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The molecular mechanisms allowing hair follicles to periodically activate their stem cells (HFSCs) are incompletely characterized. Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice have delayed anagen onset, with increased DNA damage and diminished HFSC proliferation. Open chromatin regions form near cell cycle progression and DNA damage repair genes in Irx5-/- HFSCs. DNA damage repair factor BRCA1 is an IRX5 downstream target. Inhibition of FGF kinase signaling partially rescues the anagen delay in Irx5-/- mice, suggesting that the Irx5-/- HFSC quiescent phenotype is partly due to failure to suppress Fgf18 expression. Interfollicular epidermal stem cells also show decreased proliferation and increased DNA damage in Irx5-/-mice. Consistent with a role for IRX5 as a promoter of DNA damage repair, we find that IRX genes are upregulated in many cancer types and that there is a correlation between IRX5 and BRCA1 expression in breast cancer.

Suboptimal LH surges can lead to delayed or absent ovulation during reproductive management programs in cattle. Several signaling pathways may enhance the LH signal, potentially including growth factors. In the present study, we determined whether Fibroblast growth factor 18 (FGF18), which mimics some actions of the LH surge on granulosa cells, may potentiate the action of a suboptimal dose of LH using an established bovine granulosa cell (GC) culture system. Addition of recombinant FGF18 increased the concentration of progesterone (P4) in the culture medium. A combination of LH and FGF18 in the culture medium increased the abundance of mRNA encoding EREG, EGR1 and EGR3, proteins that are early modulators of the LH-induced pre-ovulatory cascade. This study demonstrated that FGF18 may be a co-factor in the regulation of the pre-ovulatory cascade in bovine ovarian granulosa cells. [ABSTRACT FROM AUTHOR]

The pivotal role of FGF18 in the regulation of craniofacial and skeletal development has been well established. Previous studies have demonstrated that mice with deficiency in Fgf18 exhibit severe craniofacial dysplasia. Recent clinical reports have revealed that the duplication of chromosome 5q32-35.3, which encompasses the Fgf18 gene, can lead to cranial bone dysplasia and congenital craniosynostosis, implicating the consequence of possible overdosed FGF18 signaling. This study aimed to test the effects of augmented FGF18 signaling by specifically overexpressing the Fgf18 gene in cranial neural crest cells using the Wnt1-Cre; pMes-Fgf18 mouse model. The results showed that overexpression of Fgf18 leads to craniofacial abnormalities in mice similar to the Pierre Robin sequence in humans, including abnormal tongue morphology, micrognathia, and cleft palate. Further examination revealed that elevated levels of Fgf18 activated the Akt and Erk signaling pathways, leading to an increase in the proliferation level of tongue tendon cells and alterations in the contraction pattern of the genioglossus muscle. Additionally, we observed that excessive FGF18 signaling contributed to the reduction in the length of Meckel's cartilage and disrupted the development of condylar cartilage, ultimately resulting in mandibular defects. These anomalies involve changes in several downstreamsignals, including Runx2, p21, Akt, Erk, p38, Wnt, and Ihh. This study highlights the crucial role of maintaining the balance of endogenous FGF18 signaling for proper craniofacial development and offers insights into potential formation mechanisms of the Pierre Robin sequence. [ABSTRACT FROM AUTHOR]

Abstract Background Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker. Methods FGF18 mRNA expression was analyzed by real‐time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters. Results FGF18 showed high mRNA expression in PM and PM‐derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed. Conclusions FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation.

Background: Pharmacological treatments for ischemic stroke remain limited to thrombolysis, which is associated with increased risk of potentially fatal hemorrhage. Treatments with Recombinant Human Fibroblast Growth Factor 18 (rhFGF18) and Growth and Differentiation Factor 11 (rhGDF11) appear promising based on different preclinical models. The goal of this study was to compare the effects of rhFGF18 and rhGDF11 directly on survival, behavioral deficits, and histological fingerprint of cerebral ischemia in the Wistar rat middle cerebral artery occlusion (MCAO) model of stroke. Methods: Ischemia-reperfusion injury was induced using a 2-hour transient MCAO. Animals were administered rhFGF18 (infusion), rhGDF11 (multi-injection), or Phosphate Buffered Saline (PBS) vehicle control and followed for 42 days. Motor-Cognitive deficits were evaluated using the Morris Water Maze at Days 0 (pre-MCAO), 7, 21, and 42. Histopathological assessments were performed on Days 21 and 42. Results: Day 7 post-ischemia water maze performance times increased 38.3%, 2.1%, and 23.1% for PBS, rhFGF18, and rhGDF11-treated groups, respectively. Fraction of neurons with abnormal morphology (chromatolysis, pyknotic nuclei, somal degeneration) decreased in all groups toward Day 42 and was lowest for rhFGF18. AChE-positive fiber density and activity increased over time in the rhFGF18 group, remained unchanged in the rhGDF11 treatment arm, and declined in the PBS control. Metabolic increases were greatest in rhGDF11 treated animals, with both rhFGF18 and rhGDF11 achieving improvements over PBS, as evidenced by increased succinate dehydrogenase and lactate dehydrogenase activity. Finally, rhFGF18 treatment exhibited a trend for reduced mortality relative to PBS (5.6%, 95% CI [27.3%, 0.1%] vs. 22.2%, 95% CI [47.6%, 6.4%]). Conclusions: rhFGF18 treatment appears promising in improving survival and promoting motor-cognitive recovery following cerebral ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

ABSTRACT: Suboptimal LH surges can lead to delayed or absent ovulation during reproductive management programs in cattle. Several signaling pathways may enhance the LH signal, potentially including growth factors. In the present study, we determined whether Fibroblast growth factor 18 (FGF18), which mimics some actions of the LH surge on granulosa cells, may potentiate the action of a suboptimal dose of LH using an established bovine granulosa cell (GC) culture system. Addition of recombinant FGF18 increased the concentration of progesterone (P4) in the culture medium. A combination of LH and FGF18 in the culture medium increased the abundance of mRNA encoding EREG, EGR1 and EGR3, proteins that are early modulators of the LH-induced pre-ovulatory cascade. This study demonstrated that FGF18 may be a co-factor in the regulation of the pre-ovulatory cascade in bovine ovarian granulosa cells.

