Production Of Fibroblast Growth Factor Research Articles

Endothelin receptor B-deficient mice are protected from high-fat diet-induced metabolic syndrome

ObjectiveEndothelin receptor B (ETB) together with ETA mediates cellular effects of endothelin 1 (ET-1), an autocrine and endocrine peptide produced by the endothelium and other cells. It regulates vascular tone and controls kidney function. Metabolic syndrome is due to high caloric intake and is characterized by insulin resistance, dyslipidemia, and white adipose tissue (WAT) accumulation. ETA/ETB antagonism has been demonstrated to favorably influence insulin resistance. Our study explored the role of ETB in metabolic syndrome. MethodsWild type (etb+/+) and rescued ETB-deficient (etb−/−) mice were fed a high-fat diet, and energy, glucose, and insulin metabolism were analyzed, and hormones and lipids measured in serum and tissues. Cell culture experiments were performed in HepG2 cells. ResultsCompared to etb+/+ mice, etb−/− mice exhibited better glucose tolerance and insulin sensitivity, less WAT accumulation, lower serum triglycerides, and higher energy expenditure. Protection from metabolic syndrome was paralleled by higher hepatic production of fibroblast growth factor 21 (FGF21) and higher serum levels of free thyroxine (fT4), stimulators of energy expenditure. ConclusionsETB deficiency confers protection from metabolic syndrome by counteracting glucose intolerance, dyslipidemia, and WAT accumulation due to enhanced energy expenditure, effects at least in part dependent on enhanced production of thyroid hormone/FGF21. ETB antagonism may therefore be a novel therapeutic approach in metabolic syndrome.

Phosphaturic mesenchymal tumor: A chondromyxoid fibroma-like type.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that causes tumor-induced osteomalasia (TIO) in most affected patients, usually through the production of fibroblast growth factor 23 (FGF23). This tumor is often misdiagnosed due to its relative rarity and its widely varied histomorphologic spectrum. Here we describe a case of a 78-year-old woman who presented with a left middle tumor without symptoms of TIO. The histological features resembled chondromyxoid fibroma with smudgy calcification in the tumor matrix. In addition, we evaluated FGF23 expression through immunohistochemical study and reverse transcription polymerase chain reaction. PMT with chondromyxoid fibroma features are extremely rare. Examining the expression of FGF23 is useful in the diagnosis of PMT.

Ovalbumin’s potential as a wound-healing medicament in tooth extraction socket by induction of cell proliferation through the ERK2 pathway in silico

Background: The trend of studies on dental medicaments is increasing rapidly. Antibacterial or anti-inflammatory activity is most frequently studied. Ovalbumin is one of the proteins whose benefits have been studied, but these benefits are still limited because of ovalbumin’s potential for proliferative bioactivity. Purpose: The aim of this study is to examine ovalbumin’s potential as a woundhealing medicament through molecular docking analysis on a protein related to the extracellular signal-regulated kinases/mitogenactivated protein kinase (ERK/MAPK) signaling pathway. Methods: Ovalbumin was hydrolyzed through BIOPEP-UWM (The BIOPEPUWM™ database of bioactive peptides). Protein target and interaction were predicted using Similarity Ensemble Approach target prediction webserver, SuperPred webserver, STRING webserver, and Cytoscape version 3.9.1. Selected fragments were docked using Autodock Vina in PyRx 0.8 with Tukey’s multiple comparison test and Biovia Discovery Studio version 19.1.0.18287 for visualization. Results: This study found that ovalbumin has the potential to positively regulate cell proliferation, angiogenesis, and fibroblast growth factor production. Six of the 131 fragments of ovalbumin could interact with 73 proteins, and the 20 proteins with the highest probability and score of betweenness centrality showed potential for bioactivity. Five fragments and povidone-iodine interacted inside the Adenosine triphosphate (ATP) phosphorylation site of ERK2, whereas fragment 1 (F1) and glycerin interacted outside the site. F1 could decrease the binding energy required for adenosine 5′-[,-methylene]triphosphate or an ATP-analogue chemical compound to interact with ERK2 compared to the control, with a score that was not significant. Conclusion: Ovalbumin has the potential to induce cell proliferation by affecting ERK2-ligand interactions.

