Fibroblast Growth Factor Activity Research Articles

FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.

Recent advances in fibroblast growth factor 23-related hypophosphatemic disorders.

Fibroblast growth factor 23 (FGF23) is a hormone to reduce blood phosphate concentration. Excessive actions of FGF23 induce FGF23-related hypophosphatemic disorders, such as X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO). We will summarize recent advances in the diagnosis and treatment of FGF23-related hypophosphatemic disorders. The measurement of blood FGF23 is useful to make a diagnosis of FGF23-related hypophosphatemic disorders. It was reported that many patients with FGF23-related hypophosphatemic disorders, especially TIO, were misdiagnosed, therefore, it is necessary to enhance the awareness of these diseases. A novel method to inhibit excessive actions of FGF23 by a human monoclonal antibody for FGF23, burosumab, has been approved in several countries. In more long-term observation than clinical trials, burosumab has also been shown to improve biochemical abnormalities and symptoms of rickets/osteomalacia. Following these advances, several registries and consensus recommendations on FGF23-related hypophosphatemic disorders, especially XLH, have been established in each country or region. Further long-term effects of burosumab and the precise mechanism of FGF23 overproduction in patients with FGF23-related hypophosphatemic disorders need to be clarified in the future studies.

FGF2 promotes the proliferation of injured granulosa cells in premature ovarian failure via Hippo-YAP signaling pathway

Young women undergoing anticancer treatment are at risk of premature ovarian failure (POF). Endometrial-derived stem cells (EnSCs) have demonstrated significant therapeutic potential for treating ovarian insufficiency, although the underlying mechanisms remain to be fully understood. This study aims to further investigate the therapeutic effects of EnSCs, particularly through the paracrine action of fibroblast growth factor 2 (FGF2), on POF. The findings show that exogenous FGF2 enhances the survival of ovarian granulosa cells damaged by cisplatin. FGF2 stimulates the proliferation of these damaged cells by suppressing the Hippo signaling pathway and activating YAP expression. In vivo experiments also revealed that FGF2 treatment significantly improves ovarian reserve and endocrine function in mice with POF. These results suggest that FGF2 can boost the proliferative capacity of damaged ovarian granulosa cells through the Hippo-YAP signaling pathway, providing a theoretical foundation for using EnSCs and FGF2 in clinical treatments for POF.

Emerging concepts on the FGF23 regulation and activity.

Fibroblast growth factor 23 (FGF23) discovery has provided new insights into the regulation of Pi and Ca homeostasis. It is secreted by osteoblasts and osteocytes, and acts mainly in the kidney, parathyroid, heart, and bone. The aim of this review is to highlight the current knowledge on the factors modulating the synthesis of FGF23, the canonical and non-canonical signaling pathways of the hormone, the role of FGF23 in different pathophysiological conditions, and the anti-FGF23 therapy. This is a narrative review based on the search of PubMed database in the range of years 2000-2023 using the keywords local and systemic regulators of FGF23 synthesis, FGF23 receptors, canonical and non-canonical pathways, pathophysiological conditions and FGF23, and anti-FGF23 therapy, focusing the data on the molecular mechanisms. The regulation of FGF23 synthesis is complex and multifactorial. It is regulated by local factors and systemic regulators mainly involved in bone mineralization. The excessive FGF23 production is associated with different congenital diseases and with diseases occurring with a secondary high FGF23 production such as in chronic disease kidney and tumor-induced osteomalacia (TIO). The anti-FGF23 therapy appears to be useful to treat chromosome X-linked hypophosphatemia and TIO, but there are doubts about the handle of excessive FGF23 production in CKD. FGF23 biochemistry and pathophysiology are generating a plethora of knowledge to reduce FGF23 bioactivity at many levels that might be useful for future therapeutics of diseases associated with high-serum FGF23 levels.

