Identification of Fibroblast Growth Factor-18 as a Molecule to Protect Adult Articular Cartilage by Gene Expression Profiling

Mori, Yoshifumi; Saito, Taku; Chang, Song Ho; Kobayashi, Hiroshi; Ladel, Christoph; Guehring, H.; Chung, Ung‐il; Kawaguchi, Hiroshi

doi:10.1074/jbc.m113.524090

Cited by 70 publications

(64 citation statements)

References 45 publications

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“…As expected, the variability between these samples was high, so we focused our analysis on genes that increased more than 1.5-fold in four of seven replicates. GO analysis of these 1244 enriched genes revealed categories related to cell cycle, secretion and migration (figure 3F), while untreated cells were enriched for categories related to IL-6-mediated inflammation (online supplementary figure 3A); we confirmed RCGD 423 upregulated three of these genes with roles in cartilage biology ( HAS3 31 , FGF18 32 and CDK6 33; online supplementary figure 3B). We hypothesised that RCGD 423 may promote proliferation through MYC and therefore focused on the 31 genes in the M phase Gene Ontology (GO) category enriched in drug treated cells.…”

Section: Resultssupporting

confidence: 58%

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

et al. 2018

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Section: Resultssupporting

confidence: 58%

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

et al. 2018

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“…This might represent an amplification of a normal feed-forward induction of Fgf9 and Fgf18 that could function to permanently suppress growth plate chondrocyte proliferation at puberty and suppress articular chondrocyte proliferation and differentiation in adults. This model is consistent with the continued expression of endogenous Fgf18 in the postnatal growth plate and perichondrium and in adult articular chondrocytes (Ellsworth et al, 2002;Lazarus et al, 2007;Mori et al, 2014).…”

Section: Termination Of Skeletal Growthsupporting

confidence: 69%

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Karuppaiah

Lim

et al. 2016

Development

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Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cellautonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.

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“…21,23,42 To identify in situ the cells expressing Fgf18 CreERT2 in the postnatal and adult skeleton, Fgf18 Lineage neonatal mice were injected with tamoxifen and then harvested at different time points for analysis ( Figure 5A-C). 21,23,42 To identify in situ the cells expressing Fgf18 CreERT2 in the postnatal and adult skeleton, Fgf18 Lineage neonatal mice were injected with tamoxifen and then harvested at different time points for analysis ( Figure 5A-C).…”

Section: Fgf18 Creert2 Lineage During Postnatal Skeletal Developmentmentioning

confidence: 99%

“…16 In skin, Fgf18 expression is found in inner root sheath cells of the hair follicles where it is thought to maintain stem cells in a quiescent state. 21 Fgf18 is also expressed in the postnatal growth plate. 21 Fgf18 is also expressed in the postnatal growth plate.…”

Section: Introductionmentioning

confidence: 99%

Generation and validation of novel conditional flox and inducible Cre alleles targeting fibroblast growth factor 18 (Fgf18)

Hagan

Boylan

Smith

et al. 2019

Developmental Dynamics

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Background: Fibroblast growth factor 18 (FGF18) functions in the development of several tissues, including the lung, limb bud, palate, skeleton, central nervous system, and hair follicle. Mice containing a germline knockout of Fgf18 (Fgf18 −/− ) die shortly after birth. Postnatally, FGF18 is being evaluated for pathogenic roles in fibrosis and several types of cancer. The specific cell types that express FGF18 have been difficult to identify, and the function of FGF18 in postnatal development and tissue homeostasis has been hampered by the perinatal lethality of Fgf18 null mice. Results: We engineered a floxed allele of Fgf18 (Fgf18 flox ) that allows conditional gene inactivation and a CreER T2 knockin allele (Fgf18 CreERT2 ) that allows the precise identification of cells that express Fgf18 and their lineage. We validated the Fgf18 flox allele by targeting it in mesenchymal tissue and primary mesoderm during embryonic development, resulting in similar phenotypes to those observed in Fgf18 null mice. We also use the Fgf18 CreERT2 allele, in combination with a conditional fluorescent reporter to confirm known and identify new sites of Fgf18 expression. Conclusion: These alleles will be useful to investigate FGF18 function during organogenesis and tissue homeostasis, and to target specific cell lineages at embryonic and postnatal time points. K E Y W O R D Sbone development, Cre-lox recombination, FGF signaling, knock in mice, reporter gene

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Identification of Fibroblast Growth Factor-18 as a Molecule to Protect Adult Articular Cartilage by Gene Expression Profiling

Cited by 70 publications

References 45 publications

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Generation and validation of novel conditional flox and inducible Cre alleles targeting fibroblast growth factor 18 (Fgf18)

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