In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.

High concentrations of urinary calcium counteract vasopressin action via the activation of the Calcium-Sensing Receptor (CaSR) expressed in the luminal membrane of the collecting duct cells, which impairs the trafficking of aquaporin-2 (AQP2). In line with these findings, we provide evidence that, with respect to wild-type mice, CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved in AQP2 degradation. Interestingly, KI mice also had significantly higher levels of phosphorylated p38MAPK, a downstream effector of CaSR and known to phosphorylate AQP2 at Ser261. Moreover, ATF1 phosphorylated at Ser63, a transcription factor downstream of p38MAPK, was significantly higher in KI. In addition, KI mice had significantly higher levels of AQP2-targeting miRNA137 consistent with a post-transcriptional downregulation of AQP2. In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice. Together, these results provide direct evidence for a critical role of CaSR in impairing both short-term vasopressin response by increasing AQP2-pS261, as well as AQP2 abundance, via the p38MAPK-ATF1-miR137 pathway. KEY POINTS: Calcium-Sensing Receptor (CaSR) activating mutations are the main cause of autosomal dominant hypocalcaemia (ADH) characterized by inappropriate renal calcium excretion leading to hypocalcaemia and hypercalciuria. Current treatments of ADH patients with parathyroid hormone, although improving hypocalcaemia, do not improve hypercalciuria or nephrocalcinosis. In vivo treatment with calcilytic JTT-305/MK-5442 ameliorates most of the ADH phenotypes of the CaSR knock-in mice including hypercalciuria or nephrocalcinosis and reverses the downregulation of the vasopressin-sensitive aquaporin-2 (AQP2) expression, providing direct evidence for a critical role of CaSR in impairing vasopressin response. The beneficial effect of calcilytic in reducing the risk of renal calcification may occur in a parathyroid hormone-independent action through vasopressin-dependent inhibition of cAMP synthesis in the thick ascending limb and in the collecting duct. The amelioration of most of the abnormalities in calcium metabolism including hypercalciuria, renal calcification, and AQP2-mediated osmotic water reabsorption makes calcilytic a good candidate as a novel therapeutic agent for ADH.

Androgen deprivation therapy-related fracture risk in prostate cancer: an insurance claims database study in Japan.

INTRODUCTION: Androgen deprivation therapy (ADT) is widely used for the treatment of prostate cancer. ADT is associated with reduced bone density leading to an increased risk of osteoporotic fracture. The objective of this retrospective cohort study was to quantify fracture risk in men treated with ADT for prostate cancer in real-world practice in Japan. MATERIALS AND METHODS: Data were extracted from the Japanese Medical Data Vision (MDV) database. Men initiating ADT for treatment of prostate cancer between April 2010 and March 2021 were identified and matched to a cohort of prostate cancer patients not taking ADT using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared between cohorts using a Cox cause-specific hazard model. Information was extracted on demographics, comorbidities and bone densitometry. RESULTS: 30,561 men with PC starting ADT were matched to 30,561 men with prostate cancer not treated with ADT. Following ADT initiation, <5% of men underwent bone densitometry. Prescription of ADT was associated with an increased fracture risk compared to not taking ADT (adjusted hazard ratio: 1.63 [95% CI 1.52-1.75]). CONCLUSION: ADT is associated with a 1.6-fold increase in the risk of osteoporotic fracture in men with prostate cancer. Densitometry in this population is infrequent and monitoring urgently needs to be improved in order to implement effective fracture prevention.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Regulation of FGF23 Production in Osteocytes.

PURPOSE OF REVIEW: FGF23 is a bone-derived hormone working to reduce serum phosphate level. This review focuses on recent findings regarding regulatory mechanisms of FGF23 expression in osteocytes, FGF23 levels, and activities. RECENT FINDINGS: Circulatory FGF23 levels reflecting FGF23 biological activities can be regulated by both FGF23 expression and posttranslational modification of FGF23 protein. O-linked glycosylation and phosphorylation of FGF23 protein as well as enzymes that can cleave FGF23 protein are involved in the posttranslational modification. However, precise mechanisms of FGF23 protein processing are not clear. Several extracellular factors have been shown to affect FGF23 levels in kidney injuries. Contribution of these factors may be different depending on the causes and stages of kidney injury. FGF23 activities are regulated by complex mechanisms involving transcriptional and posttranslational modulations. There still remain several questions regarding the regulatory mechanisms of FGF23 expression and FGF23 processing.

Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

Prevalence of Pseudohypoparathyroidism and Nonsurgical Hypoparathyroidism in Japan in 2017: A Nationwide Survey.

BACKGROUND: Pseudohypoparathyroidism (PHP) and nonsurgical hypoparathyroidism (NS-HypoPT) are rare diseases with hypocalcemia, hyperphosphatemia, and high and low parathyroid hormone levels, respectively. In Japan, over 20 years have passed since the last survey on these diseases. We carried out a nationwide cross-sectional survey to estimate the prevalence of these diseases in 2018. METHODS: We conducted a nationwide mail-based survey targeting hospitals in 2018. From a total of 13,156 departments throughout Japan, including internal medicine, pediatrics, neurology, and psychiatry, 3,501 (27%) departments were selected using a stratified random sampling method. We asked each included department to report the number of patients with PHP and NS-HypoPT in 2017. RESULTS: The overall survey response rate was 52.0% (1,807 departments). The estimated number of patients with PHP and NS-HypoPT was 1,484 (95% confidence interval [CI], 1,143-1,825) and 2,304 (95% CI, 1,189-3,419), respectively; the prevalence per 100,000 population was 1.2 and 1.8, respectively. CONCLUSION: In this study, we generated estimates of the national prevalence of PHP and NS-HypoPT in Japan during 2017, which were found to be higher than those previously reported.

Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases.

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.

Phosphate-Sensing.

The blood level of phosphate is tightly regulated in a narrow range. Hyperphosphatemia and hypophosphatemia both lead to the development of diseases, such as hyperphosphatemic tumoral calcinosis and rickets/osteomalacia, respectively. Although several humoral factors have been known to affect blood phosphate levels, fibroblast growth factor 23 (FGF23) is the principal hormone involved in the regulation of blood phosphate. This hormone is produced by bone, particularly by osteocytes and osteoblasts, and has the effect of lowering the blood level of phosphate in the renal proximal tubules. Therefore, some phosphate-sensing mechanism should exist, at least in the bone. However, the mechanisms through which bone senses changes in the blood level of phosphate, and through which the bone regulates FGF23 production remain to be fully elucidated. Our recent findings demonstrate that high extracellular phosphate phosphorylates FGF receptor 1c (FGFR1c). Its downstream extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway regulates the expression of several transcription factors and the GALNT3 gene, which encodes GalNAc-T3, which plays a role in the regulation of posttranslational modification of FGF23 protein, which in turn enhances FGF23 production. The FGFR1c-GALNT3 gene axis is considered to be the most important mechanism for regulating the production of FGF23 in bone in the response to a high phosphate diet. Thus-in the regulation of FGF23 production and blood phosphate levels-FGFR1c may be considered to function as a phosphate-sensing molecule. A feedback mechanism, in which FGFR1c and FGF23 are involved, is present in blood phosphate regulation. In addition, other reports indicate that PiT1 and PiT2 (type III sodium-phosphate cotransporters), and calcium-sensing receptor are also involved in the phosphate-sensing mechanism. In the present chapter, we summarize new insights on phosphate-sensing mechanisms.

Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation.

Fibroblast growth factor (FGF) 23 produced by bone is a hormone that decreases serum phosphate (Pi). Reflecting its central role in Pi control, serum FGF23 is tightly regulated by serum Pi alterations. FGF23 levels are regulated by the transcriptional event and posttranslational cleavage into inactive fragments before its secretion. For the latter, O-glycosylation of FGF23 by GALNT3 gene product prevents the cleavage, leading to an increase in serum FGF23. However, the molecular basis of Pi sensing in the regulation of serum FGF23 remains elusive. In this study, we showed that high Pi diet enhanced the skeletal expression of Galnt3, but not Fgf23, with expected increases in serum FGF23 and Pi in mice. Galnt3 induction by high Pi was further observed in osteoblastic UMR 106 cells, and this was mediated by activation of the extracellular signal-regulated kinase (ERK) pathway. Through proteomic searches for the upstream sensor for high Pi, we identified one subtype of the FGF receptor (FGFR1c), which was phosphorylated by high Pi in the absence of FGFs. The mode of unliganded FGFR activation by high Pi appeared different from that of FGFR bound to a canonical FGFR ligand (FGF2) when phosphorylation of the FGFR substrate 2α and ERK was monitored. Finally, we showed that an FGFR inhibitor and conditional deletion of Fgfr1 in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral Galnt3 expression in mice. Thus, these findings uncover an unrecognized facet of unliganded FGFR function and illustrate a Pi-sensing pathway involved in regulation of FGF23 production.