Noggin promotes osteogenesis in human adipose-derived mesenchymal stem cells via FGFR2/Src/Akt and ERK signaling pathway

The balance between Noggin and bone morphogenetic proteins (BMPs) is important during early development and skeletal regenerative therapies. Noggin binds BMPs in the extracellular space, thereby preventing BMP signaling. However, Noggin may affect cell response not necessarily through the modulation of BMP signaling, raising the possibility of direct Noggin signaling through yet unspecified receptors. Here we show that in osteogenic cultures of adipose-derived stem cells (ASCs), Noggin activates fibroblast growth factor receptors (FGFRs), Src/Akt and ERK kinases, and it stabilizes TAZ proteins in the presence of dexamethasone. Overall, this leads ASCs to increased expression of osteogenic markers and robust mineral deposition. Our results also indicate that Noggin can induce osteogenic genes expression in normal human bone marrow stem cells and alkaline phosphatase activity in normal human dental pulp stem cells. Besides, Noggin can specifically activate FGFR2 in osteosarcoma cells. We believe our findings open new research avenues to further explore the involvement of Noggin in cell fate modulation by FGFR2/Src/Akt/ERK signaling and potential applications of Noggin in bone regenerative therapies.

Fibroblast growth factor-induced lens fiber cell elongation is driven by the stepwise activity of Rho and Rac.

The spheroidal shape of the eye lens is crucial for precise light focusing onto the retina. This shape is determined by concentrically aligned, convexly elongated lens fiber cells along the anterior and posterior axis of the lens. Upon differentiation at the lens equator, the fiber cells increase in height as their apical and basal tips migrate towards the anterior and posterior poles, respectively. The forces driving this elongation and migration remain unclear. We found that, in the mouse lens, membrane protrusions or lamellipodia are observed only in the maturing fibers undergoing cell curve conversion, indicating that lamellipodium formation is not the primary driver of earlier fiber migration. We demonstrated that elevated levels of fibroblast growth factor (FGF) suppressed the extension of Rac-dependent protrusions, suggesting changes in the activity of FGF controlling Rac activity, switching to lamellipodium-driven migration. Inhibitors of ROCK, myosin and actin reduced the height of both early and later fibers, indicating that elongation of these fibers relies on actomyosin contractility. Consistent with this, active RhoA was detected throughout these fibers. Given that FGF promotes fiber elongation, we propose that it does so through regulation of Rho activity.

Ellagic acid protected the gingival tissue via fibroblast and epidermal growth factors in rats.

To investigate the effect of ellagic acid (EA) in gingival tissues injury in rats. Twenty rats were categorized into two groups. In burn group, an excisional wound area was created by removing a 4-mm diameter flap from the left molar region in the mucoperiosteal region of the gingiva. In burn + ellagic acid group, 1.2mg/mL EA was administered as irrigation for one week. Animals was sacrificed under anesthesia at the end of experiment. Malondialdehyde (MDA), myeloperoxidase (MPO) and glutathione (GSH) level were measured. Hematoxylin and eosin, fibroblast growth factor (FGF) and epidermal growth factor (EGF) immunostainings were applied to tissues. MDA, MPO, inflammation and leukocyte infiltration were high in burn group. Degeneration epithelium, edema and inflammatory cell infiltration in connective tissue areas, and dilatation and congestion in blood vessels were observed in burn group. In burn + EA group, the gingival epithelium improved, collagen fiber production increased and organized dermis were observed. After burn injury, FGF and EGF activity was increased in EA treated groups. We suggest that EA have the potential for better healing outcomes in oral wounds. EA seems to have promising therapeutic efficacy to enhance oral wound healing.

Tumor-induced osteomalacia.

Tumor-induced osteomalacia is one of paraneoplastic syndromes characterized by hypophosphatemia caused by excessive actions of fibroblast growth factor 23 (FGF23). Since the cloning of FGF23 about 20 years ago, more widespread awareness of this disease has been achieved. However, there still remain several difficulties in the management of patients with this disease. In this review, these clinical problems are discussed together with the physiological and pathophysiological functions of FGF23. Personal proposals in the management of patients with suspected patients with tumor-induced osteomalacia are also presented.

Fibroblast growth factor 21 inhibits ferroptosis following spinal cord injury by regulating heme oxygenase-1.

Abstract JOURNAL/nrgr/04.03/01300535-202407000-00037/figure1/v/2023-11-20T171125Z/r/image-tiff Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury. Fibroblast growth factor 21 can inhibit ferroptosis and promote neurofunctional recovery, while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis. The relationship between heme oxygenase-1 and ferroptosis remains controversial. In this study, we used a spinal cord injury rat model to show that the levels of fibroblast growth factor 21 in spinal cord tissue decreased after spinal cord injury. In addition, there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury. Further, heme oxygenase-1 aggravated ferroptosis after spinal cord injury, while fibroblast growth factor 21 inhibited ferroptosis by downregulating heme oxygenase-1. Thus, the activation of fibroblast growth factor 21 may provide a potential treatment for spinal cord injury. These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.