Background: Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker. Methods: FGF18 mRNA expression was analyzed by real‐time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters. Results: FGF18 showed high mRNA expression in PM and PM‐derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed. Conclusions: FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 18(FGF18) is a member of the fibroblast growth factor family (FGFs). FGF18 is a class of bioactive substances that can conduct biological signals, regulate cell growth, participate in tissue repair and other functions, and can promote the occurrence and development of different types of malignant tumors through various mechanisms. In this review, we focus on recent studies of FGF18 in the diagnosis, treatment, and prognosis of tumors in digestive, reproductive, urinary, respiratory, motor, and pediatric systems. These findings suggest that FGF18 may play an increasingly important role in the clinical evaluation of these malignancies. Overall, FGF18 can function as an important oncogene at different gene and protein levels, and can be used as a potential new therapeutic target and prognostic biomarker for these tumors. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor (FGF) signaling is known to play an important role in lung organogenesis. However, we recently demonstrated that FGF10 fails to induce branching in human fetal lungs as is observed in mouse. Our previous human fetal lung RNA sequencing data exhibited increased FGF18 during the pseudoglandular stage of development, suggestive of its importance in human lung branching morphogenesis. Whereas it has been previously reported that FGF18 is critical during alveologenesis, few studies have described its implication in lung branching, specifically in human. Therefore, we aimed to determine the role of FGF18 in human lung branching morphogenesis. Human fetal lung explants within the pseudoglandular stage of development were treated with recombinant human FGF18 in air-liquid interface culture. Explants were analyzed grossly to assess differences in branching pattern, as well as at the cellular and molecular levels. FGF18 treatment promoted branching in explant cultures and demonstrated increased epithelial proliferation as well as maintenance of the double positive SOX2/SOX9 distal bud progenitor cells, confirming its role in human lung branching morphogenesis. In addition, FGF18 treated explants displayed increased expression of SOX9, FN1, and COL2A1 within the mesenchyme, all factors that are important to chondrocyte differentiation. In humans, cartilaginous airways extend deep into the lung up to the 12th generation of branching whereas in mouse these are restricted to the trachea and main bronchi. Therefore, our data suggest that FGF18 promotes human lung branching morphogenesis through regulating mesenchymal progenitor cells. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor (FGF) signaling is necessary for proper lung branching morphogenesis, alveolarization, and vascular development. Dysregulation of FGF activity has been implicated in various lung diseases. Recently, we showed that FGF18 promotes human lung branching morphogenesis by regulating mesenchymal progenitor cells. However, the underlying mechanisms remain unclear. Thus, we aimed to determine the role of FGF18 and its receptors (FGFR) in regulating mesenchymal cell proliferation, migration, and differentiation from pseudoglandular to canalicular stage. We performed siRNA assays to identify the specific FGFR(s) associated with FGF18-induced biological processes. We found that FGF18 increased proliferation and migration in human fetal lung fibroblasts (HFLF) from both stages. FGFR2/FGFR4 played a significant role in pseudoglandular stage. HFLF proliferation, while FGFR3/FGFR4 were involved in canalicular stage. FGF18 enhanced HFLF migration through FGFR2 and FGFR4 in pseudoglandular and canalicular stage, respectively. Finally, we provide evidence that FGF18 treatment leads to reduced expression of myofibroblast markers (ACTA2 and COL1A1) and increased expression of lipofibroblast markers (ADRP and PPARγ) in both stages HFLF. However, the specific FGF18/FGFR complex involved in this process varies depending on the stage. Our findings suggest that in context of human lung development, FGF18 tends to associate with distinct FGFRs to initiate specific biological processes on mesenchymal cells.

Abstract Background Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. Methods A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan–Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus–meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. Results The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor–node–metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Conclusions Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.

Gastric cancer (GC) is regarded as a major health burden all over the world. WYC-209 inhibits the growth and metastasis of tumor-repopulating cells (TRCs). However, its effectiveness on GC was unexplored. Herein, this study aims to investigate the effect of WYC-209 on GC and elucidate its underlying mechanism. We examined the effects of WYC-209 on cell survival, migration, invasion, and colony-forming capacities of two GC cell lines (AGS and HGC-27). Subsequently, RNA-seq and enrichment analyses were performed to screen the differentially expressed genes (DEGs) and the enriched signaling pathways. To further explore the underlying mechanism, loss- and gain-function experiments, Chromatin immunoprecipitation, and luciferase reporter were conducted. Finally, xenograft models were constructed to examine the effects of WYC-209 in vivo. WYC-209 significantly inhibited cell motility in vitro and tumor growth in vivo. RNA-seq performed in AGS cells after WYC-209 treatment revealed that the inhibition effect of WYC-209 on GCs may be associated with the down-regulation of fibroblast growth factor-18 (FGF18), and pleasantly, FGF18 overexpression abrogated the suppression effect of the drug. In addition, we found that WYC-209 attenuated the activation of the Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway, and impeded the FGF18 levels expressed in GCs. Importantly, the WYC-209 treatment circumvented the binding of STAT3 to the FGF18 promoter, suggested that WYC-209 down-regulated FGF18 expression via the STAT3 signaling pathway. Together, our findings presented the promise of WYC-209 in suppressing GC by down-regulating FGF18 expression through inactivating the STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. High expression of the mitotic kinase BUB1 has been shown to be associated with the development of many cancers, but the role of BUB1 in GC is still unclear. The current study aimed to investigate the role of BUB1 in GC. BUB1 inhibitor, siRNA or BUB1 overexpression plasmid-mediated functional studies were performed in vitro and in vivo to explore the oncogenic role of BUB1 in GC. The expression of BUB1 and FGF18 in GC tumor samples was determined by IHC staining. RNA-seq, Western blot, MeRIP-qPCR and Co-IP assays were used to investigate the molecular mechanisms by which BUB1 regulates GC progression. Knockdown of BUB1 significantly inhibited the proliferation and metastasis of GC cells in vitro and in vivo. Moreover, overexpression of BUB1 significantly promoted the proliferation, migration and invasion of GC cells. High expression of BUB1 and FGF18 in GC tissues predicted poor prognosis in GC patients. Mechanistically, BUB1 interacted with METTL3 and induced m6A modification of TRAF6 mRNA, further activating the NF-κB/FGF18 axis in GC cells. Our results confirmed that BUB1 acts as a positive regulator of GC cell proliferation and metastasis by activating the TRAF6/NF-κB/FGF18 pathway through METTL3-mediated m6A methylation. Targeting the BUB1/METTL3/TRAF6/NF-κB/FGF18 axis might be a novel diagnostic and therapeutic strategy in GC. [Display omitted] • High expression of BUB1 was associated with poor prognosis in GC patients. • BUB1 promotes GC cell proliferation, migration and invasion via FGF18. • BUB1 positively regulates FGF18 expression and GC progression through the TRAF6/NF-κB axis. • BUB1 activates the TRAF6/NF-κB/FGF18 pathway through METTL3-mediated m6A methylation. [ABSTRACT FROM AUTHOR]