Congenital Hyperphosphatemic Conditions Caused by the Deficient Activity of FGF23.

Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.

Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23.

INTRODUCTION: Measurement of fibroblast growth factor 23 (FGF23) has been reported to be clinically useful for the differential diagnosis of chronic hypophosphatemia. However, assays for research use only are available in Japan. Thus, the objective of this study was to examine the clinical utility of a novel and automated chemiluminescent enzyme immunoassay for the measurement of FGF23. MATERIALS AND METHODS: Participants were recruited from July 2015 to January 2017 at six facilities in Japan. Thirty-eight patients with X-linked hypophosphatemic rickets (XLH 15 males, 23 females, age 0-66 years), five patients with tumour-induced osteomalacia (TIO 3 males, 2 females, age 60-73 years), and twenty-two patients with hypophosphatemia (11 males, 11 females, age 1-75 years) caused due to other factors participated in this study. RESULTS: With the clinical cut-off value of FGF23 at 30.0 pg/mL indicated in the Diagnostic Guideline of Rickets/Osteomalacia in Japan, the sensitivity and specificity of FGF23-related hypophosphatemic rickets/osteomalacia without vitamin D deficiency (disease group-1) were 100% and 81.8%, respectively, which distinguished it from non-FGF23-related hypophosphatemia (disease group-2). Furthermore, the diagnostic sensitivity of FGF23-related hypophosphatemia with vitamin D deficiency remained at 100%. Among the four patients with FGF23 levels ≥ 30.0 pg/mL in disease group-2, two patients with relatively higher FGF23 values were suspected to have genuine FGF23-related hypophosphatemia, due to the ectopic production of FGF23 in pulmonary and prostate small cell carcinomas. CONCLUSION: The novel FGF23 assay tested in this study is useful for the differential diagnosis of hypophosphatemic rickets/osteomalacia in a clinical setting.

FGF23 and Hypophosphatemic Rickets/Osteomalacia.

PURPOSE OF REVIEW: X-linked hypophosphatemia and tumor-induced osteomalacia are diseases characterized by hypophosphatemia with impaired proximal tubular phosphate reabsorption. Complete resection of responsible tumors is the first-line therapy for patients with tumor-induced osteomalacia. In contrast, phosphate and active vitamin D have been used for patients with X-linked hypophosphatemia and inoperable ones with tumor-induced osteomalacia. The purpose of this review is to summarize the pathogenesis of these diseases and discuss about the new treatment. RECENT FINDINGS: Excessive FGF23 production has been shown to underline several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemia and tumor-induced osteomalacia. Burosumab, an anti-FGF23 monoclonal antibody, was approved for clinical use, while the indications of burosumab are different depending on countries. The inhibition of excessive FGF23 activity has been approved as a new therapy for several kinds of hypophosphatemic diseases. Further studies are necessary to clarify the long-term effects and safety of burosumab.

Fibroblast growth factor receptor as a potential candidate for phosphate sensing.

PURPOSE OF REVIEW: Phosphate plays essential roles in many biological processes. Serum phosphate level needs to be regulated because hypophosphatemia and hyperphosphatemia cause rickets/osteomalacia and ectopic calcification, respectively. Fibroblast growth factor (FGF) 23 is the principal hormone to regulate serum phosphate level. FGF23 is produced by the bone and works to reduce serum phosphate level by binding to FGF receptor (FGFR) 1c and α-Klotho complex in the kidney. It has been unclear how the bone senses the changes of serum phosphate level and how the bone regulates the production of FGF23. RECENT FINDINGS: Our recent results indicate that high extracellular phosphate activates FGFR1c. Its downstream intracellular signalling pathway regulates the expression of GALNT3 encoding a protein involved in the regulation of the posttranslational modification of FGF23 protein. This FGFR1c-GALNT3 axis is considered to be the main regulatory mechanism of enhanced FGF23 production in response to high phosphate. SUMMARY: We propose that FGFR1c works as a phosphate-sensing molecule in the regulation of FGF23 production and serum phosphate level. Feedback system is present in the regulation of serum phosphate involving FGFR1c and FGF23. These findings uncover so far unrecognized function of FGFR and molecular basis of phosphate sensing.