Recurrent Soft Tissue Infections Associated With Burosumab Therapy in X-Linked Hypophosphatemic Rickets

Abstract X-linked hypophosphatemic rickets (XLH) is a genetic disorder characterized by elevated fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and inadequate bone mineralization. Burosumab, a monoclonal antibody that inhibits FGF23 activity, has shown promise in improving renal phosphate reabsorption and clinical outcomes in XLH patients. However, the potential side effects of burosumab, particularly its impact on immune function and susceptibility to infections, remain a subject of concern. In this case report, we describe a 57-year-old male individual with XLH who experienced recurrent soft tissue infections while receiving burosumab therapy. The infections included an olecranon abscess, a cervical retropharyngeal phlegmon with a sternocleidomastoid abscess, and suprapubic cellulitis, all of which were treated with antibiotic therapy. Following discontinuation of burosumab therapy, the patient did not experience further soft tissue infections. These observations suggest a potential association between burosumab therapy and an increased risk of soft tissue infections. Mechanistically, disruption of the FGF23-Klotho signaling axis may lead to impaired humoral immunity mediated by B lymphocytes and compromised innate immune response mediated by macrophages. Further investigation is warranted to better understand the immunological effects of burosumab and its implications for infectious complications in XLH patients.

Correlation of bioactive components of platelet rich plasma derived from human female adult peripheral blood and umbilical cord blood with age

Platelet-rich plasma (PRP) has gained significant attention in the field of regenerative medicine due to its potential therapeutic applications. However, few studies have reported the components, especially anti-ageing-related components, of PRP derived from umbilical cord blood (UCB). It is essential to understand the influence of age on the composition and efficacy of PRP to optimize its clinical use. The present study compared the concentrations of bioactive components in PRP from healthy female adults and UCB-derived PRP. PRP was obtained from blood samples from females in four age groups (12 per group): neonates (UCB donors) and adults aged 18–25, 26–45, and 46–65 years, respectively. The concentrations of epidermal growth factor, basic fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1, platelet-derived growth factor-AA (PDGF-AA), PDGF-AB/BB, vascular endothelial growth factor A, RANTES, TIMP-1, TIMP-2, GDF11, and clusterin and activity of superoxide dismutase, catalase, and glutathione peroxidase (GPx) in the PRP samples were determined and compared among groups. Pairwise comparisons between the groups showed statistically significant differences in the concentrations of some bioactive components of PRP, such as FGF-2, PDGF-AB/BB, and clusterin, and GPx activity. UCB-derived PRP contains various active ingredients such as VEGF-A, CAT activity, and TIMP-2. Contrary to expectations, UCB-derived PRP did not show higher concentrations of the anti-ageing protein GDF11. Because UCB is a rich source of bioactive components with low immunogenicity, its use in PRP preparation is an important research direction for future studies.

Short-term fasting of mice elevates circulating fibroblast growth factor 23 (FGF23).

Phosphate and vitamin D homeostasis are controlled by fibroblast growth factor 23 (FGF23) from bone suppressing renal phosphate transport and enhancing 24-hydroxylase (Cyp24a1), thereby inactivating 1,25(OH)2 D3 . Serum FGF23 is correlated with outcomes in several diseases. Fasting stimulates the production of ketone bodies. We hypothesized that fasting can induce FGF23 synthesis through the production of ketone bodies. UMR106 cells and isolated neonatal rat ventricular myocytes (NRVM) were treated with ketone body β-hydroxybutyrate. Mice were fasted overnight, fed ad libitum, or treated with β-hydroxybutyrate. Proteins and further blood parameters were determined by enzyme-linked immunoassay (ELISA), western blotting, immunohistochemistry, fluorometric or colorimetric methods, and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). β-Hydroxybutyrate stimulated FGF23 production in UMR106 cells in a nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB)-dependent manner, and in NRVMs. Compared to fed animals, fasted mice exhibited higher β-hydroxybutyrate and FGF23 serum levels (based on assays either detecting C-terminal or intact, biologically active FGF23 only), cardiac, pancreatic, and thymic Fgf23 and renal Cyp24a1 expression, and lower 1,25(OH)2 D3 serum concentration as well as renal Slc34a1 and αKlotho (Kl) expression. In contrast, Fgf23 expression in bone and serum phosphate, calcium, plasma parathyroid hormone (PTH) concentration, and renal Cyp27b1 expression were not significantly affected by fasting. Short-term fasting increased FGF23 production, as did administration of β-hydroxybutyrate, effects possibly of clinical relevance in view of the increasing use of FGF23 as a surrogate parameter in clinical monitoring of diseases. The fasting state of patients might therefore affect FGF23 tests.

