A case of Serratia granuloma in the soft tissue around the left kidney: a role of PTHrP in the formation of Serratia granuloma

Serratia marcescens is an ubiquitous, saprophytic gram-negative bacillus that is associated with infections such as bacteremia, pneumonia and osteomyelitis. However, it has not been known to form granulomas. A 72-year-old man with a history of tricuspidal insufficiency, mitral insufficiency and ureterolithiasis presented with lumbago on the left side. He was admitted to our hospital, where abscess formation in the subcapsular space and perirenal fat space of the left kidney, and left renal calculi were identified by computed tomography of the abdomen. As infection and/or a tumor were suspected, nephrectomy was performed. The histopathological findings in the resected kidney indicated severe infiltration by inflammatory cells with lymphoid follicles in the interstitium, and the proliferation of mesangial cells and matrix in glomerulus. Furthermore, giant cell granulomas were observed in the soft tissue around the kidney. As an aerobic culture of the abscess from the granulomas only produced Serratia marcescens, these granulomas were diagnosed as Serratia marcescens granulomas. In addition, expressions of PTHrP and PTH/PTHrP-receptor were observed in the giant cells in Serratia granuloma, which suggested that PTHrP might be involved in giant cell formation in Serratia granuloma by autocrine and/or paracrine mechanisms.     

Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.     

Parathyroid Hormone Gene rs6256 and Calcium Sensing Receptor Gene rs1801725 Variants are not Associated with Susceptibility to Colorectal Cancer in Iran

Background: Substantial evidence from epidemiological studies has suggested that increased levels of calcium may play a protective role against colorectal cancer (CRC). Given the vital role of calcium sensing receptor (CaSR) and parathyroid hormone (PTH) in the maintenance of calcium homeostasis, we explored whether the rs1801725 (A986S) variant located in exon 7 of the CaSR gene and the rs6256 variant located in exon 3 of PTH gene might be associated with CRC risk. Materials and Methods: In this study 860 subjects including 350 cases with CRC and 510 controls were enrolled and genotyped using PCR-RFLP methods. Results: We observed no significant difference in genotype or allele frequencies between the cases with CRC and controls for both CaSR and PTH genes either before or after adjustment for confounding factors including age, BMI, sex, smoking status, and family history of CRC. Furthermore, no evidence for effect modification of any association of rs1801725 and rs6256 variants and CRC by BMI, sex, or tumor site was observed. In addition, there was no significant difference in genotype and allele frequencies between the normal weight (BMI <25 kg/m2) cases and overweight/ obese (BMI ≥25 kg/m2) cases for the two SNPs. Conclusions: These data indicated that the CaSR gene A986S variant is not a genetic contributor to CRC risk in the Iranian population. Furthermore, our results suggest for the first time that PTH gene variant does not affect CRC risk. Nonetheless, further studies with larger sample size are needed to validate these findings.     

重组人甲状旁腺素(1-34)对角质形成细胞分泌IL-6和IL-8的影响

目的研究人甲状旁腺素(PTH)(1-34)对角质形成细胞分泌IL-6和IL-8的影响,探讨其治疗银屑病的分子机理。方法体外培养人角质形成细胞株(HaCaT),研究中设空白对照组、骨化三醇组、骨化三醇和PTH(1-34)联合组以及1.0×10-7mol/L～1.0×10-10mol/L4个不同剂量的PTH(1-34)给药组。48h后收集上清液,用酶联免疫吸附法(ELISA)检测HaCaT细胞分泌至培养液中IL-6和IL-8的含量。结果在1.0×10-7mol/L～1.010-10mol/L四个梯度浓度PTH(1-34)及联合骨化三醇处理48h后,HaCaT细胞分泌IL-6量和空白对照组、骨化三醇组比较,差异无统计学意义,而IL-8的分泌量明显降低(P<0.05),且1.0×10-7mol/LPTH(1-34)处理组IL-8分泌量明显低于其他各组。结论PTH(1-34)治疗银屑病的作用机制可能部分通过调节IL-8的表达和分泌来实现。     

Modulation by epidermal growth factor of the basal 1,25(OH)2D3 receptor level and the heterologous up-regulation of the 1,25(OH)2D3 receptor in clonal osteoblast-like cells

Summary The effects of epidermal growth factor (EGF) on basal 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) receptor level and on parathyroid hormone (PTH)-induced 1,25-(OH)₂D₃ (OH)₂D₃ receptor up-regulation were studied in the phenotypically osteoblastic cell line UMR 106. EGF in concentrations exceeding 0.1 ng/ml reduced the number of 1,25(OH)₂D₃ binding sites without changing the binding affinity. Maximal reduction was 30% at about 1 ng/ml. This reduction was independent of a change in cAMP content. EGF dose-dependently attenuated both PTH-induced 1,25(OH)₂D₃ receptor up-regulation and PTH-stimulated cAMP production without and effect on the ED₅₀ of the PTH effects. For both PTH responses the IC₅₀ and the maximal effective dose were similar, 0.1 ng/ml an 1 ng/ml EGF, respectively. Reduction was first seen at 0.01 ng/ml EGF. At this concentration. EGF reduced PTH-stimulated 1,25-(OH)₂D₃ receptor binding without an inhibition of the cAMP response. Time-course studies with 1 ng/ml EGF revealed that at 2 h preincubation EGF reduced the heterologous up regulation by PTH, and maximal inhibition was seen after 4 h. In contrast, PTH-stimulated cAMP production was just significantly inhibited only after 6 h, with 60% inhibition after 24 h preincubation. The effects of prostaglandin E₂ and forskolin on both 1,25(OH)₂D₃ binding and cAMP production were inhibited in a similar fashion. On the other hand, dibutyryl cAMP- and 3-isobutyl-1-methylxanthinestimulated 1,25(OH)₂D₃ binding were not affected by EGF. Taken together, our results demonstrate that EGF reduces both the basal number of 1,25(OH)₂D₃ binding sites and the heterologous up-regulation of the 1,25(OH)₂D₃ receptor. The current data suggest that EGF reduces heterologous upregulation of the 1,25(OH)₂D₃ receptor independent of as well as dependent on the cAMP messenger system. The EGF effect is not primarily located at the PTH receptor, at cAMP phosphodiesterase, or at protein kinase A level.     

The effect of 1,25 dihydroxycholecalciferol on parathyroid hormone secretion by monolayer cultures of bovine parathyroid cells

Summary Controversy exists over a direct effect of 1,25(OH)₂D₃ on PTH secretion. To investigate the possibility that the suppressive effect of 1,25(OH)₂D₃ on PTH secretion may be demonstrable in 1,25(OH)₂D₃-depleted tissue and/or after prolonged periods of exposure to 1,25(OH)₂D₃, primary monolayer cultures of bovine parathyroid cells were established in 1∶1 DMEM/Ham's F-12 media supplemented with 2% calf serum but not 1,25(OH)₂D₃. Ionized calcium was maintained at 1.0 mM. Experiments were performed on 4-day-old culture cells. PTH concentration was measured using both a mid-region/carboxyl and an amino-terminal PTH antisera. 1,25(OH)₂D₃ at a concentration of 0.1 ng/ml suppressed PTH secretion by 32±7% after 48 hours. High calcium concentration (2.0 mM) suppressed PTH secretion by 37±10% and this effect was not additive over that of 1,25(OH)₂D₃. PTH secretion rate recovered fully 48 hours after normalization of the external calcium concentration but not after the removal of 1,25(OH)₂D₃. It is concluded that 1,25(OH)₂D₃ directly suppresses PTH secretion by monolayer culture of bovine parathyroid cells.