Aromatase in adipose tissue exerts osteoprotective function in male mice via phosphorus regulation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE263849 | GEO | 2024/07/22
REPOSITORIES: GEO
Similar Datasets
Project description:This data describes the first case of oncogenic osteomalacia due to a plexiform fibrohistiocytic tumor which coincidentally has been found for the first time to induce profound muscle weakness via the overexpression of three phosphatonins which resolved fully upon radical resection of the tumor. Much of the literature suggests that oncogenic osteomalacia is usually caused by a benign mesenchymal tumor secreting fibroblast growth factor subtype-23 (FGF23) but other phosphatonins are rarely implicated.We have previously reported a seemingly typical case of oncogenic osteomalacia. Following curative neoplasm resection, we now report unique molecular characteristics and biology of this tumor never described before. A 25-year-old man had been diagnosed with severe oncogenic osteomalacia that gradually crippled him over 6 years. 68Ga-DOTA-TATE PET-CT scan localized the culprit tumor to his left sole which on resection revealed a plexiform fibrohistiocytic tumor positive for CD34 and CD163 with osteoclast-like giant cells and scattered stromal dendritic cells within the tumor. Circulating FGF23 which was elevated more than 2-folds declined to undetectable levels 24 hours after surgery. Microarray analysis showed over 150-fold upregulation in FGF23, matrix extracellular phosphoglycoprotein (MEPE) and secreted frizzled-related protein subtype 4 (sFRP4) genes which corresponded to the same proteins overexpressed on Western blots
2020-10-30 | GSE160445 | GEO
Project description:We used gene array analysis of cortical bone to identify Phex-dependent gene transcripts regulating Fgf23 production and mineralization in Hyp mice. We discovered that activation of Fgf receptor- and Wnt-pathways contribute to increased Ffg23 gene transcription in Hyp bone. We found evidence in Hyp bone for increased expression of Fgf1, Fgf7, and Egr2 in the Fgf-signaling pathway and decrements in Sost and Cpz and increments in Sfrp1 and 4 in the Wnt-signaling pathway. Moreover, activation of Fgf and Wnt-signaling stimulated, whereas Tgf β inhibited Fgf23 promoter activity in osteoblasts. We also observed reductions in Bmp1, a metalloproteinase that metabolizes the Fgf23 regulatory extracellular matrix protein Dmp1. These findings suggest that elevation of Fgf23 expression in osteocytes is regulated by interactions between cell surface expression of Phex, extracellular matrix proteins and paracrine effects of Fgf and Wnt. Alterations were also found in enzymes regulating the posttranslational processing and stability of Fgf23, including decrements in the glycosyltransferase Galnt3 and the proprotein convertase Pcsk5. In addition, we found that the Pcsk5 and the glycosyltransferase Galnt3 were decreased in Hyp bone, suggesting that reduced post-translational processing of FGF23 may also contribute to increased Fgf23 levels in Hyp mice. With regards to mineralization, we identified additional candidates to explain the intrinsic mineralization defect in Hyp osteoblasts, including increases in the mineralization inhibitors Mgp and Thbs4, as well as increases in local pH altering factors, carbonic anhydrase 12 (Car12) and 3 (Car3) and the sodium-dependent citrate transporter (Slc13a5). These studies demonstrate the complexity of gene expression alterations in bone that accompanies inactivating Phex mutations and identify novel pathways that may coordinate Fgf23 expression and mineralization of extracellular matrix in Hyp bone. We isolated total RNAs from long bones of both WT and Hyp mice at 12 days of age. Since the RNA yields from the long bones are very low, we combined 2 bone samples with same genotype (WT or Hyp) for one RNA extraction. We will compare the difference of the gene expressions between Hyp and WT. We will use 4 samples in each animal condition.
