Bone-derived Hormone Research Articles

OR32-5 Associations between Circulation Lipocalin 2, Body Composition, and Glucose Metabolism in Active Acromegaly

Objective: Patients with active acromegaly display a range of abnormalities in glucose metabolism and increased bone turnover. Lipocalin 2 (Lcn2) is newly identified as a bone-derived hormone with metabolic regulatory effects. To elucidate interactions between bone and energy homeostasis in active acromegaly patients, we sought to determine whether these patients were characterized by alterations in circulating levels of Lcn2, and potential interactions with body composition and glucose metabolism. Methods: Bone-derived hormone Lcn2 (by ELISA), osteocalcin (by immunoanalysis), body composition (by dual-energy x-ray absorptiometry), and glucose metabolism [homeostasis model assessment, early-phase insulin release (InsAUC30/GluAUC30) and InsAUC120/GluAUC120] were evaluated in 54 acromegalic patients (21 males and 33 females) and in 31 age-, gender-, and body mass index-matched healthy controls (14 males and 17 females). Acromegalic patients were classified as low- or high-Lcn2 group according to the median of Lcn2 level. Results: 1) Acromegalic patients had lower Lcn2 (32.25±11.77 ng/ml vs 58.38±29.66 ng/ml, P < 0.01), higher bone formation markers (osteocalcin and total P1NP, P < 0.05 and P < 0.01, respectively), and higher bone resorption markers (β-Crosslaps, P < 0.001) than controls. After pituitary surgery, serum levels of Lcn2 increased significantly (42.40±16.20 ng/ml vs 33.39±13.45 ng/ml,P<0.01) accompanied with decreased GH and IGF-1 levels. 2) Acromegalic patients had more lean body mass (P < 0.05), less total and trunk fat mass (P < 0.05) than controls. Positive correlation was found for Lcn2 and total or trunk lean mass (r = 0.457, 0.444, P < 0.01). No correlation was observed with Lcn2 and total or trunk fat mass. 3)Lcn2 was not correlated with fasting blood glucose or HbA1c. Compared to low-Lcn2 group, acromegalic patients in high-Lcn2 group had lower HOMA-β (105.23±63.52 vs 190.60±150.83, P < 0.05). Early-phase insulin release (InsAUC30/GluAUC30) and InsAUC120/GluAUC120 were also decreased in high-Lcn2 group (P < 0.01). No difference was found in HOMA-IR between low- and high-Lcn2 group. Conclusion: These data confirm and establish novel and complex interactions between bone, energy metabolism, and β cell function and suggest an unfavorable effect of Lcn2 and GH/IGF-I in combination.

Molecular Control of Phosphorus Homeostasis and Precision Treatment of Hypophosphatemic Disorders.

Serum phosphorus is maintained in a narrow range by balancing dietary phosphate absorption, influx and efflux of phosphorus from bone and intracellular stores, and renal reabsorption of filtered phosphate. Acute hypophosphatemia, typically caused by transient increases in cellular uptake, can lead to severe complications such as cardiopulmonary dysfunction and rhabdomyolysis that can warrant parenteral phosphate repletion. Chronic hypophosphatemia, however, generally represents true phosphate deficiency and may result in long-term metabolic and skeletal complications, particularly in children due to the critical importance of phosphorus to skeletal mineralization and longitudinal growth. In addition to the well characterized roles of vitamin D and parathyroid hormone (PTH), a new bone-kidney axis has been discovered that regulates phosphate homeostasis through the bone-derived hormone Fibroblast Growth Factor 23 (FGF23) and its phosphaturic actions that are mediated by activation of fibroblast growth factor receptors (FGFRs) complexed with α-Klotho in renal tubules. Chronic hypophosphatemia can now be classified as FGF23 dependent or independent. In cases of FGF23 dependent hypophosphatemia, traditional non-specific treatments with elemental phosphorus and 1,25(OH)2 vitamin D (calcitriol) can now be replaced with a targeted approach by using an FGF-23 blocking antibody (Burosumab).