Shift in Calcium From Peripheral Bone to Axial Bone After Tumor Resection in Patients With Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. After successful tumor resection, patients can recover from hypophosphatemia quicky. However, data on the changes in bone mineral density (BMD) and microstructure in the short term after surgery remained unclear. This work aimed to investigate the postoperative changes in BMD and microstructure both in peripheral and axial bone in TIO patients. We evaluated BMD and microarchitecture in 22 TIO patients using high-resolution peripheral quantitative computed tomography (HR-pQCT) and dual-energy x-ray absorptiometry (DXA) before and 3 months after surgery in this retrospective study. In this study, a total of 22 TIO patients who had recovered serum phosphate levels postoperatively were enrolled. After surgery, areal BMD (aBMD) increased by 21.6% in the femoral neck, by 18.9% in the total hip, and by 29.5% in the lumbar spine. Moreover, TBS increased by 14.1% (all P < .001). In contrast, trabecular or cortical volumetric BMD (vBMD), and microstructure of trabecular bone (trabecular number, separation and bone volume ratio) and cortical bone (cortical thickness and porosity) at the distal radius or tibia were further deteriorated. Correlation analyses found that changes in femoral neck and total hip aBMD were both conversely associated with changes in trabecular vBMD and bone volume ratio, while positively correlated with change in trabecular separation at the distal radius. Although aBMD and microstructure in the axial bone were improved, vBMD and microstructure in the peripheral bone were further impaired shortly after surgery. Correlation of improvement of aBMD in the total hip and femoral neck with deterioration of vBMD and microstructure at the distal radius indicated a shift in calcium from the peripheral bone to the axial bone in the short term after tumor resection in TIO patients.

Tumor-induced Osteomalacia Secondary to Phosphaturic Mesenchymal Tumor.

HomeRadiology: Imaging CancerVol. 5, No. 2 PreviousNext Images in CancerFree AccessTumor-induced Osteomalacia Secondary to Phosphaturic Mesenchymal TumorAmit Agarwal , Girish Bathla, Vivek GuptaAmit Agarwal , Girish Bathla, Vivek GuptaAuthor AffiliationsFrom the Departments of Radiology (A.A.) and Neuroradiology (V.G.), Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; and Department of Radiology, Mayo Clinic, Rochester, Minn (G.B.).Address correspondence to A.A. (email: [email protected]).Amit Agarwal Girish BathlaVivek GuptaPublished Online:Mar 10 2023https://doi.org/10.1148/rycan.220170MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia, is an uncommon paraneoplastic syndrome characterized by urinary phosphate wasting due to an increased production of fibroblast growth factor 23 (FGF23), secondary to an underlying phosphaturic mesenchymal tumor (PMT). Patients usually present with bone pain and pathologic fractures caused by hypophosphatemic hyperphosphaturic osteomalacia (Fig 1), characterized by high serum FGF23 levels (Fig 2) and low serum calcitriol levels. Given the rarity of this entity and nonspecific clinical and imaging features, these tumors are challenging to diagnose and can go undetected for many years (1). Tumors can be found in any osseous or soft-tissue location, however, and are typically observed in the extremities, most commonly the femur, of middle-aged adults. TIO is also associated with other mesenchymal tumors, including solitary fibrous tumors and giant cell tumors, primarily due to FGF23 secretion. A combination of nuclear scans using somatostatin analogs, such as gallium-68 tetraazacyclododecane tetraacetic acid octreotate (68Ga-DOTATATE) and indium-111 (111In)-pentetreotide (OctreoScan), provides the highest sensitivity for detecting tumors, which are usually small in size and not evident at clinical examination. These lesions appear to be moderately fluorodeoxyglucose avid, potentially aiding in diagnosis, but have wide variability in uptake and limited specificity. CT and MRI are noncontributory for initial location but are usually needed later to evaluate anatomic extent. Surgical resection of PMTs is typically curative, resulting in complete resolution of the syndrome (2,3). While few cases of PMT have been reported, it is important to consider this diagnosis in all patients with hypophosphatemic osteomalacia.Figure 1: (A) Methylene diphosphonate bone scan in a 65-year-old female patient with bone pain reveals multiple foci of increased uptake (arrowheads) over bilateral femur and sternum, along with prominent costochondral beadings (rosary), suggesting metabolic bone disease (osteomalacia). Serologic workup revealed a high serum fibroblast growth factor 23 (FGF23) level of 1155 reference unit (RU)/mL (reference range, ≤180 RU/mL) with low serum phosphate level and elevated alkaline phosphatase level. (B) Coronal noncontrast CT image of the lumbar spine reveals a lytic lesion in the right transverse process of L3 (arrow) with (C) increased fluorodeoxyglucose uptake (standardized uptake value, 9.8) (arrow) on the axial PET/CT image.Figure 1:Download as PowerPointOpen in Image Viewer Figure 2: Histopathologic features of phosphaturic mesenchymal tumors, with predominantly spindled cells on hematoxylin-eosin (H&E) stains and strong expression of fibroblast growth factor 23 (FGF-23) mRNA on in situ hybridization (ISH).Figure 2:Download as PowerPointOpen in Image Viewer Disclosures of conflicts of interest: A.A. Consulted for and expert testimony for Authnetic4D in 2020; institutional CME fund (attending meetings/travel); stocks in Gilead Pharma. G.B. Grant from Foundation of Sarcoidosis Research, unrelated to current work. V.G. No relevant relationships.Keywords: Osteomalacia, Phosphaturic, Spine, Tumor MicroenvironmentAuthors declared no funding for this work.