2009-12-21 | E-GEOD-14242 | biostudies-arrayexpress
Project description:FGF23 is a bone-derived hormone that mediates renal phosphate reabsorption and 1,25(OH)2 vitamin D metabolism via its required co-receptor alpha-Klotho (KL). The functional pathways guiding this hormone’s activity in kidney have not been studied extensively, and whether using other factors with overlapping signaling profiles to produce FGF23-like responses is unclear. To map FGF23-related genes, gene array and single-cell RNA sequencing were utilized on wild type mouse kidneys. After identifying Heparin-binding EGF-like growth factor (HBEGF) as an up-regulated gene in response to FGF23 delivery, KL-null and phosphate-deficient diet fed mouse models and in vitro experiments were utilized to further test HBEGF bioactivity in kidney. Gene array demonstrated that HBEGF was significantly up-regulated following FGF23 delivery to wild type (WT) mice. Next, mice injected with HBEGF had phenotypes consistent with partial FGF23-mimetic activity including robust induction of EGR1, and increased CYP24A1 mRNAs. Single cell RNA sequencing showed overlapping HBEGF and EGFR expression in the proximal tubule (PT), and KL expression in PT and distal tubule (DT) segments. In KL-null mice devoid of canonical FGF23 signaling, HBEGF injections significantly increased EGR1 and CYP24A, and correction of basally-elevated CYP27B1 was observed. In addition, mice placed on a phosphate deficient diet to suppress FGF23 had endogenously increased CYP27B1 mRNA, which was rescued in mice receiving HBEGF. In HEK293 renal epithelial cells, HBEGF and FGF23 increased CYP24A1 mRNA. Targeting pathways known to be downstream of FGF23 in kidney may help to control renal phosphate handling in diseases of altered FGF23 bioactivity.
2020-10-01 | GSE138992 | GEO
Project description:Fibroblast growth factor-23 (FGF23), a circulating protein produced in bone, causes renal inorganic phosphate (Pi) wasting by down-regulation of sodium phosphate co-transporter 2a (Npt2a). The mechanism behind this action is unknown. We have previously generated transgenic mice (TG) expressing human wild-type FGF23 under the control of the α1 (I) collagen promoter. In this study we performed a large scale gene expression study of kidneys from TG mice and wild-type littermates. Several genes that play a role in Pi regulation had decreased expression levels, such as Npt2a, but also Pdzk1 which is a scaffolding protein known to interact with NPT2a. Importantly, the Klotho gene, a suggested crucial co-factor for FGF23 receptor binding and activation, was the most affected decreased gene. However, other genes proposed to regulate Pi levels, such as secreted Frizzled Related Protein 4 (sFRP4), Na+/H+ exchanger regulatory factor 1 (NHERF1) and the FGF-receptors 1-4, revealed no changes. Interestingly, expression levels of inflammatory response genes were increased and histological analysis revealed tubular nephropathy in the TG mice kidneys. In conclusion, FGF23 TG mice have altered kidney gene expression levels of several genes thought to be part of Pi homeostasis and an increase in inflammatory response genes, data supported by histological analysis. These findings may lead to further understanding of how FGF23 mediates its actions on renal Pi regulation. Experiment Overall Design: Five kidneys from FGF23 TG mice and five kidneys from WT littermates was used for Affymetrix Genechip analysis. One Genechip was used/animal. Animals were 8 weeks old when kidneys were collected.
2008-06-15 | E-GEOD-6979 | biostudies-arrayexpress
Project description:That phosphate homeostasis is tightly linked to skeletal mineralization is probably best underscored by the fact that the phosphaturic hormone FGF23 is primarily expressed by terminally differentiated osteoblasts/osteocytes, and that increased circulating FGF23 levels are causative for different types of hypophosphatemic rickets. In contrast, FGF23-inactivation results in hyperphosphatemia, and unexpectedly this phenotype is associated with severe osteomalacia in Fgf23-deficient mice. In this context it is interesting that different types of bone cells have been shown to respond to extracellular phosphate, thereby raising the concept that phosphate can act as a signaling molecule. To identify phosphate-responsive genes in primary murine osteoblasts we performed genome-wide expression analysis with cells maintained in medium containing either 1 mM or 4 mM sodium phosphate for 6 hours. As confirmed by qRT-PCR, this analysis revealed that several known osteoblast differentiation markers (Bglap, Ibsp or Phex) were unaffected by raising extracellular phosphate levels. In contrast, we found that the expression of Enpp1 and Ank, two genes encoding inhibitors of matrix mineralization, was induced by extracellular phosphate, while the expression of Sost and Dkk1, two genes encoding inhibitors of bone formation, was negatively regulated. The ability of osteoblasts to respond to extracellular phosphate was dependent on their differentiation state, and shRNA-dependent repression of the phosphate transporter Slc20a1 in MC3T3-E1 cells partially abolished their molecular response to phosphate. Taken together, our results provide further evidence for a role of extracellular phosphate as a signaling molecule and raise the possibility that severe hyperphosphatemia can negatively affect skeletal mineralization.