Ectopic expression of Klotho in fibroblast growth factor 23 (FGF23)-producing tumors that cause tumor-induced rickets/osteomalacia (TIO)

Tumor-induced rickets/osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumors that ectopically express fibroblast growth factor 23 (FGF23). FGF23 is a bone-derived hormone that regulates serum phosphate concentrations. Patients with TIO develop hypophosphatemic rickets/osteomalacia due to FGF23 excess and suffer from symptoms such as leg deformities, bone pain, skeletal muscle myopathy, and multiple fractures/pseudofractures. Usually, successful surgical removal of the causative tumors normalizes serum FGF23 and phosphate concentrations in patients with TIO. Most FGF23-producing tumors associated with TIO are histologically called phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). The precise mechanism by which these tumors ectopically overproduce FGF23 outside of bone is yet to be clarified. Therefore, we performed an RNA sequencing analysis of a PMTMCT that was found in the left parotid gland of a patient with TIO. Among the upregulated genes, we focused on Klotho, the protein product of which is a single pass transmembrane protein that works along with an FGF receptor 1c as a receptor complex for FGF23. Subsequent histological analysis confirmed the ectopic expression of Klotho in other PMTMCTs. From these results, we assume that the ectopic expression of Klotho in PTMMCTs enables a positive feedback loop in FGF23 production via the activation of FGF receptor 1c and exacerbates disease manifestations in TIO.

Effects of parathyroidectomy on blood bone markers and heart rate variability in patients with stage 5 chronic kidney disease.

Decreased heart rate variability (HRV) is closely related to abnormal cardiac autonomic nervous function, especially sympathetic hyperactivity, which intensifies the risk of cardiovascular events and sudden death. HRV parameters are lower in chronic kidney disease (CKD) and parathyroidectomy (PTX) can improve these abnormalities in severe secondary hyperparathyroidism (SHPT) patients. However, few studies have evaluated correlations between circulating bone markers and HRV in CKD patients. We conducted a cross-sectional study including 134 stage 5 CKD patients with 100 controls and a prospective study of 29 PTX patients with follow-up. Circulating bone biomarkers included: (1) intact parathyroid hormone (iPTH) as bone remodeling regulator; (2) bone-specific alkaline phosphatase (BAP), representing bone formation; (3) tartrate-resistant acid phosphatase 5b (TRACP-5b), indicating bone resorption; and (4) bone-derived hormone, fibroblast growth factor 23 (FGF23). Stage 5 CKD patients had higher circulating iPTH, BAP, TRACP-5b, and FGF23 than controls and these bone markers were significantly elevated in SHPT patients. Baseline iPTH, BAP, and lnFGF23 were independently associated with HRV in CKD patients. After PTX with a follow-up (median interval: 6.7months), high blood iPTH, BAP, TRACP-5b, FGF23, and attenuated HRV were ameliorated. Furthermore, improved HRV indices were associated with reduced iPTH, BAP, TRACP-5b, and FGF23. Circulating bone markers are correlated with HRV in CKD 5 patients and PTX can improve decreased HRV, which are associated with corrected bone markers in severe SHPT patients. Thus, we propose that PTH increases sympathetic tone and both high circulating PTH levels and sympathetic hyperactivity increase bone turnover, and that the products of bone turnover influence HRV.

Twist1-Haploinsufficiency Selectively Enhances the Osteoskeletal Capacity of Mesoderm-Derived Parietal Bone Through Downregulation of Fgf23.

Craniofacial development is a program exquisitely orchestrated by tissue contributions and regulation of genes expression. The basic helix–loop–helix (bHLH) transcription factor Twist1 expressed in the skeletal mesenchyme is a key regulator of craniofacial development playing an important role during osteoskeletogenesis. This study investigates the postnatal impact of Twist1 haploinsufficiency on the osteoskeletal ability and regeneration on two calvarial bones arising from tissues of different embryonic origin: the neural crest-derived frontal and the mesoderm-derived parietal bones. We show that Twist1 haplonsufficiency as well Twist1-sh-mediated silencing selectively enhanced osteogenic and tissue regeneration ability of mesoderm-derived bones. Transcriptomic profiling, gain-and loss-of-function experiments revealed that Twist1 haplonsufficiency triggers its selective activity on mesoderm-derived bone through a sharp downregulation of the bone-derived hormone Fgf23 that is upregulated exclusively in wild-type parietal bone.

Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.

Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences. We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10-24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

Role of Fibroblast Growth Factor-23 in Innate Immune Responses.

Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone that activates FGFR/α-Klotho binary complexes in the kidney renal tubules to regulate phosphate reabsorption and vitamin D metabolism. The objective of this review is to discuss the emerging data that show that FGF-23 has functions beyond regulation of mineral metabolism, including roles in innate immune and hemodynamic responses. Excess FGF-23 is associated with inflammation and adverse infectious outcomes, as well as increased morbidity and mortality, particularly in patients with chronic kidney disease. Enhancer elements in the FGF-23 promoter have been identified that mediate the effects of inflammatory cytokines to stimulate FGF-23 gene transcription in bone. In addition, inflammation induces ectopic expression of FGF-23 and α-Klotho in macrophages that do not normally express FGF-23 or its binary receptor complexes. These observations suggest that FGF-23 may play an important role in regulating innate immunity through multiple potential mechanisms. Circulating FGF-23 acts as a counter-regulatory hormone to suppress 1,25D production in the proximal tubule of the kidney. Since vitamin D deficiency may predispose infectious and cardiovascular diseases, FGF-23 effects on innate immune responses may be due to suppression of 1,25D production. Alternatively, systemic and locally produced FGF-23 may modulate immune functions through direct interactions with myeloid cells, including macrophages and polymorphonuclear leukocytes to impair immune cell functions. Short-acting small molecules that reversibly inhibit FGF-23 offer the potential to block pro-inflammatory and cardiotoxic effects of FGF-23 with less side effects compared with FGF-23 blocking antibodies that have the potential to cause hyperphosphatemia and soft tissue calcifications in animal models. In conclusion, there are several mechanisms by which FGF-23 impacts the innate immune system and further investigation is critical for the development of therapies to treat diseases associated with elevated FGF-23.

Physiological Actions of Fibroblast Growth Factor-23.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone suppressing phosphate reabsorption and vitamin D hormone synthesis in the kidney. At physiological concentrations of the hormone, the endocrine actions of FGF23 in the kidney are αKlotho-dependent, because high-affinity binding of FGF23 to FGF receptors requires the presence of the co-receptor αKlotho on target cells. It is well established that excessive concentrations of intact FGF23 in the blood lead to phosphate wasting in patients with normal kidney function. Based on the importance of diseases associated with gain of FGF23 function such as phosphate-wasting diseases and chronic kidney disease, a large body of literature has focused on the pathophysiological consequences of FGF23 excess. Less emphasis has been put on the role of FGF23 in normal physiology. Nevertheless, during recent years, lessons we have learned from loss-of-function models have shown that besides the paramount physiological roles of FGF23 in the control of 1α-hydroxylase expression and of apical membrane expression of sodium-phosphate co-transporters in proximal renal tubules, FGF23 also is an important stimulator of calcium and sodium reabsorption in distal renal tubules. In addition, there is an emerging role of FGF23 as an auto-/paracrine regulator of alkaline phosphatase expression and mineralization in bone. In contrast to the renal actions of FGF23, the FGF23-mediated suppression of alkaline phosphatase in bone is αKlotho-independent. Moreover, FGF23 may be a physiological suppressor of differentiation of hematopoietic stem cells into the erythroid lineage in the bone microenvironment. At present, there is little evidence for a physiological role of FGF23 in organs other than kidney and bone. The purpose of this mini-review is to highlight the current knowledge about the complex physiological functions of FGF23.