Evocalcet in patients with primary hyperparathyroidism: an open-label, single-arm, multicenter, 52-week, dose-titration phase III study.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is caused by parathyroid adenoma, primary parathyroid hyperplasia, or parathyroid carcinoma. For some patients with PHPT controlling serum calcium levels is critical. MATERIALS AND METHODS: We conducted an open-label, single-arm, 52-week, phase III study in Japanese patients with hypercalcemia due to PHPT to demonstrate efficacy and safety of evocalcet, a new calcimimetic. Patients with intractable PHPT (n = 13), postsurgical recurrence (n = 2), and parathyroid carcinoma (n = 3) were enrolled. Evocalcet administration started at a dose of 2 mg once or twice daily and was titrated to achieve the target serum corrected calcium (cCa) concentration (≤ 10.3 mg/dL) for two consecutive weeks (maximal dose 24 mg/day). RESULTS: Fourteen patients achieved the target (77.8%; 95% confidence interval [CI] 52.4-93.6). The lower limit of 95% CI exceeded the predetermined reference limit (11%), and thus, efficacy was confirmed. Of 18 patients, 12 (66.7%; 95% CI 41.0-86.7) showed decreased serum cCa of ≥ 1.0 mg/dL from the baseline for two consecutive weeks during the titration phase. Sixteen patients entered the maintenance phase, and 15 patients completed the study. Treatment-emergent adverse events (TEAEs) were recorded in 18/18 patients (100%) and drug-related TEAEs in 8/18 (44.4%). The most commonly observed drug-related TEAE was nausea (2/18 patients). No unexpected drug-related TEAEs were observed. All drug-related TEAEs were mild in severity. No patient discontinued the study because of drug-related TEAEs. CONCLUSION: Evocalcet demonstrated long-term effectiveness in reducing serum cCa concentrations and safety without any unexpected drug-related TEAEs in PHPT patients.

How do we sense phosphate to regulate serum phosphate level?

Abnormal phosphate levels result in several pathological conditions such as rickets/osteomalacia and ectopic calcification indicating that there must be a system that regulates phosphate level within a narrow range. FGF23 has been shown to be an essential hormone regulating serum phosphate level. FGF23 binds to Klotho-FGF receptor complex to reduce serum phosphate level. Several reports suggested that FGF receptor is involved in the regulation of FGF23 production. It has been also shown that high extracellular phosphate can activate several intracellular signaling pathways. However, it has been unclear whether and how phosphate regulates FGF23 production in vivo. Our recent results indicate that high extracellular phosphate directly activates FGF receptor 1 and the downstream intracellular signaling enhances FGF23 production. Thus, there is a negative feedback system for the regulation of serum phosphate level involving FGF receptor and FGF23. We propose that FGF receptor works at least as one of phosphate sensors in the maintenance of serum phosphate level.

Management manual for cancer treatment-induced bone loss (CTIBL): position statement of the JSBMR.

Androgen deprivation therapy and aromatase inhibitors are known to cause a decrease in bone mineral density and an increase in fractures. Patients receiving these treatments have been shown to have a fracture risk equal to or greater than that of patients with osteoporosis with prevalent fractures. This manual was created to prevent fractures in patients with cancer treatment-induced bone loss with high fracture risks who cannot be treated under the current Japanese guideline for the prevention and treatment of osteoporosis. This manual recommends drug treatment for patients with BMD - 2.0 ≤ T score < - 1.5 with the family history of hip fracture or 15% or more 10-year probability of major osteoporotic fractures by FRAX®; or in patients with BMD T score < - 2.0. It is important to verify whether the use of this manual can reduce fractures and improve the quality of life of patients with cancer treatment-induced bone loss by prospective studies.