2015-05-30 | GSE47505 | GEO
Project description:FGF23 has been known to play an important role of calcium-phosphorus (Ca-P) metabolism. Recently, biological roles of FGF23 other than Ca-P metabolism were reported, such as commitment to myocardium enlargement and immunological roles in spleen. Thus, it was thought FGF23 might have roles other than Ca-P metabolism in renal tubule epithelial cells. So, we tried to identify new biological roles of FGF23 in those cells using DNA microarray analysis in mouse renal tubule epithelial cell line, mIMCD3, with FGF23 stimulation. As the results, expressions of 8 genes were upregulated and those of 18 genes were downregulated in mIMCD3 with FGF23 stimulation compared to those in mIMCD3 without FGF23 stimulation. Three out of 8 upregulated genes were protein coding genes and remaining 5 genes were non protein coding genes. Fifteen out of 18 downregulated genes were protein coding genes and remaining 3 genes were non protein coding genes.
2018-04-18 | GSE100847 | GEO
Project description:We used gene array analysis of cortical bone to identify Phex-dependent gene transcripts regulating Fgf23 production and mineralization in Hyp mice. We discovered that activation of Fgf receptor- and Wnt-pathways contribute to increased Ffg23 gene transcription in Hyp bone. We found evidence in Hyp bone for increased expression of Fgf1, Fgf7, and Egr2 in the Fgf-signaling pathway and decrements in Sost and Cpz and increments in Sfrp1 and 4 in the Wnt-signaling pathway. Moreover, activation of Fgf and Wnt-signaling stimulated, whereas Tgf β inhibited Fgf23 promoter activity in osteoblasts. We also observed reductions in Bmp1, a metalloproteinase that metabolizes the Fgf23 regulatory extracellular matrix protein Dmp1. These findings suggest that elevation of Fgf23 expression in osteocytes is regulated by interactions between cell surface expression of Phex, extracellular matrix proteins and paracrine effects of Fgf and Wnt. Alterations were also found in enzymes regulating the posttranslational processing and stability of Fgf23, including decrements in the glycosyltransferase Galnt3 and the proprotein convertase Pcsk5. In addition, we found that the Pcsk5 and the glycosyltransferase Galnt3 were decreased in Hyp bone, suggesting that reduced post-translational processing of FGF23 may also contribute to increased Fgf23 levels in Hyp mice. With regards to mineralization, we identified additional candidates to explain the intrinsic mineralization defect in Hyp osteoblasts, including increases in the mineralization inhibitors Mgp and Thbs4, as well as increases in local pH altering factors, carbonic anhydrase 12 (Car12) and 3 (Car3) and the sodium-dependent citrate transporter (Slc13a5). These studies demonstrate the complexity of gene expression alterations in bone that accompanies inactivating Phex mutations and identify novel pathways that may coordinate Fgf23 expression and mineralization of extracellular matrix in Hyp bone.
2009-12-21 | GSE14242 | GEO
Project description:Tight control of both extracellular and intracellular inorganic phosphate (Pi) levels is critical to the normal functioning of virtually all biochemical and physiological processes. The kidney participates in Pi homeostasis by controlling Pi reabsorption from the primary urine. Pi is freely filtered at the kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical sodium-dependent phosphate transporters NaPi-IIa/NaPi-IIc/Pit2. The molecular identity of transporter(s) involved in the basolateral Pi efflux remains unknown. Recent evidence has suggested that the retroviral receptor XPR1 might be a candidate for this role. Here we show that conditional inactivation of Xpr1 in the renal tubule in mice results in impaired renal Pi reabsorption associated with a generalized proximal tubular dysfunction, or Fanconi syndrome, characterized by glycosuria, aminoaciduria, calciuria and albuminuria. Bone histomorphometry showed that the Xpr1-deficient mice develop hypophosphatemic osteomalacia secondary to the renal dysfunction. The analysis of Pi transport in primary culture of the proximal tubular cells revealed that the Pi efflux was significantly affected in cells devoid of Xpr1. These results identify XPR1 as a major player in Pi homeostasis and as a potential therapeutic target in bone and kidney disorders.
2016-12-01 | GSE87450 | GEO
Project description:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium ion concentration ([Na+]) plays a significant role in bone metabolism. Both hyponatremia (low serum [Na+]) and hypernatremia (high serum [Na+]) have been shown to affect bone remodeling. However, nothing is known about the impact of [Na+] on FGF23 production. Here, we show that elevated [Na+] (by +20 mM) suppressed FGF23 formation, whereas low [Na+] (by -20 mM) led to an increase in FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these findings, in a pilot study, we found that human hyponatremic patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.