Ginsenoside Rb1 (Rb1) is a major active compound in Panax ginseng and has shown considerable anti‐inflammation effects. Osteoarthritis (OA) is one of the major degenerative disorders affecting the knee. MiR‐21‐5p is a potential therapeutic target for OA treatment. This study explored the anti‐OA effects of Rb1 by focusing on its interaction with the miR‐21‐5p/FGF18 axis. OA was induced in rats using monoiodoacetate (MIA) and managed with Rb1. Then, changes in the histological structure and miR‐21‐5p‐mediated signaling pathway were measured in joint tissues. The role of miR‐21‐5p/FGF18 in the anti‐OA effects of Rb1 was confirmed by inducing its levels in rats and chondrocytes. Rb1 improved the histological structure and suppressed the production of cytokines in joint tissues. At the molecular level, Rb1 down‐regulated miR‐12‐5p levels and up‐regulated FGF18 levels. In chondrocytes, Rb1 increased cell viability, suppressed inflammation, down‐regulated miR‐21‐5p levels, and up‐regulated FGF18 levels. The restored level of miR‐21‐5p compromised the anti‐OA effects of Rb1. In a nutshell, our study reported that the anti‐OA effects of Rb1 relied on the inhibited expression of miR‐21‐5p. Practical applications: Ginsenoside Rb1 (Rb1) is a major active compound in Panax ginseng and has shown considerable anti‐osteoarthritis (OA) effects. The current study not only relates the anti‐OA function of ginsenoside Rb1 with microRNA but also provides valuable information for exploring novel targets for the development the anti‐OA strategies. [ABSTRACT FROM AUTHOR]

Background: The tongue is a muscular fleshy organ in the oral cavity that is anatomically divided into the dorsal, ventral, anterior, and posterior part. The intricate tissue organisation and diverse origins of the tongue make it a complex organ of the oral cavity. Objectives: To reveal the signalling molecules involved in the formation of the dorsal and ventral parts of the tongue through microarray analysis. Methods: Dorsal and ventral tongue tissues were isolated from embryonic day 14 mice by micro-dissection. RNA was extracted from the dorsal and ventral tongue tissues separately for microarray analysis. Microarray data were confirmed by quantitative reverse transcription polymerase chain reaction and whole-mount in situ hybridisation. Results: Microarray analysis revealed expression of 33,793 genes. Of these, 931 genes were found to be equally expressed in both the dorsal and ventral parts of the tongue. On limiting the fold-change cut-off to over 1.5-fold, 725 genes were expressed over 1.5-fold in the ventral part and 1,672 in the dorsal part of the tongue. The qPCR and whole-mount in situ hybridisation revealed the expressions of angiopoietin 2 (Angpt2), fibroblast growth factor 18 (Fgf18), mesenchyme homeobox gene1 (Meox1), and SPARC-related modular calcium binding 2 (Smoc2) in the ventral part of the tongue. Conclusions: Numerous signalling molecules can be selected from our microarray results to examine their roles in tongue development and disease model systems. In the near future, the selection of candidate genes and their functional evaluations will be performed through loss- and gain-of-function mutation studies. [ABSTRACT FROM AUTHOR]

FGF18 was discovered in 1998. It is a pleiotropic growth factor that stimulates major signalling pathways involved in cell proliferation and growth, and is involved in the development and homeostasis of many tissues such as bone, lung, and central nervous system. The gene consists of five exons that code for a 207 amino acid glycosylated protein. FGF18 is widely expressed in developing and adult chickens, mice, and humans, being seen in the mesenchyme, brain, skeleton, heart, and lungs. Knockout studies of FGF18 in mice lead to perinatal death, characterised by distinct phenotypes such as cleft palate, smaller body size, curved long bones, deformed ribs, and reduced crania. As can be expected from a protein involved in so many functions FGF18 is associated with various diseases such as idiopathic pulmonary fibrosis, congenital diaphragmatic hernia, and most notably various types of cancer such as breast, lung, and ovarian cancer., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. Methods: A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan–Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus–meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. Results: The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor–node–metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Conclusions: Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy. [ABSTRACT FROM AUTHOR]

Jian Wu,1,2 Xiang Tao,3,4 Hong Zhang,5 Xiang-Hua Yi,1 Yin-Hua Yu4 1Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, People’s Republic of China; 2Department of Pathology, Gongli Hospital, Second Military Medical University, Shanghai 200135, People’s Republic of China; 3Department of Pathology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 4Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People’s Republic of China; 5Department of Pharmacy, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, People’s Republic of ChinaCorrespondence: Xiang Tao Email tutufoliage@hotmail.comHong Zhang Email Hongzh97@tongji.edu.cnObjective: The aim of this study was to evaluate whether estrogen promoted the proliferation and invasion of endometrial carcinoma (EC) cells through paracrine FGFs in endometrial stromal cells (ESCs).Patients and Methods: We screened gene alterations in a primary ESC culture after 10 nM estrogen treatment using an Agilent mRNA microarray. We knocked down stromal FGF18 expression in a co-culture system and aimed to explore the contribution of E2-induced stromal FGF18 to the proliferation and invasion of EC cells. To determine the effective receptors and detailed downstream signaling of FGF18, we co-cultured estrogen-treated hESCs with FGFR1-, FGFR2-, FGFR3- or FGFR4-knockdown Ishikawa cells. Finally, we detected FGF18 expression in clinical samples, including several primary cultures of different ESCs and a series of tissue microarrays (TMAs) of 90 patients with EC.Results: A few genes altered significantly in estrogen-treated primary ESCs, but only FGF18 was noticeably enhanced among the FGF family genes. Knockdown of FGF18 expression in hESCs inhibited the promoting effect of FGF18 on the proliferation and invasion of EC cells. FGF18 bound FGFR2 and FGFR3 in Ishikawa cells to activate downstream ERK and Akt pathways and to promote the viability of EC cells. The FGF18-FGFR2 and FGF18-FGFR3 pathways had close correlations with Survivin and CD44V6 expression but not with P53. Primary ESCs of endometrioid EC (EEC, type I EC) had higher FGF18 expression than ESCs of normal endometrium (NE), endometrial atypical hyperplasia (EAH) and type II EC.Conclusion: Estrogen induced FGF18 in ESCs to promote the proliferation and invasion of EC cells, and FGFR inhibitors should be considered as promising candidate targets for EC treatment.Keywords: FGF18, paracrine, proliferation, invasion, endometrial stromal cells, ESCs, endometrial carcinoma, EC