Circulating FGF23 is not associated with cardiac dysfunction, atherosclerosis, infection or inflammation in hemodialysis patients.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone regulating serum inorganic phosphate (Pi) concentration. FGF23 is also involved in the development of chronic kidney disease (CKD)-mineral and bone disorder. Serum FGF23 concentration begins to increase early in the progression of CKD and can be remarkably high in hemodialysis patients with end-stage renal disease. It has been reported that high FGF23 concentration is a risk factor for cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. FGF23 was also shown to induce cardiac hypertrophy directly acting on cardiomyocytes. However, it is still controversial whether high FGF23 is causing cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. In the current study, we investigated whether FGF23 concentration is associated with cardiac dysfunction, atherosclerosis, infection or systemic inflammation in Japanese hemodialysis patients. We recruited 119 hemodialysis patients and examined the association between serum FGF23 concentration and several parameters concerning mineral metabolism, cardiac dysfunction, atherosclerosis, infection, and systemic inflammation. Serum FGF23 concentration was independently associated with serum calcium and Pi concentration (ß = 0.276, p < 0.001; ß = 0.689, p < 0.001). However, serum FGF23 concentration was not associated with parameters of cardiac dysfunction, atherosclerosis, infection, and systemic inflammation, either. Our results do not support the hypothesis that high FGF23 in dialysis patients is the cause of cardiac dysfunction, atherosclerosis, infection or systemic inflammation.

FGF23 and Bone and Mineral Metabolism.

FGF23 is a phosphotropic hormone produced by the bone. FGF23 works by binding to the FGF receptor-Klotho complex. Klotho is expressed in several limited tissues including the kidney and parathyroid glands. This tissue-restricted expression of Klotho is believed to determine the target organs of FGF23. FGF23 reduces serum phosphate by suppressing the expression of type 2a and 2c sodium-phosphate cotransporters in renal proximal tubules. FGF23 also decreases 1,25-dihydroxyvitamin D levels by regulating the expression of vitamin D-metabolizing enzymes, which results in reduced intestinal phosphate absorption. Excessive actions of FGF23 cause several types of hypophosphatemic rickets/osteomalacia characterized by impaired mineralization of bone matrix. In contrast, deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis with high 1,25-dihydroxyvitamin D levels. These results indicate that FGF23 is a physiological regulator of phosphate and vitamin D metabolism and indispensable for the maintenance of serum phosphate levels.

Earlier Onset in Autosomal Dominant Hypophosphatemic Rickets of R179 than R176 Mutations in Fibroblast Growth Factor 23: Report of 20 Chinese Cases and Review of the Literature.

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary disorder characterized by variant onset ages and diverse phenotypes. Our aim is to explore the genotype-phenotype correlations between ADHR patients with R176 and R179 mutations in FGF23 gene. Clinical manifestations, laboratory examinations, and genetic analyses were collected from 20 patients in six Chinese ADHR kindreds in our hospital. Previously published ADHR literatures were reviewed. Among 20 Chinese ADHR mutation carriers, 11 patients revealed overt symptoms. 10/11 (90.9%) of which were females. Patients with R179 mutations presented with earlier onset than those with R176 mutation [1.3 (1.0, 37.0) years vs. 28.5 (19.0, 44.0) years]. More patients with R179 mutations had a history of rickets with lower extremity deformity [3/4 (75%) vs. 1/7 (14.3%), p < 0.05]. The serum phosphate, i-FGF23 and c-FGF23 levels of patients with R179 and R176 mutations were 0.47 ± 0.14 mmol/L versus 0.57 ± 0.17 mmol/L, 79.6 ± 87.0 pg/mL versus 79.9 ± 107.4 pg/mL, and 33.4 ± 3.0 RU/mL versus 121.3 ± 177.6 RU/mL, respectively. 7/11 of patients had iron deficiency at onset of disease. When combined with previously reported seven ADHR families, difference was observed in the age of onset among symptomatic patients with R179 and R176 mutations [1.0 (0.9, 37.0) years vs. 24.5 (1.2, 57.0) years, p < 0.05]. Patients with R179 mutation were more likely to have rickets than R176 mutation (11/13, 84.6% vs. 5/20, 25.0%, p < 0.01) and lower extremity deformity (10/13, 76.9% vs. 6/19, 31.6%, p < 0.01). ADHR patients with R179 mutations had earlier onset age and more rickets compared to those with mutations in R176, which partially explained the clinical heterogeneity of ADHR.

[Osteocytes and Wnt signaling.]

Osteocytes has many functions such as sensing mechanical stress to bone, regulating formation and activity of osteoclasts as well as modulation of bone metabolism and function of other organs through production of humoral factors such as sclerostin and FGF23. Sclerostin suppresses bone formation and stimulate bone resorption by inhibiting Wnt activity. FGF23 regulates phosphate metabolism mainly acting on kidney. In contrast, it is also reported that sclerostin works in kidney and FGF23 inhibits Wnt activity in osteoblasts. However, the physiological significance of these actions of sclerostin and FGF23 needs to be established by future investigations.