Associations between bone and energy metabolism in cows fed diets differing in level of dietary cation-anion difference and supplemented with cholecalciferol or calcidiol

Bone-derived hormones play an important role in metabolism. This study examined the hypothesis that interactions between bone and energy metabolism, particularly those involving osteocalcin, are present in dairy cattle and have feedback mechanisms over time. Associations between metabolites in blood were examined in 32 Holstein cows blocked by parity and milk yield and randomly allocated to diets containing either 0.27 mg/kg dry matter (DM) calcidiol or cholecalciferol for an anticipated intake of 3 mg/d (120,000 IU/d) at 11 kg of DM, and positive (+130 mEq/kg DM) or negative (-130 mEq/kg DM) dietary cation-anion difference (DCAD) from 252 d of gestation to calving. Blood was sampled every 3 d, from 9 d prepartum to 30 d postpartum, and plasma concentrations of vitamin D3, 25-hydroxyvitamin D3, adiponectin, C-telopeptide of type 1 collagen (CTX1), glucose, insulin-like growth factor 1 (IGF1), insulin, undercarboxylated osteocalcin (uOC), and carboxylated osteocalcin (cOC) were determined. Feeding calcidiol compared with cholecalciferol increased plasma concentrations of 25-hydroxyvitamin D3 pre- (264.2 ± 8.0 vs. 61.3 ± 8.0 ng/mL) and postpartum (170.8 ± 6.2 vs. 51.3 ± 6.2 ng/mL) but decreased concentrations of vitamin D3 pre- (1.2 ± 0.6 vs. 14.5 ± 0.6 ng/mL) and postpartum (1.9 ± 0.4 vs. 3.2 ± 0.6 ng/mL). Prepartum, cows fed the negative DCAD diet had reduced concentrations of vitamin D3 and glucose compared with cows fed a positive DCAD. The combination of negative DCAD and cholecalciferol reduced IGF1 concentrations prepartum. The DCAD treatment had no effect on postpartum concentrations of metabolites. Nulliparous cows had increased concentrations of OC, CTX1, IGF1, glucose, and insulin compared with parous cows. Time series analysis identified associations between metabolites on the same day and over 3-d lags up to ±9 d that suggest feedback between 25-hydroxyvitamin D3 and vitamin D3 in the negative lags, indicating that 25-hydroxyvitamin D3 may exert feedback on vitamin D3 but not vice versa. We found evidence of a feedback mechanism between vitamin D3 and IGF1, with positive effect size (ES) on the same day and 3 d later, and negative ES 9 d later, that was more evident in cholecalciferol-fed cows. This suggests an important role of IGF1 in integrating bone metabolism with energy and protein metabolic pathways. Evidence of feedback was found between uOC and particularly cOC with IGF1, with positive ES on the same day but negative ES 6 d before and 6 d after. An association between uOC or cOC and IGF1 has not been previously identified in cattle and suggests that both uOC and cOC may have marked biological activity. Associations between OC and insulin identified in mice were not observed herein, although associations between OC and glucose were similar to those between IGF1 and glucose, supporting associations between glucose, OC, and IGF1. We provide further statistical evidence of crosstalk between vitamin D compounds, bone hormones, and energy metabolism in cattle. In particular, associations between uOC or cOC and IGF1 may provide links between prepartum diets and observations of prolonged increases in milk production and allow better control of peripartum metabolism.

Early postoperative measurement of fibroblast growth factor 23 predicts severe acute kidney injury in infants after cardiac surgery .

Aims: Acute kidney injury (AKI) occurs in 30 – 40% of children after cardiac surgery (CS) and is associated with poor prognosis. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone with a pivotal role in phosphorus and vitamin D metabolism. We assessed FGF23 as an early marker for severe AKI (sAKI) in infants after CS. Materials and methods: Samples were previously collected in a multicenter observational study from children after CS. Serum FGF23 (n = 41) and urine AKI biomarker levels (n = 35) were assessed 4 – 8 hours after bypass. sAKI was defined as ≥ 100% rise in serum creatinine over baseline. Non-parametric and ROC analyses were used to evaluate the association between FGF23, urine AKI markers, and sAKI in the week after CS. Results: Serum FGF23, urine NGAL, and urine KIM1 were higher in sAKI patients. The AUC-ROC for urine NGAL (0.74, [0.49 – 0.99]), urine KIM1 (0.79, [0.68 – 0.98]), and serum FGF23 (0.74, [0.5 – 0.9]) showed fair prediction of sAKI. Conclusion: Early measurement of FGF23 has predictive ability in infants who develop sAKI after CS with cardiopulmonary bypass.