Preferential FGF18/FGFR activity in pseudoglandular versus canalicular stage human lung fibroblasts.

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.

Analysis of the Effect of Substrate Stiffness on the Efficacy of Fibroblast Growth Factor 2 and Bone Morphogenetic Protein 4 in Inducing Pro-Regenerative Astrocyte Phenotype: A Research Protocol

Introduction: Astrocytes are glial cells essential for neuronal development and repair and are thus a highly promising target for regenerative therapies for neurodegenerative disease. Neurodegeneration has been connected to the degradation of extracellular matrix (ECM) components. ECM's structural properties, such as stiffness, influence the phenotypic outcomes of growing cells. Notably, astrocytes are induced into an A2 (pro-regenerative) phenotype when grown on stiff substrates or exposed to specific signalling molecules, particularly fibroblast growth factor 2 (FGF-2) and bone morphogenetic protein 4 (BMP-4). Given that the ECM can bind and sequester growth factors, it is possible that matrix stiffness may modulate the efficacy of these molecules. Methods: In this in vitro study, rat primary cortical astrocytes will be cultured on soft and stiff substrates and exposed to varying amounts of FGF-2 and BMP-4. This study aims to determine the effect of substrate stiffness on the efficacy of FGF-2 and BMP-4 in promoting pro-regenerative phenotype. Cell proliferation and glial fibrillary acidic protein (GFAP) expression are key indicators of reactive astrocytes, including pro-regenerative astrocytes. 5-bromo-2-deoxyuridine staining will be used to analyze proliferation. GFAP expression will be determined using anti-GFAP antibody conjugated with Alexa Fluor 594. Further, pro-regenerative phenotypic genes Clcf1, Tgm2, and Ptgs2 will be detected via polymerase chain reaction to differentiate from pro-inflammatory astrocytes, a separate category of reactive astrocytes. Anticipated Results: We hypothesize there will be a greater positive correlation between the concentration of FGF-2 or BMP-4 and expression of markers of pro-regenerative phenotype under stiff substrate conditions, compared to softer substrate, thus indicating dependency or synergy between FGF-2 or BMP-4 and extracellular matrix-dependent pathways. Discussion: The correlation between FGF-2 or BMP-4 concentration and the prominence of A2 astrocyte phenotype indicators will be graphed and reported along with a comparison of these correlations between soft and stiff substrate groups. The authors will attempt to conclude whether substrate stiffness significantly effects the activities of FGF-2 or BMP-4. Conclusion: We hope the results of this proposed study will inform the development of neuroregenerative therapies involving astrocytes by indicating the necessity for greater focus on either the application of signalling molecules or modification of ECM.

1527-P: Anorexia Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1) Is Dependent on Reduced GABA Receptor Activation

