be released from the extracellular matrix to activate intracellular ERK signaling and regulate expression of chondrocyte-specific genes, suggesting that FGF-2 plays a homeostatic role in articular chondrocytes (20). The involvement of FGF ligands in the maintenance of articular cartilage suggests that FGF receptors (FGFRs) may also play an important role in articular cartilage homeostasis. Notably, FGFR-1 and FGFR-3 are highly expressed in human articular chondrocytes and have been implicated in cartilage metabolism (21). Valverde-Franco et al showed that Fgfr3-knockout (KO) mice exhibited abnormal cartilage metabolism and early signs of OA, suggesting that FGFR-3 signaling may have a chondroprotective role during the development of OA (22). It is hypothesized that activation of FGFR-1 may exert antianabolic and procatabolic effects on adult human articular cartilage (12). However, since conditional deletion of Fgfr1 is known to have a lethal effect on mouse embryos (23), it is impossible to investigate the in vivo function of FGFR-1 in articular cartilage homeostasis using conventional Fgfr1-KO mice. In this study, we investigated the role of FGFR-1 in articular cartilage function postnatally, using mice with tamoxifen-inducible and cartilage-specific conditional knockout (cKO) of the Fgfr1 gene (hereinafter referred to as Fgfr1 cKO mice). We evaluated the effects of FGFR-1 on the function of articular chondrocytes and the degeneration of articular cartilage in mice using 2 models of OA, as well as an antigen-induced arthritis (AIA) model. Our study demonstrated that Fgfr1 deficiency in mice attenuates articular cartilage degeneration in all 3 arthritis models. In addition, we found that blockade of FGFR-1 signaling could antagonize the IL-1β–induced up-regulation of MMP-13 and enhance the expression of FGFR-3 in human articular chondrocytes.