The Body-wide Transcriptome Landscape of Disease Models

SummaryVirtually all diseases affect multiple organs. However, our knowledge of the body-wide effects remains limited. Here, we report the body-wide transcriptome landscape across 13–23 organs of mouse models of myocardial infarction, diabetes, kidney diseases, cancer, and pre-mature aging. Using such datasets, we find (1) differential gene expression in diverse organs across all models; (2) skin as a disease-sensor organ represented by disease-specific activities of putative gene-expression network; (3) a bone-skin cross talk mediated by a bone-derived hormone, FGF23, in response to dysregulated phosphate homeostasis, a known risk-factor for kidney diseases; (4) candidates for the signature activities of many more putative inter-organ cross talk for diseases; and (5) a cross-species map illustrating organ-to-organ and model-to-disease relationships between human and mouse. These findings demonstrate the usefulness and the potential of such body-wide datasets encompassing mouse models of diverse disease types as a resource in biological and medical sciences. Furthermore, the findings described herein could be exploited for designing disease diagnosis and treatment.

Hepatic Production of Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease.

The bone-derived hormone fibroblast growth factor (FGF) 23 controls phosphate homeostasis and urinary phosphate excretion. FGF23 plasma levels increase in the early stage of renal insufficiency to prevent hyperphosphatemia. Recent evidence suggests that this increase has effects on cardiac and immune cells that compromise patients' health. Patients with autosomal dominant polycystic kidney disease (ADPKD) have been reported to have higher FGF23 concentrations than other patients with similar renal function. The significance of this finding has remained unknown. Analyzing the FGF23 plasma levels in 434 patients with ADPKD and 355 control subjects with a measured glomerular filtration rate (mGFR) between 60 and 120 mL/min per 1.73 m2, we confirmed that patients with ADPKD had higher FGF23 plasma concentrations than controls. Remarkably, this difference did not translate into renal phosphate leakage. Using different assays for FGF23, we found that this discrepancy was explained by a predominant increase in the cleaved C-terminal fragment of FGF23, which lacks phosphaturic activity. We found that FGF23 plasma concentration independently correlated with the severity of cystic liver disease in ADPKD. We observed that, in contrast to control liver tissues, the cystic liver from patients with ADPKD markedly expressed FGF23 messenger RNA and protein. In line with this finding, the surgical reduction of polycystic liver mass was associated with a decrease in FGF23 plasma levels independently of any modification in mGFR, phosphate, or iron status. Our findings demonstrate that severely polycystic livers produce FGF23 and increase levels of circulating FGF23 in patients with ADPKD.

Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility.

Skeletal muscle dysfunction accompanies the clinical disorders of chronic kidney disease (CKD) and hereditary hypophosphatemic rickets. In both disorders, fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D metabolism, becomes chronically elevated. FGF23 has been shown to play a direct role in cardiac muscle dysfunction; however, it is unknown whether FGF23 signaling can also directly induce skeletal muscle dysfunction. We found expression of potential FGF23 receptors ( Fgfr1-4) and α-Klotho in muscles of two animal models (CD-1 and Cy/+ rat, a naturally occurring rat model of chronic kidney disease-mineral bone disorder) as well as C2C12 myoblasts and myotubes. C2C12 proliferation, myogenic gene expression, oxidative stress marker 8-OHdG, intracellular Ca2+ ([Ca2+]i), and ex vivo contractility of extensor digitorum longus (EDL) or soleus muscles were assessed after treatment with various amounts of FGF23. FGF23 (2-100 ng/ml) did not alter C2C12 proliferation, expression of myogenic genes, or oxidative stress after 24- to 72-h treatment. Acute or prolonged FGF23 treatment up to 6 days did not alter C2C12 [Ca2+]i handling, nor did acute treatment with FGF23 (9-100 ng/ml) affect EDL and soleus muscle contractility. In conclusion, although skeletal muscles express the receptors involved in FGF23-mediated signaling, in vitro FGF23 treatments failed to directly alter skeletal muscle development or function under the conditions tested. We hypothesize that other endogenous substances may be required to act in concert with FGF23 or apart from FGF23 to promote muscle dysfunction in hereditary hypophosphatemic rickets and CKD.