A case of tumor-induced osteomalacia masked by acute kidney injury

Introduction:Hypophosphatemia in patients with tumor-induced osteomalacia (TIO) is due to abnormal excess production of fibroblast growth factor 23 (FGF-23) causing urinary phosphate wasting. However, in patients with coexisting acute kidney injury (AKI), hypophosphatemia may not be apparent as AKI reduces filtration and excretion of phosphate.Case report:We describe a case of 36-year-old woman who presented with right-sided abdominal pain. Initial laboratory testing revealed non oliguric AKI with creatinine (Cr) of 2.0 mg/dL (baseline 1.2 mg/dL), low phosphate (1.8 mg/dL), and normal parathyroid (PTH) levels. Hypophosphatemia in the setting of AKI and normal PTH raised suspicion for renal phosphate wasting disorder independent of PTH, triggering an order for FGF-23 level. Further into hospital stay, the AKI worsened (Cr rose to 7.2 mg/dL) and phosphate levels increased to 6.7 mg/dL casting doubt on the initial suspicion. However, FGF-23 level resulted at 12,715 RU/mL, strongly suggesting TIO. Random liver biopsy was obtained as part of TIO work up due to liver ultrasound findings of hepatomegaly, diffuse parenchymal heterogenicity mimicking steatosis and potential ill-defined mass. Liver specimen showed tumor cells positive for CD56 and Ki-67, indicating high-grade metastatic neuro endocrine tumor which was the likely source of FGF-23. Patient rapidly deteriorated and opted for comfort measures.Conclusion:TIO typically manifests with overt hypophosphatemia. This case highlights the fact that decreased glomerular filtration rate may mask the degree of urinary phosphate wasting resulting in normal to high serum phosphate level. This warrants high index of suspicion to diagnose an underlying phosphate wasting disorder in the setting of normal to high serum phosphate levels and reduced kidney function.