When suffering from osteoarthritis (OA), articular cartilage homeostasis is out of balance and the living quality declines. The treatment of knee OA has always been an unsolved problem in the world. At present, symptomatic treatment is mainly adopted for OA. Drug therapy is mainly used to relieve pain symptoms, but often accompanied with adverse reactions; surgical treatment involves the problem of poor integration between the repaired or transplanted tissues and the natural cartilage, leading to the failure of repair. Biotherapy which aims to promote cartilage in situ regeneration and to restore endochondral homeostasis is expected to be an effective method for the prevention and treatment of OA. Disease-modifying osteoarthritis drugs (DMOADs) are intended for targeted treatment of OA. The DMOADs prevent excessive destruction of articular cartilage through anti-catabolism and stimulate tissue regeneration via excitoanabolic effects. Sprifermin (recombinant human FGF18, rhFGF18) is an effective DMOAD, which can not only promote the proliferation of articular chondrocyte and the synthesis of extracellular matrix, increase the thickness of cartilage in a dose-dependent manner, but also inhibit the activity of proteolytic enzymes and remarkedly slow down the degeneration of cartilage. This paper reviews the unique advantages of Sprifermin in repairing cartilage injury and improving cartilage homeostasis, aiming to provide an important strategy for the effective prevention and treatment of cartilage injury-related diseases.

FGF5 and FGF18 are key factors in the regulation of the hair follicle cycle. FGF5 is overexpressed during the late anagen phase and serves as a crucial regulatory factor that promotes the anagen-to-catagen transition in the hair follicle cycle. FGF18, which is overexpressed during the telogen phase, mainly regulates the hair follicle cycle by maintaining the telogen phase and inhibiting the entry of hair follicles into the anagen phase. The inhibition of FGF5 may prolong the anagen phase, whereas the inhibition of FGF18 may promote the transition of the hair follicles from the telogen phase to the anagen phase. In the present study, we used siRNA to suppress FGF5 or FGF18 expression as a way to inhibit the activity of these genes. Using qPCR, we showed that FGF5-targeting siRNA modified by cholesterol was more effective than the same siRNA bound to a cell-penetrating peptide at suppressing the expression of FGF5 both in vitro and in vivo. We then investigated the effects of the cholesterol-modified siRNA targeting either FGF5 or FGF18 on the hair follicle cycle in a depilated area of the skin on the back of mice. The cholesterol-modified siRNA, delivered by intradermal injection, effectively regulated the hair follicle cycle by inhibiting the expression of FGF5 and FGF18. More specifically, intradermal injection of a cholesterol-modified FGF5-targeted siRNA effectively prolonged the anagen phase of the hair follicles, whereas intradermal injection of the cholesterol-modified FGF18-targeted siRNA led to the mobilization of telogen follicles to enter the anagen phase earlier. The inhibitory effect of the cholesterol-modified FGF18-targeted siRNA on FGF18 expression was also evaluated for a topically applied siRNA. Topical application of a cream containing the cholesterol-modified FGF18-targeted siRNA on a depilated area of the skin of the back of mice revealed comparable inhibition of FGF18 expression with that observed for the same siRNA delivered by intradermal injection. These findings suggested that alopecia could be prevented and hair regrowth could be restored either through the intradermal injection of cholesterol-modified siRNA targeting FGF5 or FGF18 or the topical application of FGF18 siRNA.

FGF5 and FGF18 are key factors in the regulation of the hair follicle cycle. FGF5 is overexpressed during the late anagen phase and serves as a crucial regulatory factor that promotes the anagen-to-catagen transition in the hair follicle cycle. FGF18, which is overexpressed during the telogen phase, mainly regulates the hair follicle cycle by maintaining the telogen phase and inhibiting the entry of hair follicles into the anagen phase. The inhibition of FGF5 may prolong the anagen phase, whereas the inhibition of FGF18 may promote the transition of the hair follicles from the telogen phase to the anagen phase. In the present study, we used siRNA to suppress FGF5 or FGF18 expression as a way to inhibit the activity of these genes. Using qPCR, we showed that FGF5-targeting siRNA modified by cholesterol was more effective than the same siRNA bound to a cell-penetrating peptide at suppressing the expression of FGF5 both in vitro and in vivo. We then investigated the effects of the cholesterol-modified siRNA targeting either FGF5 or FGF18 on the hair follicle cycle in a depilated area of the skin on the back of mice. The cholesterol-modified siRNA, delivered by intradermal injection, effectively regulated the hair follicle cycle by inhibiting the expression of FGF5 and FGF18. More specifically, intradermal injection of a cholesterol-modified FGF5-targeted siRNA effectively prolonged the anagen phase of the hair follicles, whereas intradermal injection of the cholesterol-modified FGF18-targeted siRNA led to the mobilization of telogen follicles to enter the anagen phase earlier. The inhibitory effect of the cholesterol-modified FGF18-targeted siRNA on FGF18 expression was also evaluated for a topically applied siRNA. Topical application of a cream containing the cholesterol-modified FGF18-targeted siRNA on a depilated area of the skin of the back of mice revealed comparable inhibition of FGF18 expression with that observed for the same siRNA delivered by intradermal injection. These findings suggested that alopecia could be prevented and hair regrowth could be restored either through the intradermal injection of cholesterol-modified siRNA targeting FGF5 or FGF18 or the topical application of FGF18 siRNA. [ABSTRACT FROM AUTHOR]

