BoneKEy-Osteovision | Commentary

FGFR3 finds its key in the growth plate



DOI:10.1138/2002039

The molecular era of chondrogenesis started with the discovery that the fibroblast growth factor receptor 3 (FGFR3) (OMIM 134934), a tyrosine kinase type of receptor, controls chondrocyte proliferation (1-3). Indeed, achondroplasia patients (who have few chondrocytes) all have an activating mutation in FGFR3. Later, mutations in FGFR3 were found also to cause other chondrodysplasias while loss-of-function and gain-of-function studies in mice established that FGFR3 and its ligand(s) act as negative regulators of chondrocyte differentiation and proliferation. These studies established the pivotal role that FGF signaling pathways play during chondrogenesis and thereby endochondral ossification. Moreover, the observation that gain-of-function mutations in genes encoding FGFR3 but also FGFR1 (OMIM 136350) and FGFR2 (OMIM 176943) can cause craniosynostosis established that the FGF signaling pathway is also involved in intramembranous ossification (). However, and to the present time, the identity of the physiological ligand for FGFR3 that is involved in its control of chondrogenesis and osteogenesis has remained elusive. Two studies published in a recent issue of Genes and Development, one by the Ornitz lab (), and one by the Takada lab (), address elegantly this question.

It has long been known that members of the FGF family contribute to skeletal patterning (). For instance, FGF8 (OMIM 600483) and FGF10 (OMIM 602115) are necessary in vivo for limb outgrowth while other members of the family such as FGF4, -9 and -17 (OMIM 194980, 600921, 603725) are expressed in the developing limb. Yet, there is no available genetic evidence that any of them is the ligand of FGFR3 in the growth plate cartilage or during skull development. FGF18 (OMIM 603726) is a close relative of FGF8 and FGF17. Ectopic application of FGF18 in chick limb inhibited bone growth, suggesting that it could play a role in cell differentiation and/or proliferation during skeletogenesis (). Two lines of evidence presented in these two papers indicate that FGF18 is a ligand of FGFR3 in the growth plate.

The first line of evidence comes from the comparison between Fgf18 expression and Fgfr3 expression during calvaria and long bone development. Fgf18 expression in calvaria can be detected as early as embryonic day 12 (E12) in osteoblast progenitors while Fgfr1, 2 and 3 are expressed in the ventral mesenchyme. At E14 Fgf18 and Fgfr3 become detectable in the same cells of the osteogenic mesenchyme. At E16 and later Fgf18 is expressed in differentiating osteoblasts whereas Fgfr2 and 3 are now expressed in cells of the osteogenic front. In developing long bones Fgf18 is predominantly expressed in cells of the perichodrium, as is Fgfr2, while Fgfr3 is expressed in proliferating and prehypertrophic chondrocytes. This pattern of expression was more consistent with FGF18 being a ligand for FGFR3 in growth plate than in any other part of the developing skeleton.

The second and more convincing line of evidence is that FGF18-deficient mice exhibit a similar cartilage phenotype to FGFR3-deficient mice () i.e. an expanded zone of proliferating and hypertrophic chondrocytes associated with increased chondrocyte proliferation and differentiation. The FGF18-deficient mice also display increased expression of Indian hedgehog (IHH), another major regulator of chondrogenesis in the growth plate. This latter result suggests that a function of FGF18 may be to inhibit IHH signaling in prehypertrophic chondrocytes. Although FGF18-deficient mice are smaller at birth and their cartilage phenotype is not as severe as in FGFR3-deficient mice these data are compelling evidence that FGF18 is a ligand of FGFR3 in the growth plate. The milder chondrocyte phenotype of FGF18-deficient mice compared to FGFR3-deficient mice may be explained by the existence of another ligand. Clearly, more genetic studies of this type are needed to decipher completely how FGF signaling occurs during skeletogenesis, yet these two studies can be viewed as major progress in our understanding of chondrocyte proliferation and differentiation.

These two papers also show that at the same time FGF18 inhibits chondrocyte differentiation and proliferation, it promotes osteogenesis. Indeed, in absence of Fgf18 there is a delay in osteogenesis, a delay in the expression of Cbfa1 and Osteocalcin, the earliest and latest markers of osteoblast differentiation, respectively, in long bones while Cbfa1 expression was not decreased in osteoblasts of the calvaria. These delays in osteoblast differentiation and proliferation are not observed in FGFR3-deficient mice and their presence indicates that FGF18 binds different receptor(s) in osteoblasts. The observation that FGF18 has opposing functions during chondrogenesis and osteogenesis highlights the complexity of the molecular interactions taking place during skeletogenesis. It is clear that deletion of other Fgfs in the entire organism as well as specifically in osteoblasts and/or chondrocytes will allow the identification of additional ligands for FGF receptors.


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