Hyperparathyroidism in a Large Cohort of Chinese Patients With Tumor-induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Hyperparathyroidism (HPT) including secondary HPT (SHPT) and tertiary HPT (THPT) in TIO patients, which is believed to be associated with phosphate supplementation, has not been well documented. To clarify the prevalence, clinical characteristics, and risk factors for HPT in a large cohort of Chinese patients with TIO in our hospital. This retrospective study enrolled 202 patients with TIO. Occurrence of HPT in patients with TIO. HPT was observed in 91 patients (91/202, 45.1%): 84 patients (41.6%) with SHPT and 7 patients (3.5%) with THPT. All patients with THPT underwent parathyroidectomy and only 1 patient experienced recurrence. Compared with patients without HPT, patients with SHPT had longer disease duration, higher rate of phosphate and calcitriol supplementation, lower serum calcium, lower urine calcium excretion, and higher urine phosphate excretion. Compared with patients with SHPT, patients with THPT had even longer disease duration and a higher rate of phosphate and calcitriol supplementation. PTH levels showed positive correlation with intact FGF23 and 1,25-dihydroxyvitamin D levels, but not 25-hydroxy vitamin D level in patients with TIO. Multivariate logistic regression analysis showed that long disease duration and phosphate supplementation were independently associated with occurrence of HPT in patients with TIO. Further logistic regression analysis and restricted cubic spline model revealed dose-response relationship between cumulative dose of phosphate supplementation and PTH levels. HPT is common in patients with TIO. To avoid the occurrence of HPT in patients with TIO, timely diagnosis and tumor resection is necessary and an excessive dose of phosphate supplementation is not suggested before surgery.

Treatment of X-Linked Hypophosphatemia in Children

The conventional treatment for X-linked hypophosphatemia (XLH), consisting of phosphorus supplementation and a biologically active form of vitamin D (alfacalcidol or calcitriol), is used to treat rickets and leg deformities and promote growth. However, patients’ adult height often remains less than −2 SD. Moreover, adverse events, such as renal calcification and hyperparathyroidism, may occur. The main pathology in XLH is caused by excessive production of fibroblast growth factor 23 (FGF23). Several studies have demonstrated that treatment with burosumab, a blocking neutralizing antibody against FGF23, is better than conventional therapy for severe XLH and has no serious, short-term side effects. Thus, treatment with burosumab may be an option for severe XLH. The present article reviews the conventional and burosumab therapies. In addition to the fact that the long-term efficacy of antibody-based treatment has not been demonstrated, there are other, unresolved issues concerning the burosumab treatment of XLH.

Infigratinib Reduces Fibroblast Growth Factor 23 (FGF23) and Increases Blood Phosphate in Tumor‐Induced Osteomalacia

ABSTRACTTumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25‐dihydroxy‐vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1‐fibroblast growth factor receptor 1 (FN1‐FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1‐FGFR1 proteins, the effectiveness of infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, was studied in an open‐label, single‐center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)‐DOTATATE and 18Fluoride (18F)‐Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment‐related, dose‐limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher‐than‐expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment‐related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life‐limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Roles of osteocytes in phosphate metabolism.

Osteocytes are dendritic cells in the mineralized bone matrix that descend from osteoblasts. They play critical roles in controlling bone mass through the production of sclerostin, an inhibitor of bone formation, and receptor activator of nuclear factor κ B ligand, an inducer of osteoblastic bone resorption. Osteocytes also govern phosphate homeostasis through the production of fibroblast growth factor 23 (FGF23), which lowers serum phosphate levels by increasing renal phosphate excretion and reducing the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)2D), an active metabolite of vitamin D. The production of FGF23 in osteocytes is regulated by various local and systemic factors. Phosphate-regulating gene homologous to endopeptidase on X chromosome (PHEX), dentin matrix protein 1 (DMP1), and family with sequence similarity 20, member C function as local negative regulators of FGF23 production in osteocytes, and their inactivation causes the overproduction of FGF23 and hypophosphatemia. Sclerostin has been suggested to regulate the production of FGF23, which may link the two functions of osteocytes, namely, the control of bone mass and regulation of phosphate homeostasis. Systemic regulators of FGF23 production include 1,25(OH)2D, phosphate, parathyroid hormone, insulin, iron, and inflammation. Therefore, the regulation of FGF23 in osteocytes is complex and multifactorial. Recent mouse studies have suggested that decreases in serum phosphate levels from youth to adulthood are caused by growth-related increases in FGF23 production by osteocytes, which are associated with the down-regulation of Phex and Dmp1.