The pivotal role of FGF18 in the regulation of craniofacial and skeletal development has been well established. Previous studies have demonstrated that mice with deficiency in Fgf18 exhibit severe craniofacial dysplasia. Recent clinical reports have revealed that the duplication of chromosome 5q32-35.3, which encompasses the Fgf18 gene, can lead to cranial bone dysplasia and congenital craniosynostosis, implicating the consequence of possible overdosed FGF18 signaling. This study aimed to test the effects of augmented FGF18 signaling by specifically overexpressing the Fgf18 gene in cranial neural crest cells using the Wnt1-Cre;pMes-Fgf18 mouse model. The results showed that overexpression of Fgf18 leads to craniofacial abnormalities in mice similar to the Pierre Robin sequence in humans, including abnormal tongue morphology, micrognathia, and cleft palate. Further examination revealed that elevated levels of Fgf18 activated the Akt and Erk signaling pathways, leading to an increase in the proliferation level of tongue tendon cells and alterations in the contraction pattern of the genioglossus muscle. Additionally, we observed that excessive FGF18 signaling contributed to the reduction in the length of Meckel's cartilage and disrupted the development of condylar cartilage, ultimately resulting in mandibular defects. These anomalies involve changes in several downstream signals, including Runx2, p21, Akt, Erk, p38, Wnt, and Ihh. This study highlights the crucial role of maintaining the balance of endogenous FGF18 signaling for proper craniofacial development and offers insights into potential formation mechanisms of the Pierre Robin sequence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lv, Wang, Lin, Zheng, Zhang and Hu.)

Summary: Objective: Fibroblast growth factor 18 (FGF18) is involved in chondrogenesis and articular cartilage repair. We investigated tissue distribution and pharmacokinetics of radioactive [3H]sprifermin, a recombinant human FGF18, in rats after a single intravenous (i.v.) or intra-articular (i.a.) injection. Design: In two studies (48–96-h [n = 23] and 28-day [n = 12]), 35 male albino (Sprague Dawley) rats received single i.v. or i.a. dose [3H]sprifermin (0.24 mg/kg). Radioactivity was measured in blood, serum, and (in animals receiving i.a. administration) in the knee joint by liquid scintillation counting. Radioactivity in organs, tissues, and distribution in the whole body were measured with whole-body autoradiography. Results: After i.v. injection, radioactivity peaked in serum and whole blood after 4 and 24 h, respectively, with greater total radioactivity in serum. After i.a. injection, radioactivity peaked in serum and whole blood after 24 and 48 h, respectively; intact [3H]sprifermin was not detected in vena caval serum and systemic exposure was low, approximately 20% of that with i.v. injection. Following i.v. injection, radioactivity was mainly found in the liver, adrenal glands, kidney, and spleen; following i.a. injection, radioactivity was preferentially concentrated in articular cartilage after initial distribution in the joint capsule, and still evident in the joint after 28 days. Conclusions: After i.a. injection of [3H]sprifermin in rats, radioactivity was concentrated in the knee joint, particularly articular cartilage, with low levels in other investigated tissues. Systemic exposure to sprifermin was greater with i.v. than i.a. injection. Subsequent clinical investigation in patients with osteoarthritis has reported consistent results.

Fibroblast growth factor 18 (FGF18) is a member of the FGF family and contributes to a broad range of biological events. The important role of the overexpression of FGF18 has been identified in the progression of several types of cancers. However, there is still little information on the biological role of FGF18 on clear cell renal cell carcinoma (ccRCC), which is of interest in investigating the biological functions of FGF18 in ccRCC. Our results showed that FGF18 was lowly expressed in ccRCC tissues compared to paired normal renal tissue from the TCGA database and clinical cohort of Huashan Hospital and that high expression of FGF18 correlated with a good prognosis in ccRCC patients. In addition, overexpression of FGF18 significantly inhibited the proliferation ability of ccRCC cell lines in vitro and in vivo. Gene set enrichment analysis (GSEA) identified epithelial-mesenchymal transition (EMT) involved in a high FGF18 expression group of ccRCC patients in the TCGA cohort, which was further validated with EMT related markers in FGF18 overexpressed ccRCC cell lines. Furthermore, FGF18 overexpression significantly inhibited the PI3K/Akt pathway in ccRCC cells. Taken together, this study concludes that FGF18 is of potential value as a target for ccRCC.

Background/Aims: Fibroblast growth factors (FGFs) and their high-affinity receptors contribute to autocrine and paracrine growth stimulation in several human malignant tumors, including breast cancer. However, the mechanisms underlying the carcinogenic actions of FGF18 remain unclear. Methods: The transcription level of FGF18 under the hypoxic condition was detected with quantitative PCR (qPCR). A wound-healing assay was performed to assess the role of FGF18 in cell migration. A clonogenicity assay was used to determine whether FGF18 silencing affected cell clonogenicity. Western blotting was performed to investigate Akt/GSK3β/β-catenin pathway protein expression. Binding of β-catenin to the target gene promoter was determined by chromatin immunoprecipitation (ChIP) assays. Results: FGF18 promoted the epithelial-mesenchymal transition (EMT) and migration in breast cancer cells through activation of the Akt/GSK3β/β-catenin pathway. FGF18 increased Akt-Ser473 and -Thr308 phosphorylation, as well as that of GSK3β-Ser9. FGF18 also enhanced the transcription of proliferation-related genes (CDK2, CCND2, Ki67), metastasis-related genes (TGF-β, MMP-2, MMP-9), and EMT markers (Snail-1, Snail-2, N-cadherin, vimentin, TIMP1). β-catenin bound to the target gene promoter on the ChIP assay. Conclusion: FGF18 contributes to the migration and EMT of breast cancer cells following activation of the Akt/GSK3β/β-catenin pathway. FGF18 expression may be a potential prognostic therapeutic marker for breast cancer.