Previously, we reported that in multiple rodent models of type 2 diabetes, remission of hyperglycemia lasting for weeks can be induced by a single intracerebroventricular (icv) injection of FGF1. This effect is accompanied by a potent but transient anorexic response that is sufficiently robust as to hinder efforts to translate these findings towards the clinic. To understand the mechanism underlying FGF1-induced anorexia, we considered 1) our recent finding that icv FGF1 induces acute and sustained inhibition of hypothalamic AgRP neurons, and 2) prior work showing that parabrachial nucleus that express calcitonin gene-related peptide (PBNCGRP neurons) are both highly anorexigenic and tonically inhibited by GABAergic projections from AgRP neurons. We therefore hypothesized that FGF1-induced anorexia involves activation PBNCGRPneurons arising from reduced GABAergic input. Consistent with this hypothesis, we report that PBNCGRPneurons are robustly activated following icv FGF1 injection (based on c-Fos staining) via a mechanism that appears to be indirect, since the c-Fos induction is not associated with FGF receptor (FGFR) activation (detected by pERK staining in the PBN). We next asked whether the anorexic response to icv FGF1 administration can be blunted by systemic administration of a GABAA receptor agonist. Consistent with this hypothesis, we found that continuous subcutaneous infusion of the GABAA receptor agonist Bretazenil blunts the anorexic response to icv FGF1 injection by ~50% at a dose that has no effect intake in control mice. Similarly, the effect of FGF1 to induce c-Fos in the PBN was largely blocked by Bretazenil, and our preliminary findings indicate that CGRP neurons are among those in which this effect occurred. Together, these data suggest that FGF1-induced anorexia results from reduced GABAergic inhibition of PBNCGRP neurons. Disclosure J.M.Scarlett: None. K.M.Alonge: None. B.N.Phan: None. G.J.Morton: Research Support; Novo Nordisk A/S. M.W.Schwartz: Consultant; NodThera, Research Support; Novo Nordisk A/S. Funding U.S. Department of Defense (PRMRP W81XWH-21-1-0635); National Institutes of Health (DK083042)

THE MAIN CLINICAL AND PATHOGENETIC FEATURES OF THE COMORBID COURSE OF NON-ALCOHOLIC STEATOHEPATITIS, OBESITY AND HYPERTENSION

SUMMARY. The incidence of nonalcoholic steatohepatitis (NASH) in the population is 20–40 %, in obese patients – 50–90 %. The presence of NASH significantly reduces the quality of life of patients. The presence of concomitant arterial hypertension in patients can cause a cascade of reactions of mutual burdens, which will lead to the progression of all comorbid diseases. The aim – to investigate the differences between clinical and laboratory parameters in the comorbid course of NASH on the background of obesity. In addition, we studied the state of hepatic circulation and the functional state of the endothelium depending on the presence of comorbid hypertension. Material and Methods. Systematic review with further analysis, comparison, systematization and generalization of scientific literature in MEDLINE, Cochrane and PubMed databases of relevant articles on the study of psychological characteristics of women of childbearing age diagnosed with psychogenic infertility. Results. In recent years, NASH has increasingly been seen as an additional independent risk factor for cardiovascular disease and a predictor of its complications. The course of NASH under conditions of comorbidity with obesity in comparison with the isolated course is characterized by a predominance of hypertension of II degree (60.0 %), increased variability of systolic blood pressure (SBP) during the day with increasing duration of “pressure load” during the day. The comorbid course of NASH with obesity and hypertension (HT) there is a significant activation of the processes of liver tissue fibrosis, the content of protein-bound oxyproline in the blood, fibronectin, hexosamines, sialic acids, fucose, not bound to protein due to the activation of fibroblast growth factor, in response to which there is usually inadequate compensatory activation of collagenolysis (increase in the content of free oxyproline in the blood, which was inhibited by excessively activated proteinase-inhibitory system). Conclusions. The comorbidity of NASH with HT and obesity is a powerful pathogenetic factor that worsens the quality of life of patients to a much greater extent than the severity of a single disease. It's crucial to have multidisciplinary approach in the treatment of people with comorbidity of HT with NASH on the background of obesity.

FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.

FIRST INTERIM ANALYSIS OF THE INTERNATIONAL X-LINKED HYPOPHOSPHATAEMIA (XLH) REGISTRY: ORTHOPAEDIC BASELINE CHARACTERISTICS