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis.

Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

Phosphaturic Mesenchymal Tumors in the Head and Neck Demonstrate a Broad Clinical and Morphologic Spectrum.

Phosphaturic mesenchymal tumour (PMT) is a rare tumour that occurs in bone or soft tissue and is associated with production of fibroblast growth factor 23 (FGF23) leading to tumor-induced osteomalacia. We report three cases of PMT involving the head and neck that highlight the broad spectrum of clinical and histologic features of PMT. One of these lesions from the hard palate demonstrated an admixture of epithelial and mesenchymal elements, a feature that can pose a diagnostic challenge. The diagnostic utility of immunohistochemistry including FGF23, somatostatin receptor 2A, SATB2, ERG and CD56 is discussed. The biochemical pathway in the development of PMT associated tumor induced osteomalacia and its role in investigations and management of PMT is also described.

Pindborg Tumor-An Uncommon Odontogenic Tumor Detected by 68Ga-DOTATOC.

A 62-year-old-woman with a suspected Tumor-induced-osteomalacia (TIO), a rare neoplastic syndrome that results in renal phosphate wasting with hypophosphatemia, underwent 68Ga-DOTATOC PET/CT on the suspicion of a mesenchymal tumor producing Fibroblast growth factor 23 (FGF23). Imaging revealed a small osteolytic, somatostatin receptor (SSTR) positive lesion containing calcifications in the alveolar process of the maxilla. No other SSTR-positive focus was found. A biopsy was performed by an oral and maxillofacial surgeon that revealed a calcifying epithelial odontogenic tumor (Pindborg tumor). This case shows that epithelial odontogenic tumors as an uncommon benign tumor entity can also be SSTR-positive.

Serum Metabolomics Reveals Dysregulation and Diagnostic Potential of Oxylipins in Tumor-induced Osteomalacia.

Excessive production of fibroblast growth factor 23 (FGF23) by a tumor is considered the main pathogenesis in tumor-induced osteomalacia (TIO). Despite its importance to comprehensive understanding of pathogenesis and diagnosis, the regulation of systemic metabolism in TIO remains unclear. We aimed to systematically characterize the metabolome alteration associated with TIO. By means of liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 96 serum samples (32 from TIO patients at initial diagnosis, pairwise samples after tumor resection, and 32 matched healthy control (HC) subjects). In order to screen and evaluate potential biomarkers, statistical analyses, pathway enrichment and receiver operating characteristic (ROC) were performed. Metabolomic profiling revealed distinct alterations between TIO and HC cohorts. Differential metabolites were screened and conducted to functional clustering and annotation. A significantly enriched pathway was found involving arachidonic acid metabolism. A combination of 5 oxylipins, 4-HDoHE, leukotriene B4, 5-HETE, 17-HETE, and 9,10,13-TriHOME, demonstrated a high sensitivity and specificity panel for TIO prediction screened by random forest algorithm (AUC = 0.951; 95% CI, 0.827-1). Supported vector machine modeling and partial least squares modeling were conducted to validate the predictive capabilities of the diagnostic panel. Metabolite profiling of TIO showed significant alterations compared with HC. A high-sensitivity and high-specificity panel with 5 oxylipins was tested as diagnostic predictor. For the first time, we provide the global profile of metabolomes and identify potential diagnostic biomarkers of TIO. The present work may offer novel insights into the pathogenesis of TIO.