Fibroblast growth factor 18 (FGF18) is a member of the FGF family and contributes to a broad range of biological events. The important role of the overexpression of FGF18 has been identified in the progression of several types of cancers. However, there is still little information on the biological role of FGF18 on clear cell renal cell carcinoma (ccRCC), which is of interest in investigating the biological functions of FGF18 in ccRCC. Our results showed that FGF18 was lowly expressed in ccRCC tissues compared to paired normal renal tissue from the TCGA database and clinical cohort of Huashan Hospital and that high expression of FGF18 correlated with a good prognosis in ccRCC patients. In addition, overexpression of FGF18 significantly inhibited the proliferation ability of ccRCC cell lines in vitro and in vivo. Gene set enrichment analysis (GSEA) identified epithelial-mesenchymal transition (EMT) involved in a high FGF18 expression group of ccRCC patients in the TCGA cohort, which was further validated with EMT related markers in FGF18 overexpressed ccRCC cell lines. Furthermore, FGF18 overexpression significantly inhibited the PI3K/Akt pathway in ccRCC cells. Taken together, this study concludes that FGF18 is of potential value as a target for ccRCC. [ABSTRACT FROM AUTHOR]

Abstract Bone is a metabolically active organ that undergoes continuous remodeling throughout life. However, many complex skeletal defects such as large traumatic bone defects or extensive bone loss after tumor resection may cause failure of bone healing. Effective therapies for these conditions typically employ combinations of cells, scaffolds, and bioactive factors. In this review, we pay attention to one of the three factors required for regeneration of bone, bioactive factors, especially the fibroblast growth factor (FGF) family. This family is composed of 22 members and associated with various biological functions including skeletal formation. Based on the phenotypes of genetically modified mice and spatio-temporal expression levels during bone fracture healing, FGF2, FGF9, and FGF18 are regarded as possible candidates useful for bone regeneration. The role of these candidate FGFs in bone regeneration is also discussed in this review.

Increasing Cashmere production can add value because it is the primary product of Cashmere goats. Recent years, peoples find miRNAs are crucial in regulating the development of hair follicle. Following Solexa sequencing, many miRNAs were distinguishingly expressed in telogen skin samples of goats and sheep in earlier study. But the method through which miR-21 controls the growth of hair follicles is still ambiguous. Bioinformatics analysis was used to predict the target genes of miR-21. The mRNA level of miR-21 in telogen Cashmere goat skins was higher than in anagen, according to the results of qRT-PCR, and the target genes expressed similarly with miR-21. Western blot showed similar trend, the protein expression of FGF18 and SMAD7 were lower in anagen samples. The Dual-Luciferase reporter assay confirmed miRNA-21's relationship with its target gene, and the consequences indicated found FGF18 and SMAD7 have positive correlations with miR-21. Western blot and qRT-PCR distinguished the expression of protein and mRNA in miR-21 and its target genes. According to the consequence, we found that target genes expression was increased by miR-21 in HaCaT cells. This study identified that miR-21 might take part in the development of Cashmere goat's hair follicles by targeting FGF18 and SMAD7.

Objective Growing evidence indicates that microRNAs (miRNA) play a critical role in the pathogenesis of OA, and overexpressing or silencing miRNA expression in OA models can contribute to the development of miRNA-based therapeutics. The objective of this study was to determine whether intra-articular injection of miRNA can inhibit OA progression. Methods The miRNA expression profile was determined in OA cartilage tissues and controls. Functional analysis of the miRNAs on extracellular matrix degradation was performed after miRNA mimic or inhibitor transfection. Luciferase reporter assays and western blotting were employed to determine miRNA targets. To investigate the functional mechanism of miR-21-5p in OA development, miR-21-5pfl/flCol2a1-CreER and wild-type mice were subject to surgical destabilization of the medial meniscus. Therapeutically, wild-type mice undergoing surgical destabilization of the medial meniscus were treated with intra-articular injection of agomir- and antagomir-21-5p. Results We found that expression of miR-21-5p was significantly up-regulated in OA cartilage tissues. The articular cartilage degradation of miR-21-5p conditional knockout mice was significantly alleviated compared with that of wild-type mice in spontaneous and destabilization of the medial meniscus models. Through gain-of-function and loss-of-function studies, miR-21-5p was shown to significantly affect matrix synthesis genes expression, and chondrocyte proliferation and apoptosis. Further, fibroblast growth factor 18 (FGF18) was identified as a target of miR-21-5p. Intra-articular injection of antagomir-21-5p significantly attenuated the severity of experimental OA. Clinically, FGF18 expression level was correlated with miR-21-5p expression and a modified Mankin scale. Conclusion Our findings reveal a miRNA functional pathway important for OA development, highlighting miRNA-21-5p silencing as an attractive therapeutic regimen in future clinical trials involving patients with OA. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial pathology marked by amyloid beta (Aβ) accumulation, tau hyperphosphorylation, and progressive cognitive decline. Previous studies show that fibroblast growth factor 18 (FGF18) exerts a neuroprotective effect in experimental models of neurodegeneration; however, how it affects AD pathology remains unknown. This study aimed to ascertain the impact of FGF18 on the behavioral and neuropathological changes in the rat model of sporadic AD induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). The rats were treated with FGF18 (0.94 and 1.88 pmol, ICV) on the 15th day after STZ injection. Their cognitive function was assessed in the Morris water maze and passive avoidance tests for 5 days from the 16th to the 21st days. Aβ levels and histological signs of neurotoxicity were detected using the enzyme-linked immunosorbent assay (ELISA) assay and histopathological analysis of the brain, respectively. FGF18 mildly ameliorated the STZ-induced cognitive impairment; the Aβ accumulation was reduced; and the neuronal damage including pyknosis and apoptosis was alleviated in the rat brain. This study highlights the promising therapeutic potential for FGF18 in managing AD. • FGF18 treatment mildly reversed STZ-induced spatial and emotional memory deficits. • FGF18 treatment reduced brain Aβ1–42 levels in ICV-STZ rats. • FGF18 treatment alleviated the brain 8-OHdG and LC3β immunopositivity in ICV-STZ rats. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 18 (FGF18) plays an important functional role in skeletal growth and development. The FGF18 gene was characterized in pearl oyster Pinctada fucata martensii (PmFGF18) with the full-length sequence containing an open reading frame of 714 bp encoding 237 amino acids. The domain analysis of PmFGF18 showed a distinctive FGF domain, with a high similarity to FGF18 protein sequences from Crassostrea gigas (43.35%) and C. virginica (37.43%). PmFGF18 expression was revealed in all analyzed tissues with a significantly higher expression level in the fast-growing group than the slow-growing group. The analysis of PmFGF18 polymorphism demonstrated 33 SNPs (single nucleotide polymorphisms) in the CDS and promoter region of PmFGF18 sequence. Association analysis revealed 19 SNPs (2 SNPs from CDS and 17 SNPs from the promoter region) associating significantly with growth traits. Among the associated SNPs, one SNP g.50918198 A > C was verified in the other breeding line. Therefore, PmFGF18 can be utilized as a candidate gene for growth, and its related SNPs could be used in selective breeding of P. f. martensii for the improvement of growth traits.

