Fibroblast Growth Factor (FGF) 18 Signals through FGF Receptor 3 to Promote Chondrogenesis

Abstract

Signaling by fibroblast growth factor (FGF) 18 and FGF receptor 3 (FGFR3) have been shown to regulate proliferation, differentiation, and matrix production of articular and growth plate chondrocytes in vivo and in vitro. Notably, the congenital absence of either FGF18 or FGFR3 resulted in similar expansion of the growth plates of fetal mice and the addition of FGF18 to human articular chondrocytes in culture enhanced proliferation and matrix production. Based on these and other experiments it has been proposed that FGF18 signals through FGFR3 to promote cartilage production by chondrocytes. Its role in chondrogenesis remains to be defined. In the current work we used the limb buds of FGFR3 ؉/؉ and FGFR3 ؊/؊ embryonic mice as a source of mesenchymal cells to determine how FGF18 signaling affects chondrogenesis. Confocal laser-scanning microscopy demonstrated impaired cartilage nodule formation in the FGFR3؊/؊ cultures. Potential contributing factors to the phenotype were identified as impaired mitogenic response to FGF18, decreased production of type II collagen and proteoglycan in response to FGF18 stimulation, impaired interactions with the extracellular matrix resulting from altered integrin receptor expression, and altered expression of FGFR1 and FGFR2. The data identified FGF18 as a selective ligand for FGFR3 in limb bud mesenchymal cells, which suppressed proliferation and promoted their differentiation and production of cartilage matrix. This work, thus, identifies FGF18 and FGFR3 as potential molecular targets for intervention in tissue engineering aimed at cartilage repair and regeneration of damaged cartilage.

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

“…In contrast, the expression of FGFR1 in hypertrophic chondrocytes suggests a role for FGFR1 in regulating cell survival, cell differentiation, ECM production and cell death (Peters et al, 1992). Recently, findings from our laboratory and others suggest that FGF-18 signals selectively through FGFR3 in human articular chondrocytes and mice to suppress cellular proliferation and promote limb mesenchymal cell differentiation (Davidson et al, 2005;Muddasani et al, 2008), as opposed to bFGF-FGFR1 binding that characterizes increased proliferation and catabolic effects seen in articular and IVD cartilage (Figure 3).…”

“…In contrast to the controversial role of bFGF in joint and spine disc cartilage, FGF-18 is a well-known anabolic growth factor involved in osteogenesis, chondrogenesis, and articular cartilage repair (Ellsworth et al, 2002;Liu et al, 2002;Ohbayashi et al, 2002;Davidson et al, 2005;Moore et al, 2005), and here we will review its role in joint cartilage. To date, the role of FGF-18 in the IVD has yet to be studied.…”

Altered gene expression in early osteochondrosis lesions

“…2 Fibroblast growth factor receptor 3 (FGFR3) has been shown to inhibit chondrocyte proliferation, with FGF18 possibly the important ligand in growth cartilage. 3,4 Endochondral ossification is blocked in Runx2-deficient mice, indicating an essential role for this transcription factor in chondrocyte differentiation. It has been shown that expression of Runx2 induces hypertrophy, alkaline phosphatase activity, and expression of type X collagen and matrix metalloproteinase-13 (MMP-13) 5 in chondrocytes, as well as mineralization of the cartilage matrix.…”

Effect of chondrocyte-derived early extracellular matrix on chondrogenesis of placenta-derived mesenchymal stem cells

“…However, cells that were not precultured had higher wet mass and collagen type II mRNA levels at 3 weeks. It is known well that MSC proliferation is downregulated once differentiation is initiated [35,36]. The decreased proliferation rate of precultured hPDMSCs may therefore be due to increased chondrogenesis.…”