O15 Tumour-induced osteomalacia: a diagnostic challenge

Case report - IntroductionTumor-induced osteomalacia is a rare acquired metabolic bone disorder characterised by isolated renal phosphate wasting due to abnormal tumour production of fibroblast growth factor 23 (FGF23). Bloods show hypophosphatemia. However, given the lack of awareness of this disease, and the non-specific nature of the presenting symptoms, diagnosis is often delayed for years or even missed.With this case report, we want to shed light on this rare bone disorder and highlight the importance of not ignoring a low phosphate level.Case report - Case descriptionWe report the case of a 63-year-old gentleman who presented to us with a history of progressive bone pain, marked muscle weakness and fatigue. He had a persistently raised parathyroid hormone and very high alkaline phosphatase. Calcium was low normal, but vitamin D was normal. Phosphate was noted to be low and had been so since 6 years prior to being referred. X-ray pelvis showed sclerotic-looking iliac bones, but an isotope bone scan showed no evidence of metastatic disease.We referred him to our endocrinology colleagues to investigate for possible primary hyperparathyroidism. However, ultrasound scan of neck showed no abnormal parathyroid gland. PET and CT scan of the chest, abdomen and pelvis did not show any significant pathology. MIBI scan of parathyroid glands showed diffuse thyroid uptake. The SPECT-CT images showed a well-defined focal area of increased activity, posterior to the mid/lower pole of the right thyroid lobe, possibly indicative of hyperfunctioning parathyroid tissue. The radiologist questioned the possibility of renal osteodystrophy and resultant secondary hyperparathyroidism. However, there was no evidence for renal dysfunction with a creatinine of 80 umol/L.We referred this gentleman to the Oxfordshire Osteoporosis and Metabolic Bone Service. Bloods showed a raised P1NP. This was felt to be consistent with tumour-induced osteomalacia. Oversecretion of FGF23 was confirmed and DOTATATE scan revealed two areas of uptake: one in the right hip and one in the skull.Meanwhile, the patient had been started on Sandoz Phosphate and alfacalcidol, and his bone aches improved on this combination therapy.He had radio-ablation of the hip lesion this year and has now stopped all his medication. His fatigue and muscle strength has improved dramatically. The skull lesion is being monitored for now with yearly imaging and follow-up in the metabolic bone clinic.Case report - DiscussionTumour-induced or oncogenic osteomalacia is extremely rare. Symptoms include chronic muscle and bone pain, weakness, and fatigue and can result in fragility fractures due to osteomalacia. Lack of awareness of these clinical manifestations and relevance of low phosphate levels often leads to a diagnostic delay or misdiagnosis. As seen in our case, it took multiple investigations and almost 2 years before this gentleman had a confirmation of his diagnosis.The pathogenesis of tumour-induced osteomalacia involves tumour expression of fibroblast growth factor 23. This hormone inhibits reabsorption of phosphate in the proximal renal tubule and down-regulates renal conversion of 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D. Replacing phosphate on its own paradoxically increases PTH levels. The metabolic abnormalities may be partially or completely corrected with phosphate supplementation and calcitriol. In our patient, his PTH levels remained elevated, but alkaline phosphatase improved, as did calcium and phosphate levels.Unlike many other causes of osteomalacia, tumour-induced osteomalacia is curable by resection of the offending tumour. However, finding the responsible FGF23-secreting tumour can be incredibly challenging. There is ongoing research into medical treatment for this condition, especially if the tumour is not found or is unresectable, or the patient is not a surgical candidate.Case report - Key learning pointsLow phosphate levels can be easily overseen, with significant consequences. This case emphasises the need to recognise hypophosphatemia and to look for its cause. Conversely, it also illustrates the need to investigate all patients with persistent musculoskeletal symptoms for hypophosphatemia.Our case underscores the importance of being aware of the rare condition of tumour-induced osteomalacia. This will enable early recognition and treatment of the metabolic abnormality, before the development of any deleterious effects of osteomalacia on the skeleton.

Fibroblast Growth Factor 21 and Its Association With Oxidative Stress and Lipid Profile in Type 2 Diabetes Mellitus.