Bone-derived hormones and their systemic regulation.

Bone has several functions such as supporting our body, protecting internal organs and contributing to hematopoiesis. Recently, it has been revealed that bone also works as an endocrine tissue and systemically regulates functions of other organs. It has been reported that fibroblast growth factor 23(FGF23)regulates phosphate metabolism and osteocalcin affect glucose/energy metabolism. In addition, sclerostin, interleukin-11(IL-11)and lipocalin 2 have been also found to be bone-derived humoral factors. Further investigation concerning the network systems among multiple organs via bone-derived hormones may lead to the development of new drugs.

Osteocalcin in the brain: from embryonic development to age-related decline in cognition.

A remarkable, unexpected aspect of the bone-derived hormone osteocalcin is that it is necessary for both brain development and brain function in the mouse, as its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behaviour. The regulation of cognitive function by osteocalcin, together with the fact that its circulating levels decrease in midlife compared with adolescence in all species tested, raised the prospect that osteocalcin might be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this Review, recent data indicate that this is indeed the case and that osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young wild-type mice. The diversity and amplitude of the functions of osteocalcin in the brain, during development and postnatally, had long called for the identification of its receptor in the brain, which was also recently achieved. This Review presents our current understanding of the biology of osteocalcin in the brain, highlighting the bony vertebrate specificity of the regulation of cognitive function and pointing toward where therapeutic opportunities might exist.

X-Linked Hypophosphatemia and FGF23-Related Hypophosphatemic Diseases: Prospect for New Treatment.

Phosphate plays essential roles in many biological processes, and the serum phosphate level is tightly controlled. Chronic hypophosphatemia causes impaired mineralization of the bone matrix and results in rickets and osteomalacia. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate metabolism. FGF23 excess induces hypophosphatemia via impaired phosphate reabsorption in the renal proximal tubules and decreased phosphate absorption in the intestines. There are several types of genetic and acquired FGF23-related hypophosphatemic diseases. Among these diseases, X-linked hypophosphatemia (XLH), which is caused by inactivating mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, is the most prevalent form of genetic FGF23-related hypophosphatemic rickets. Another clinically relevant form of FGF23-related hypophosphatemic disease is tumor-induced osteomalacia (TIO), a paraneoplastic syndrome associated with FGF23-producing tumors. A combination of active vitamin D and phosphate salts is the current medical therapy used to treat patients with XLH and inoperative TIO. However, this therapy has certain efficacy- and safety-associated limitations. Several measures to inhibit FGF23 activity have been considered as possible new treatments for FGF23-related hypophosphatemic diseases. In particular, a humanized monoclonal antibody for FGF23 (burosumab) is a promising treatment in patients with XLH and TIO. This review will focus on the phosphate metabolism and the pathogenesis and treatment of FGF23-related hypophosphatemic diseases.

Cardiovascular Effects of Renal Distal Tubule Deletion of the FGF Receptor 1 Gene.

The bone-derived hormone fibroblast growth factor-23 (FGF-23) activates complexes composed of FGF receptors (FGFRs), including FGFR1, and α-Klotho in the kidney distal tubule (DT), leading to increased sodium retention and hypertension. However, the role of FGFR1 in regulating renal processes linked to hypertension is unclear. Here, we investigated the effects of selective FGFR1 loss in the DT. Conditional knockout (cKO) of FGFR1 in the DT (FGFR1DT-cKO mice) resulted in left ventricular hypertrophy (LVH) and decreased kidney expression of α-Klotho in association with enhanced BP, decreased expression of angiotensin converting enzyme 2, and increased expression of the Na+-K+-2Cl- cotransporter. Notably, recombinant FGF-23 administration similarly decreased the kidney expression of α-Klotho and induced LVH in mice. Pharmacologic activation of FGFR1 with a monoclonal anti-FGFR1 antibody (R1MAb1) normalized BP and significantly attenuated LVH in the Hyp mouse model of excess FGF-23, but did not induce a response in FGFR1DT-cKO mice. The hearts of FGFR1DT-cKO mice showed increased expression of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6), consistent with cardiac effects of soluble Klotho deficiency. Moreover, administration of recombinant soluble Klotho lowered BP in the Hyp mice. Thus, FGFR1 in the DT regulates systemic hemodynamic responses opposite to those predicted by the actions of FGF-23. These cardiovascular effects appear to be mediated by paracrine FGF control of kidney FGFR1 and subsequent regulation of soluble Klotho and TRPC6. FGFR1 in the kidney may provide a new molecular target for treating hypertension.

