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    • In addition to the four

    2022-07-21

    In addition to the four classical FGFRs there is an additional receptor, FGFR like-1 (FGFRL1, also known as FGFR5) (Ornitz and Itoh, 2015, Trueb et al., 2003). FGFRL1 gene was discovered in a cartilage specific cDNA library in 2000 (Trueb, 2011, Trueb et al., 2003) and thereafter it has been found in many mammalian tissue types including kidney, liver, skeletal muscle, PRIMA-1MET sale and lung (Trueb, 2011). It is also expressed in skeleton and especially in the growth plates of long bones (Trueb, 2011) and targeted inactivation of FGFRL1 gene in mice led to an array of phenotypes including disturbed skeletal development (Catela et al., 2009). Patients with craniosynostosis have been found to carry FGFRL1 mutations (Trueb, 2011) and in meta-analyses of genome-wide association studies FGFRL1 through critical microRNA target site polymorphisms for bone mineral density proved to be important for bone formation (Niu et al., 2015). FGFRL1 is located on the cell membrane, able to bind several FGFs of which FGF2, FGF3 and FGF8 bind it with high to intermediate affinity (Ornitz and Itoh, 2015, Trueb, 2011, Trueb et al., 2003). FGFRL1 differs from the classical FGFRs as it has only a truncated intracellular domain which is unable to cause transphosphorylation of the tyrosine residues and activate most downstream signaling pathways (Ornitz and Itoh, 2015, Trueb, 2011). For this reason it was first thought to be a nonfunctional member of the FGFR family. However, FGFRL1 has been shown to have a negative effect on proliferation (Trueb, 2011, Trueb et al., 2003) but the data on differentiation is controversial and calls for new studies to explore this issue further. The mechanisms of FGFRL1 are not known but it has been suggested to function as a decoy receptor for various FGFs and/or modulator of secondary intracellular signaling transducers such as SHP-1 and -2 (Ornitz and Itoh, 2015, Trueb, 2011, Silva et al., 2013). Interestingly, in a recent study SHP-1 was reported to be a positive regulator of osteoblastogenesis (Tang et al., 2015).
    Materials and methods
    Results
    Discussion
    Conclusions We developed two immortalized mesenchymal stromal cell lines which can be used to model osteoblast and adipocyte differentiation. Osteoblast differentiation during cultures was demonstrated with osteoblast marker genes and ALP staining. Adipocyte differentiation was characterized on the basis of the morphology of the cells and expression of marker genes. These cell lines are valid models for in vitro studies on osteogenic and adipogenic differentiation of MSCs. Our study suggests that FGFRL1 is involved in FGFR2-and FGFR1-mediated differentiation of MSCs to osteoblasts and adipocytes, respectively (Fig. 7). Expression of FGFRL1 is strongly increased during the differentiation process and it seems to follow the changes in FGFR1 and FGFR2. Furthermore, FGF2 treatment caused similar responses in FGFRL1 as in FGFR2 and in FGFR1 during osteoblast and adipocyte differentiation, respectively. Our results suggest that FGFR1 and FGFR2 regulate expression of FGFRL1 which in turn may support or modulate FGFR-driven signaling in MSCs. The study highlights a novel role for FGFRL1 on MSC differentiation to osteoblasts and adipocytes.
    Acknowledgements Cell lines were created and their initial characterization was done in European Union 6th framework project (LSHB-CT-2006-037168, EXERA). The further work was supported by Academy of Finland, Sigrid Juselius, University of Turku and Ida Montin foundations.
    Introduction Phenotypic and genetic alternations associated with tumorigenesis were gradually uncovered by large scale applications of gene sequencing and proteomics approaches1., 2., 3.. Along with these genomics-wide studies, we have witnessed the spurt of kinase inhibitors developed for targeted cancer treatment. Currently, more than 38 kinase drugs were approved by U.S. Food and Drug Administration (FDA), and most of them are targeting receptor tyrosine kinases4., 5., 6.. However, cancer is a complex neoplasia, processing extensive phenotypic heterogeneity and numerous genetic and transcriptional variations7., 8., 9., 10.. Therefore, continuous efforts are needed to develop novel drugs as precision medicine for cancer patients.