IntroductionCardiovascular diseases are the leading cause of mortality in diabetic patients. Oxidative stress and mitochondrial dysfunction lead to diabetic cardiomyopathy (DCM) characterized by impaired cardiac structure and function. Hyperglycemia causes oxidative stress, which can lead to microvascular complications, macrovascular complications, and atherosclerosis. Peripheral tissues produce fibroblast growth factor 21 (FGF-21), which has anti-inflammatory properties, increases oxidation of fatty acids, and improves insulin sensitivity. Its increased levels are found in metabolic syndrome and type 2 diabetes mellitus and may also lead to coronary heart disease. Our study sought to measure the serum FGF-21 levels and their associations with lipid profile parameters and oxidative stress in patients with type 2 diabetes mellitus.MethodologyOne-hundred fifty (150) patients of both genders with type 2 diabetes mellitus were recruited along with 150 controls. Simple random sampling was done. After taking relevant history and physical examination, we drew venous blood samples of each patient and sent them to the institutional laboratory for analysis of fasting blood sugar (FBS) levels, glycated hemoglobin (HbA1C), lipid profile, and FGF-21 serum levels. Oxidative stress parameter malondialdehyde (MDA) was estimated and the total antioxidant status by ferric reducing antioxidant power assay (FRAP) was assessed. Patients were followed up after three months to record the glycemic index, and the values were recorded. We used SPSS Software 25.0 (SPSS, Inc., Chicago, USA) to analyze the data. For consideration of results to be statistically significant, a 𝑃 value of < 0.05 was selected.ResultsThe levels of serum cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were increased in diabetics compared to controls and were statistically significant (p<0.05). High-density lipoprotein (HDL) cholesterol was lower in diabetic patients as compared to the controls (p<0.05). There was a statistically significant increase in the level of MDA in diabetics compared to controls (p˂0.005). Serum levels of total antioxidant status (FRAP) were decreased in diabetics in comparison with controls (p˂0.005). Serum FGF-21 level was statistically increased in diabetics compared to controls (p˂0.005). FGF-21 and MDA are positively correlated and FGF-21 and FRAP are negatively correlated. Serum FGF-21 is positively correlated with total cholesterol, triglycerides, serum LDL cholesterol, and HDL cholesterol.ConclusionOur study concludes that there is a significant correlation between fibroblast growth factor 21, oxidative stress, and abnormal lipid profile in type 2 diabetic patients. FGF-21 could be the target of certain medications used to treat metabolic disorders and obesity.

Abstract #1003217: A Case of X-Linked Hypophosphatemic Rickets with Tertiary Hyperparathyroidism

X-linked hypophosphatemic rickets is a disorder characterized by renal phosphate wasting and subsequent bone demineralization. It is caused by a loss of function mutation of the phosphate regulating endopeptidase gene on the X chromosome leading to an increased production of fibroblast growth factor 23 (FGF23). Increased FGF23 inhibits phosphate reabsorption in the kidney. The resulting hypophosphatemia leads to bone demineralization and rickets. Standard treatment includes phosphate supplementation which lowers ionized calcium concentration eliciting an upregulation of parathyroid hormone (PTH). Progression to tertiary hyperparathyroidism due to development of autonomous hyperfunction of the parathyroid glands has been reported. We present a rare case of X-linked hypophosphatemic rickets with tertiary hyperparathyroidism.

Myostatin regulates the production of fibroblast growth factor 23 (FGF23) in UMR106 osteoblast\u2013like cells