2023-06-23 | GSE235694 | GEO
Project description:Global microarray was performed from Trans-Iliac Bone biopsy from the patient with clinically characterized Fibrogensis imperfecta ossium (FIO). A 40-year-old male patient with clinically characterized Fibrogensis imperfecta ossium (FIO) includes fragility fracture with osteomalacia (Losserâ??s zone). On examination, his height was 158 cm, weight 47 kg, body mass index (BMI) 16.5, and his blood pressure was 120/80 mmHg. He had no palpable goiter, neck masses or lymphadenopathy. He had no exostosis or bony deformity. He had difficulty in getting up from squatting position and needed a stick to help with walking. The hip joint movements were painful and restricted.. The rest of the examination including abdomen was other wise normal or non-contributory. His laboratory evaluation was as follows: hemoglobin 13.2gm/dl, total WBC 7200/mm3 and erythrocyte sedimentation rate12 mm for 1st hour. Mean ± SD (3 values) serum calcium (Ca) adjusted for albumin was 9.5 ± 1.3 mg/dl (reference range: 8.5 - 11mg/dl). Serum phosphate (PO4) was 3.5 ± 0.3 mg/dl (reference range 3.5-5.0 mg/dl), serum magnesium 1.6mg/dl (reference range 1.58-2.55 mg/dl), total alkaline phosphatase (AP) 39.6 ± 2.6 KA Units (reference range: 3 â?? 13 KA Units), serum creatinine (Cr) was 1.1 mg/dl. Liver function tests were normal. Twenty four hour mean urine Ca, and phosphorus was 65.3 and 563 mg/d, respectively. The renal tubular handling of phosphate was normal (TmP/GFR 4.2 mg/dl â?? normal 2.4-4.2). The serum intact parathyroid hormone (iPTH) level by immunochemilunometry was 19 pg/ml (reference range: 10-69 pg/ml).Serum 25-hydroxyvitamin D level was 59.9( reference range 9 â?? 37 ng/ml). Serum 1,25-hydroxyvitamin D level was 76.6 ng/ml (reference range â?? 3 ng/ml). Arterial blood gases and urine pH were within normal range. Thyroid function tests were normal. Serum tissue transglutaminase antibody (tTG) titre was negative. Urine for Bence Jones protein was negative and serum electrophoresis was normal. Radiographs of the skull and hands were normal. The lumbar spine showed â??rugger â??jerseyâ?? spine with osteopenia . Views of the pelvis showed bilateral coxa vera and bilateral femur neck fracture with â??fishnet appearanceâ??. The chest radiograph showed multiple Looser zones with fractures of several ribs. The lower end of tibia showed â??fishnet appearanceâ??, tendon calcification and new bone formation. Ultrasonography of the neck did not reveal any abnormality in the thyroid or parathyroid glands. Ultrasonography of the abdomen and KUB region was normal. A 99mTc sestamibi scan was normal. Bone mineral density (BMD) of the hip with a T-score of -2.2 SD. Magnetic resonance imaging of pelvis showed fracture of bilateral neck and hypointense marrow on T1W and T2W sequences . A 99mTc MDP bone scan showed increased radiotracer uptake bilaterally in the shoulders, elbows, wrists, small joints of hands, multiple sites at bilateral ribs, the entire vertebral column, and lower end of tibia but not the skull (beheaed scan). Transiliac bone biopsy showed thickened bony trabeculae with obliteration of marrow spaces and at places, focal areas of exaggerated osteoclastic activity. There was prominent osteoblastic proliferation as well as osteoid like areas were also seen. At places it showed sclerosis, eaten up edges of bone and foci of new calcification (bone formation). With the above mentioned clinical and investigation proile a diagnosis of FIO was considered most likely FIO may easily be misdiagnosed because of its superficial similarity to axial osteomalacia osteoporosis, and other metabolic bone disorders with pathological fractures. Bone pain or pathological fractures in a previously healthy adult should lead to radiological and biochemical investigation. Generalized increase in radiological bone density may indicate myelofibrosis or fluorosis but an increased level of alkaline phosphatase favours Pagetâ??s disease or osteomalacia. Bone biopsy suggests gross osteomalacia until the nostic process is rarely logical, but it would not be so delayed if bone sections were always examined under polarized light. There are many unsolved problems in this crippling condition. Apart from complete ignorance of the cause, yet it is not known, what is replacing the mature collagen of bone, why other collagen-containing tissues are apparently unaffected. Why patients commonly have circulating paraprotein and whether there is any effective treatment. Till date, there is no literature has been reported exploring the genes involved in the pathogenesis of FIO. Hence, aim of present study is identification of various genes involved in the regulation of various signaling pathways involved in pathogenesis of FIO. Total RNA was isolated from Trans-Iliac Bone biopsy (Control Individual (n=1) & Patient (n=1)) using TRIZOL method and global microarray was performed on Affymetrix Genechip HumanPrimview platform. The array was performed on duplicate.
2016-07-31 | E-GEOD-43861 | biostudies-arrayexpress