Early loss of up to 50% of cells is common for in vitro chondrogenesis of mesenchymal stromal cells (MSC) in pellet culture, reducing the efficacy and the tissue yield for cartilage engineering. Enhanced proliferation could compensate for this unwanted effect, but relevant signaling pathways remain largely unknown. The aim of this study was to identify the contribution of bone morphogenetic protein (BMP), fibroblast growth factor (FGF), insulin‐like growth factor (IGF), and hedgehog (HH) signaling toward cell proliferation during chondrogenesis and investigate whether a further mitogenic stimulation is possible and promising. Human MSC were subjected to chondrogenesis in the presence or absence of pathway inhibitors or activators up to Day 14 or from Days 14 to 28, before proliferation, DNA and proteoglycan content were quantified. [3H]‐thymidine incorporation revealed arrest of proliferation on Day 3, after which cell division was reinitiated. Although BMP signaling was essential for proliferation throughout chondrogenesis, IGF signaling was relevant only up to Day 14. In contrast, FGF and HH signaling drove proliferation only from Day 14 onward. Early BMP4, IGF‐1, or FGF18 treatment neither prevented early cell loss nor allowed further mitogenic stimulation. However, application of the HH‐agonist purmorphamine from Day 14 increased proliferation 1.44‐fold (p < 0.05) and late BMP4‐application enhanced the DNA and proteoglycan content, with significant effects on tissue yield. Conclusively, a differential and phase‐dependent contribution of the four pathways toward proliferation was uncovered and BMP4 treatment was promising to enhance tissue yield. Culture forms less prone to size limitations by nutrient/oxygen gradients and a focus on early apoptosis prevention may be considered as the next steps to further enhance chondrocyte formation from MSC. [ABSTRACT FROM AUTHOR]

Different approaches have been developed to improve the scaffold properties that provide structural support and biological interaction to achieve the desired environment for tissue regeneration. We previously reported that addition of human fibroblast growth factor 18 (hFGF18) to acryloyl group-modified cholesterol-bearing pullulan (CHPOA) nanogel-crosslinked (NanoClik) hydrogels that contain human bone morphogenetic protein 2 (hBMP2) stabilized bone healing in mouse calvarial defect model. In this study, we evaluated the use of disc-shaped dried nanogel-crosslinked gel as carriers of growth factors in order to seek possible clinical application in future. Both conventionally-dried NanoClik disc and nanogel-crosslinked porous (NanoCliP) disc made by freeze-drying that contained the growth factors induced bone healing but not as much as with NanoClik hydrogel application but addition of RGD peptides (RGD-NanoCliP disc) improved the healing. All type of discs showed the same biphasic ovalbumin-Alexa Fluor 488 protein release profile in vitro, an initial burst followed by a gradual sustained release more than one week, which was confirmed in vivo. Histological analysis showed remarkable new bone formation with more calcification in RGD-NanoCliP disc with the growth factors and the osteogenesis appeared to begin in the dura mater in contact with the disc. These observations suggest: (1) the fitness of the durable discs to the bone defect is a critical factor for bone healing, which is supplemented by addition of RGD peptides, (2) the porosity is suitable for osteoblast recruitment, (3) growth factor release pattern of the CHPOA nanogel based gels is ideal for bone healing. [ABSTRACT FROM AUTHOR]

Cartilage integration remains a clinical challenge for treatment of focal articular defects. Cartilage exhibits limited healing capacity that declines with tissue maturation. Many approaches have been investigated for their ability to stimulate healing of mature cartilage or integration of repair tissue or tissue‐engineered constructs with native cartilage. Growth factors present in immature tissue may enhance chondrogenesis and promote integrative repair of cartilage defects. In this study, we assessed the role of one such factor, fibroblast growth factor 18 (FGF18). Studies using FGF18 have shown a variety of positive effects on cartilage, including stimulation of chondrocyte proliferation, matrix biosynthesis, and suppression of proteinase activity. To explore the role of FGF18 on cartilage defect repair, we hypothesized that treatment with recombinant human FGF18 (sprifermin) would increase matrix synthesis in a defect model, thus improving integration strength. To test this hypothesis, 6 mm cartilage cylinders were harvested from juvenile bovine knees. A central 3 mm defect was created in each explant, and this core was removed and replaced. Resulting constructs were cultured in control or sprifermin‐containing medium (weekly 24‐h exposure of 100 ng/ml sprifermin) for 4 weeks. Mechanical testing, biochemical analysis, micro‐CT, scanning electron microscopy, and histology were used to assess matrix production, adhesive strength, and structural properties of the cartilage‐cartilage interface. Results showed greater adhesive strength, increased collagen content, and larger contact areas between core and annular cartilage in the sprifermin‐treated group. These findings present a novel treatment for cartilage injuries that have potential to enhance defect healing and lateral cartilage–cartilage integration. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2648–2656, 2018. [ABSTRACT FROM AUTHOR]

Even though distinctive advances in the field of esophageal cancer therapy have occurred over the last few years, patients’ survival rates remain poor. FGF8, FGF18, and FGFR4 have been identified as promising biomarkers in a number of cancers; however no data exist on expression of FGF8, FGF18, and FGFR4 in adenocarcinomas of the esophago-gastric junction (AEG). A preliminary analysis of the Cancer Genome Atlas (TCGA) database on FGF8, FGF18, and FGFR4 mRNA expression data of patients with AEG was performed. Furthermore, protein levels of FGF8, FGF18, and FGFR4 in diagnostic biopsies and post-operative specimens in neoadjuvantly treated and primarily resected patients using immunohistochemistry were investigated. A total of 242 patients was analyzed in this study: 87 patients were investigated in the TCGA data set analysis and 155 patients in the analysis of protein expression using immunohistochemistry. High protein levels of FGF8, FGF18, and FGFR4 were detected in 94 (60.7%), 49 (31.6%) and 84 (54.2%) patients, respectively. Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 was an independent prognostic factor for diminished overall survival for all patients and for neoadjuvantly treated patients. By contrast, FGF18 overexpression was significantly associated with longer survival rates in neoadjuvantly treated patients. In addition, FGF8 protein level correlated with Mandard regression due to neoadjuvant therapy, indicating potential as a predictive marker. In summary, FGF8 and FGF18 are promising candidates for prognostic factors in adenocarcinomas of the esophago-gastric junction and new potential targets for new anti-cancer therapies.