Myostatin is a signaling molecule produced by skeletal muscle cells (myokine) that inhibits muscle hypertrophy and has further paracrine and endocrine effects in other organs including bone. Myostatin binds to activin receptor type 2B which forms a complex with transforming growth factor-β type I receptor (TGF-βRI) and induces intracellular p38MAPK and NFκB signaling. Fibroblast growth factor 23 (FGF23) is a paracrine and endocrine mediator produced by bone cells and regulates phosphate and vitamin D metabolism in the kidney. P38MAPK and NFκB-dependent store-operated Ca2+ entry (SOCE) are positive regulators of FGF23 production. Here, we explored whether myostatin influences the synthesis of FGF23. Fgf23 gene expression was determined by qRT-PCR and FGF23 protein by ELISA in UMR106 osteoblast–like cells. UMR106 cells expressed activin receptor type 2A and B. Myostatin upregulated Fgf23 gene expression and protein production. The myostatin effect on Fgf23 was significantly attenuated by TGF-βRI inhibitor SB431542, p38MAPK inhibitor SB202190, and NFκB inhibitor withaferin A. Moreover, SOCE inhibitor 2-APB blunted the myostatin effect on Fgf23. Taken together, myostatin is a stimulator of Fgf23 expression in UMR106 cells, an effect at least partially mediated by downstream TGF-βRI/p38MAPK signaling as well as NFκB-dependent SOCE.

Age-adjusted mortality from pancreatic cancer increased NINE-FOLD in japan from 1950 to 1995 – Was a low-protein quasi-vegan diet a key factor in their former low risk?

During the last half of the twentieth century, age-adjusted mortality from pancreatic cancer in Japan rose about nine-fold in both sexes. Well-characterized risk factors such as smoking, obesity/metabolic syndrome, and heavy alcohol use appear to explain only a modest part of this rise. It is proposed that a diet relatively low in protein, and particularly low in animal protein, was a key determinant of the low risk for pancreatic cancer in mid-century Japan. It is further proposed that pancreatic acinar cells, owing to their extraordinarily high rate of protein synthesis, are at high risk for ER stress; that such stress plays a fundamental role in the induction of most pancreatic cancers; and that low-protein diets help to offset such stress by modulating activities of the kinases GCN2 and mTORC1 while increasing autocrine and systemic production of fibroblast growth factor 21. This model appears to clarify the role of various risk factors and protective factors in pancreatic cancer induction. A vegan or quasi-vegan low-protein diet may have broader potential for decreasing risk for a range of common “Western” cancers.

Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease

Background and aims:Oxidative stress (OS) induces the production of fibroblast growth factor 21 (FGF21). Previous data have revealed that FGF21 protects cells from OS injury and death, making it a potential therapeutic option for many diseases with increased OS. However, the association of this growth factor with OS markers in humans with chronic kidney disease (CKD) remains unknown. This study aims to evaluate the association of serum FGF21 with serum total antioxidant capacity (TAC) and oxidized low-density lipoproteins (OxLDL) in subjects in different stages of kidney disease.Methods:This is a cross-sectional study that included 382 subjects with different stages of CKD, irrespective of type 2 diabetes (T2D) diagnosis. Associations of serum FGF21 with OxLDL, TAC, sex, age, body mass index (BMI), fasting plasma glucose, estimated glomerular filtration rate (eGFR), T2D, and smoking, were evaluated through bivariate and partial correlation analyses. Independent associations of these variables with serum FGF21 were evaluated using multiple linear regression analysis.Results:Serum FGF21 was significantly and positively correlated with age (r = 0.236), TAC (lnTAC) (r = 0.217), and negatively correlated with eGFR (r = −0.429) and male sex (r = −0.102). After controlling by age, sex, BMI, T2D, smoking, and eGFR; both TAC and OxLDL were positively correlated with FGF21 (r = 0.117 and 0.158 respectively, p < 0.05). Using multiple linear regression analysis, eGFR, male sex, T2D, OxLDL, and TAC were independently associated with serum FGF21 (STDβ = −0.475, 0.162, −0.153, 0.142 and 0.136 respectively; p < 0.05 for all) adjusted for age, BMI, smoking, and fasting plasma glucose.Conclusion:A positive association between serum FGF21 and OS has been found independently of renal function in humans. Results from the present study provide novel information for deeper understanding of the role of FGF21 in OS in humans with CKD and T2D; mechanistic studies to explain the association of serum FGF21 with oxidative stress in CKD are needed.