X-Linked Hypophosphataemia (XLH) is a rare, progressive, hereditary phosphate-wasting disorder characterised by excessive activity of fibroblast growth factor 23. The International XLH Registry was established to provide information on the natural history of XLH and impact of treatment on patient outcomes. The cross-sectional orthopaedic data presented are from the first interim analysis.The XLH Registry (NCT03193476) was initiated in August 2017, aims to recruit 1,200 children and adults with XLH, and will run for 10 years. At the time of analysis (Last Patient In: 30/11/2020; Database Lock: 29/03/2021) 579 subjects diagnosed with XLH were enrolled from 81 hospital sites in 16 countries (360 (62.2%) children, 217 (37.5%) adults, and 2 subjects of unknown age).Of subjects with retrospective clinical data available, skeletal deficits were the most frequently self-reported clinical problems for children (223/239, 93.3%) and adults (79/110, 71.8%). Retrospective fracture data were available for 183 subjects (72 children, 111 adults); 50 had a fracture (9 children, 41 adults). In children, fractures tended to occur in tibia/fibula and/or wrist; only adults reported large bone fractures. Joint conditions were noted for 46 subjects (6 children, 40 adults). For adults reporting osteoarthritis, knees (60%), hips (42.5%), and shoulders (22.5%) were the most frequently affected joints. Retrospective orthopaedic surgery data were collected for 151 subjects (52 children, 99 adults). Osteotomy was the most frequent surgery reported (n=108); joint replacements were recorded for adults only.This is the largest set of orthopaedic data from XLH subjects collected to date. Longitudinal information collected during the 10-year Registry duration will generate real-world evidence which will help to inform clinical practice.Authors acknowledge the contribution of all International XLH Registry Steering Committee members.

Effects of gallic acid on gingival wounds.

Our aim in this study was to investigate the effect of Gallic acid (GA) on gingival tissue injury. Twenty rats were categorized into two groups. In the burn group, an excisional wound area was created by removing a 4 mm diameter flap from the left molar region in the mucoperiosteal region of the gingiva. In the Burn+gallic acid group, 1.2 mg/ml GA was administered as irrigation for 1 week. Animals were sacrificed under anesthesia at the end of experiment. Malondialdehyde (MDA), myeloperoxidase (MPO) and glutathione (GSH) levels were measured. Hematoxylin Eosin, fibroblast growth factor (FGF) and epidermal growth factor (EGF) immunostaining was applied to tissues. MDA and MPO levels increased, and GSH, epithelization, FGF and EGF expression levels were decreased. Gallic acid treatment improved these scores. Degenerated gingival epithelium, disintegrity in epithelial and connective tissue fibers, edema and inflammatory cells were observed in the burn group. Gallic acid treatment after burn improved the pathologies. After burn injury, FGF and EGF activity was increased in Gallic acid-treated groups. We suggest that GA has the potential for better healing outcomes in oral wounds. GA seems to have promising therapeutic efficacy in enhancing oral wound healing.

Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model

BackgroundPostmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone regeneration delays fracture healing. Activated fibroblast growth factor receptor 3 (FGFR3) accelerates bone regeneration at juvenile age and downregulates bone mineralization at all ages. However, the impact of FGFR3 signaling on bone regeneration and bone mineralization post-menopause is still unknown. This study aimed to evaluate the impact of FGFR3 signaling on bone regeneration and bone mineralization during menopause by developing a distraction osteogenesis (DO) mouse model after ovariectomy (OVX) using transgenic mice with activated FGFR3 driven by Col2a1 promoter (Fgfr3 mice).MethodsThe OVX or sham operations were performed in 8-week-old female Fgfr3 and wild-type mice. After 8 weeks of OVX surgery, DO surgery in the lower limb was performed. The 5-day-latency period followed by performing distraction for 9 days. Bone mineral density (BMD) and bone regeneration was assessed by micro-computed tomography (micro-CT) scan and soft X-ray. Bone volume in the distraction area was also evaluated by histological analysis after 7 days at the end of distraction. Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) derived from each mouse after 8 weeks of the OVX or sham operations were also evaluated with and without an inhibitor for FGFR3 signaling (meclozine).ResultsBMD decreased after OVX in both groups, and it further deteriorated in Fgfr3 mice. Poor callus formation after DO was also observed in both groups with OVX, and the amount of regenerated bone was further decreased in Fgfr3 mice. Similarly, histological analysis revealed that Fgfr3 OVX mice showed lower bone volume. Osteogenic differentiation and mineralization of BMSCs were also deteriorated in Fgfr3 OVX mice. An inhibitor for FGFR3 signaling dramatically reversed the inhibitory effect of OVX and FGFR3 signaling on BMSC mineralization.ConclusionUpregulated FGFR3 decreased newly regenerated bone after DO and BMD in OVX mice. FGFR3 signaling can be a potential therapeutic target in patients with postmenopausal osteoporosis.