The phosphate regulating hormone fibroblast growth factor-23.

Over the last decade, the regulation of phosphate (Pi) homeostasis has been under intense investigation. By utilizing modern biochemical and genetic tools, the pathophysiological mechanisms behind several known hereditary and acquired hypo- and hyperphosphatemic diseases have been clarified. The results of these efforts have opened new insights into the causes of Pi dysregulation and hereby also the physiological mechanisms determining Pi homeostasis. Although several potential Pi-regulating proteins have been discovered and investigated, current data strongly argues for fibroblast growth factor-23 (FGF23), a hormonal factor produced in bone, as a particularly important regulator of Pi homeostasis. In this article, we review the discovery of the FGF23 protein, as well as its biochemistry, localization of production, receptor specificity and mechanisms of action.

Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men.

SUMMARY: We evaluated the relation between serum FGF23 and bone mineral density (BMD) in a community-based cohort of elderly men. There was a weak correlation between FGF23 and BMD, which was primarily dependent on body weight. INTRODUCTION: FGF23 is a hormonal factor produced in bone and regulates serum levels of phosphate (Pi) and vitamin D. FGF23 over-expression is associated with skeletal abnormalities, including rickets/osteomalacia. The relation between FGF23 and Bone Mineral Density (BMD) in the community remains unexplored. METHODS: We employed a large, population-based cohort of 3014 Swedish men aged 69-80 years, without known renal disease. BMD was measured with dual X-ray absorptiometry (DXA) in the hip and lumbar spine. Serum intact FGF23 was analyzed with a two-site monoclonal ELISA. RESULTS: There was a weak but significant correlation between FGF23 and BMD in femoral neck (r = 0.04, p < 0.05), femoral trochanter (r = 0.05, p = 0.004), total hip (r = 0.06, p = 0.0015) and lumbar spine (r = 0.07, p = 0.0004). The correlations remained significant when adjusting for biochemical covariates (Pi, calcium, PTH, 25(OH)D and renal function). However, the association became insignificant in all regions when adjusting for established confounding variables including age, height, weight and smoking. Further analysis confirmed a significant correlation between FGF23 and body weight (r = 0.13, p < 0.0001). CONCLUSIONS: The weak correlation between FGF23 and BMD in elderly male subjects is mainly due to an association between FGF23 and body weight. Therefore, FGF23 may not play a significant role in the hormonal regulation of BMD.

Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23.

Genetic ablation of fibroblast growth factor 23 from mice (Fgf-23(-/-)) results in a short lifespan with numerous abnormal biochemical and morphological features. Such features include kyphosis, hypogonadism and associated infertility, osteopenia, pulmonary emphysema, severe vascular and soft tissue calcifications, and generalized atrophy of various tissues. To determine whether these widespread anomalies in Fgf-23(-/-) mice can be ameliorated by genetically restoring the systemic actions of FGF-23, we generated Fgf-23(-/-) mice expressing the human FGF-23 transgene in osteoblasts under the control of the 2.3 kb alpha1(I) collagen promoter (Fgf-23(-/-) /hFGF-23-Tg double mutants). This novel mouse model is completely void of all endogenous Fgf-23 activity, but produces human FGF-23 in bone cells that is subsequently released into the circulation. Our results suggest that lack of Fgf-23 activities results in extensive premature ageing-like features and early mortality of Fgf-23(-/-) mice, while restoring the systemic effects of FGF-23 significantly ameliorates these phenotypes, with the resultant effect being improved growth, restored fertility, and significantly prolonged survival of double mutants. With regard to their serum biochemistry, double mutants reversed the severe hyperphosphataemia, hypercalcaemia, and hypervitaminosis D found in Fgf-23(-/-) littermates; rather, double mutants show hypophosphataemia and normal serum 1,25-dihydroxyvitamin D(3) levels similar to pure FGF-23 Tg mice. These changes were associated with reduced renal expression of NaPi2a and 1 alpha-hydroxylase, compared to Fgf-23(-/-) mice. FGF-23 acts to prevent widespread abnormal features by acting systemically to regulate phosphate homeostasis and vitamin D metabolism. This novel mouse model provides us with an in vivo tool to study the systemic effects of FGF-23 in regulating mineral ion metabolism and preventing multiple abnormal phenotypes without the interference of native Fgf-23.

Iron deficiency and iron overload in Swedish male adolescents.

OBJECTIVES: The present study was undertaken to confirm or reject recent findings indicating a high prevalence of iron deficiency in Swedish male adolescents; a second aim was to study the prevalence of genetic iron overload. DESIGN: The diagnostic criteria were: anaemia: Hb < 130 g L-1 (a): iron deficiency: serum ferritin (SF) < 12 micrograms L-1 + transferrin saturation (TS) < 16% (b): iron deficiency anaemia a + b. Iron overload: SF (90th percentile) + TS (90th percentile) in repeat tests. SETTING: Central Sweden. SUBJECTS: A total 3975 men aged 18 years studied on enrollment into military service. RESULTS: Serum ferritin averaged 36.8 micrograms L-1. Anaemia was present in 0.5%, iron deficiency anaemia in 0.17% and iron deficiency in 0.4%. If iron deficiency is defined as SF < 16 micrograms L-1, as was recently suggested, the prevalence would be 2.8%. Such a cut-off value would include 73% normal people (false positives). Iron overload had the same prevalence as iron deficiency, 0.4%. CONCLUSIONS: Iron stores, as measured by serum ferritin, are small in young men studied at the end of their growth spurt. However, iron deficiency is rare. Therefore, the present study has not been able to confirm the high prevalence of iron deficiency recently reported. A prevalence of genetic haemochromatosis of 0.4%, confirms earlier findings and would mean that 12.6% of the population are heterozygotic carriers of the iron-loading genes. These findings give no support for a proposed, more effective iron-enrichment of food. It is not needed and can be harmful.

Antianginal effect of conventional and controlled release diltiazem in stable angina pectoris.

Two preparations of diltiazem, controlled release (CR) given twice a day (b.i.d.) and plain given 4 times a day (q.i.d.), were compared in a multicentre, double-blind, crossover study in 41 patients with stable angina pectoris. Therapeutic efficacy was assessed with maximal exercise tests, patient recordings on nitroglycerine consumption and angina attacks. No significant differences between the CR and plain tablets were seen in any of the efficacy variables. Maximal workload significantly increased from 127 W on placebo to 146 W on CR tablets and to 147 W on plain tablets. Anginal attacks/week significantly decreased from 11.7 on placebo to 4.9 on CR tablets and to 5.0 on plain tablets. Consumption of nitroglycerine tablets/week significantly decreased from 6.3 on placebo to 2.6 and to 3.4 on CR and plain-tablets, respectively. The number or the seriousness of the adverse events did not differ between the groups. The results imply that diltiazem CR b.i.d. is equally potent and safe as conventional diltiazem q.i.d. in the control of stable angina pectoris.

Pneumatosis cystoides coli associated with high H2 excretion. Treatment with an elemental diet.

A patient with severe diarrhoea and gas-filled cysts in the wall of the colon is reported. The patient had normal lung function but an extremely high end-expiratory H2 fasting value. Treatment with an elemental diet for 2 weeks resulted in a decreased H2 value and in regression of the cysts. After 4 months on a normal diet extensive recurrence was observed. We conclude that excessive intestinal gas production may play a role in the pathogenesis of the cysts.