Slow growth and rapid loss of chondrogenic phenotypes are the major problems affecting chronic cartilage lesions. The role of microRNA-195 (miR-195) and its detailed working mechanism in the fore-mentioned process remains unknown. Fibroblastic growth factor 18 (FGF-18) plays a key role in cartilage homeostasis; whether miR-195 could regulate FGF-18 and its downstream signal pathway in chondrocyte proliferation and maintenance of chondrogenic phenotypes still remains unclear. The present research shows elevated miR-195 but depressed FGF-18 expressed in joint fluid specimens of 20 patients with chronic cartilage lesions and in CH1M and CH3M chondrocytes when compared with that in joint fluid specimens without cartilage lesions and in CH1W and CH2W chondrocytes, respectively. The following loss of function test revealed that downregulation of miR-195 by transfection of miR-195 inhibitors promoted chondrocyte proliferation and expression of a type II collagen α I chain (Col2a1)/aggrecan. Through the online informatics analysis we theoretically predicted that miR-195 could bind to a FGF-18 3′ untranslated region (3′UTR), also, we verified that a miR-195 could regulate the FGF-18 and its downstream pathway. The constructed dual luciferase assay further confirmed that FGF-18 was a direct target of miR-195. The executed anti-sense experiment displayed that miR-195 could regulate chondrocyte proliferation and Col2a1/aggrecan expression via the FGF-18 pathway. Finally, through an in vivo anterior cruciate ligament transection (ACLT) model, downregulation of miR-195 presented a significantly protective effect on chronic cartilage lesions. Evaluating all of the outcomes of the current research revealed that a decrease of miR-195 protected chronic cartilage lesions by promoting chondrocyte proliferation and maintenance of chondrogenic phenotypes via the targeting of the FGF-18 pathway and that the miR-195/FGF-18 axis could be a potential target in the treatment of cartilage lesions. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor (FGF) signaling is necessary for proper lung branching morphogenesis, alveolarization, and vascular development. Dysregulation of FGF activity has been implicated in various lung diseases. Recently, we showed that FGF18 promotes human lung branching morphogenesis by regulating mesenchymal progenitor cells. However, the underlying mechanisms remain unclear. Thus, we aimed to determine the role of FGF18 and its receptors (FGFR) in regulating mesenchymal cell proliferation, migration, and differentiation from pseudoglandular to canalicular stage. We performed siRNA assays to identify the specific FGFR(s) associated with FGF18-induced biological processes. We found that FGF18 increased proliferation and migration in human fetal lung fibroblasts (HFLF) from both stages. FGFR2/FGFR4 played a significant role in pseudoglandular stage. HFLF proliferation, while FGFR3/FGFR4 were involved in canalicular stage. FGF18 enhanced HFLF migration through FGFR2 and FGFR4 in pseudoglandular and canalicular stage, respectively. Finally, we provide evidence that FGF18 treatment leads to reduced expression of myofibroblast markers (ACTA2 and COL1A1) and increased expression of lipofibroblast markers (ADRP and PPARγ) in both stages HFLF. However, the specific FGF18/FGFR complex involved in this process varies depending on the stage. Our findings suggest that in context of human lung development, FGF18 tends to associate with distinct FGFRs to initiate specific biological processes on mesenchymal cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Belgacemi, Cherry, El Alam, Frauenpreis, Glass, Bellusci, Danopoulos and Al Alam.)

Enhancement of endogenous bone regeneration is a priority for integration of joint replacement hardware with host bone for stable fixation of the prosthesis. Fibroblast Growth Factor (FGF) 18 regulates skeletal development and could therefore have applications for bone regeneration and skeletal repair. This study was designed to determine if treatment with FGF 18 would promote bone regeneration and integration of orthopedic hardware in FGF receptor 3 deficient (FGFR3-/-) mice, previously characterized with impaired bone formation. Rigid nylon rods coated with 200 nm of titanium were implanted bilaterally in the femora of adult FGFR3-/- and FGFR3+/+ mice to mimic human orthopedic hardware. At the time of surgery, LEFT femora received an intramedullary injection of 0.5 μg FGF18 (Merck Serono) and RIGHT femora received PBS as a control. Treatment with FGF18 resulted in a significant increase in peri-implant bone formation in both FGFR3+/+ and FGFR3-/- mice, with the peri-implant fibrous tissue frequently seen in FGFR3-/- mice being largely replaced by bone. The results of this pre-clinical study support the conjecture that FGF18 could be used in the clinical setting to promote integration of orthopedic hardware in poor quality bone.

Fibroblast growth factor 18(FGF18) is a member of the fibroblast growth factor family (FGFs). FGF18 is a class of bioactive substances that can conduct biological signals, regulate cell growth, participate in tissue repair and other functions, and can promote the occurrence and development of different types of malignant tumors through various mechanisms. In this review, we focus on recent studies of FGF18 in the diagnosis, treatment, and prognosis of tumors in digestive, reproductive, urinary, respiratory, motor, and pediatric systems. These findings suggest that FGF18 may play an increasingly important role in the clinical evaluation of these malignancies. Overall, FGF18 can function as an important oncogene at different gene and protein levels, and can be used as a potential new therapeutic target and prognostic biomarker for these tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor ZL declared a shared parent affiliation with the authors YZ, SS, TL, QY at the time of review., (Copyright © 2023 Zhou, Sun, Ling, Chen, Zhou and You.)

Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchymeassociated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligandinduced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor β1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo. [ABSTRACT FROM AUTHOR]