Modulation of cognition and anxiety-like behavior by bone remodeling

ObjectiveThat the bone-derived hormone osteocalcin is necessary to promote normal brain development and function, along with its recently described sufficiency in reversing cognitive manifestations of aging, raises novel questions. One of these is to assess whether bone health, which deteriorates rapidly with aging, is a significant determinant of cognition and anxiety-like behavior. MethodsTo begin addressing this question, we used mice haploinsufficient for Runx2, the master gene of osteoblast differentiation and the main regulator of Osteocalcin expression. Control and Runx2+/− mice were evaluated for the expression of osteocalcin's target genes in the brain and for behavioral parameters, using two assays each for cognition and anxiety-like behavior. ResultsWe found that adult Runx2+/− mice had defects in bone resorption, reduced circulating levels of bioactive osteocalcin, and reduced expression of osteocalcin's target genes in the brain. Consequently, they had significant impairment in cognitive function and increased anxiety-like behavior. ConclusionsThese results indicate that bone remodeling is a determinant of brain function.

Pleiotropic Actions of FGF23.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, mainly produced by osteoblasts and osteocytes in response to increased extracellular phosphate and circulating vitamin D hormone. Endocrine FGF23 signaling requires co-expression of the ubiquitously expressed FGF receptor 1 (FGFR1) and the co-receptor α-Klotho (Klotho). In proximal renal tubules, FGF23 suppresses the membrane expression of the sodium–phosphate cotransporters Npt2a and Npt2c which mediate urinary reabsorption of filtered phosphate. In addition, FGF23 suppresses proximal tubular expression of 1α-hydroxylase, the key enzyme responsible for vitamin D hormone production. In distal renal tubules, FGF23 signaling activates with-no-lysine kinase 4, leading to increased renal tubular reabsorption of calcium and sodium. Therefore, FGF23 is not only a phosphaturic but also a calcium- and sodium-conserving hormone, a finding that may have important implications for the pathophysiology of chronic kidney disease. Besides these endocrine, Klotho-dependent functions of FGF23, FGF23 is also an auto-/paracrine suppressor of tissue-nonspecific alkaline phosphatase transcription via Klotho-independent FGFR3 signaling, leading to local inhibition of mineralization through accumulation of pyrophosphate. In addition, FGF23 may target the heart via an FGFR4-mediated Klotho-independent signaling cascade. Taken together, there is emerging evidence that FGF23 is a pleiotropic hormone, linking bone with several other organ systems.

Association between serum osteocalcin and body mass index: a systematic review and meta-analysis.

Osteocalcin is considered as a bone-derived hormone affecting on the body fat distribution and body mass index. Several cross-sectional studies have investigated the association between serum osteocalcin and body mass index. The aim of this study was to summarize the evidence on the relationship between serum osteocalcin and body mass index. We conducted a complete search up to November 2016 in PubMed and SCOPUS and reviewed reference list of all relevant articles and reviews. The DerSimonian-Laird method were used to pool effect sizes of eligible studies. The potential sources of heterogeneity were assessed using the standard χ 2 test.To find possible the sources of between-study heterogeneity, we carried out subgroup analyses based on sex, and type of study population. There was a significant inverse association in the overall result of this study between serum osteocalcin levels and BMI(r = -0.161; 95% CI: -0.197, -0.124, p < 0.000). In the subgroup analysis to find the sources of significant heterogeneity between-study, we observed that the type of the study population may be the source of between-study heterogeneity and the most correlation was seen in metabolic syndrome studies (r = -0.265; p = 0.000). Findings from the available data indicated an overall significant inverse association between serum osteocalcin and body mass index. Further studies based on the type of study population are needed to better clarify these associations.