scholarly journals Increased Circulatory Level of Biologically Active Full-Length FGF-23 in Patients with Hypophosphatemic Rickets/Osteomalacia

2002 ◽  
Vol 87 (11) ◽  
pp. 4957-4960 ◽  
Author(s):  
Yuji Yamazaki ◽  
Ryo Okazaki ◽  
Minako Shibata ◽  
Yukihiro Hasegawa ◽  
Kohei Satoh ◽  
...  
Keyword(s):  
Sandwich Elisa ◽  
Elevated Serum ◽  
Serum Levels ◽  
Biologically Active ◽  
Hypophosphatemic Rickets ◽  
Dihydroxyvitamin D ◽  
Autosomal Dominant Hypophosphatemic Rickets ◽  
Circulatory Level ◽  
Fgf 23

Abstract Hypophosphatemic rickets/osteomalacia with inappropriately low serum 1,25-dihidroxyvitamin D level is commonly observed in X-linked hypophosphatemic rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia and tumor-induced osteomalacia. Although the involvement of a newly identified factor, FGF-23, in the pathogenesis of ADHR and TIO has been suggested, clinical evidence indicating the role of FGF-23 has been lacking. We have previously shown that FGF-23 is cleaved between Arg179 and Ser180, and this processing abolished biological activity of FGF-23 to induce hypophosphatemia. Therefore, sandwich ELISA for biologically active intact human FGF-23 was developed using two kinds of monoclonal antibodies that requires the simultaneous presence of both the N-terminal and C-terminal portion of FGF-23. The serum levels of FGF-23 in healthy adults were measurable and ranged from 8.2 to 54.3 ng/L. In contrast, those in a patient with TIO were over 200 ng/L. After the resection of the responsible tumor, the elevated FGF-23 level returned to normal level within 1 h. The increase of serum concentrations of 1,25-dihidroxyvitamin D and phosphate, and the decrease of serum 24,25-dihydroxyvitamin D followed the change of FGF-23. In addition, the elevated serum FGF-23 levels were demonstrated in most patients with XLH. It is likely that increased serum levels of FGF-23 contributes to the development of hypophosphatemia not only in TIO but also in XLH.

Fibroblast Growth Factor 23 (FGF23) and the kidney

2009 ◽  
Vol 32 (4) ◽  
pp. 232-239 ◽  
Author(s):  
George Tsagalis ◽  
Erasmia Psimenou ◽  
Efstathios Manios ◽  
Antonios Laggouranis
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Serum Phosphate ◽  
Phosphate Concentration ◽  
Hypophosphatemic Rickets ◽  
Fibroblast Growth ◽  
Autosomal Dominant Hypophosphatemic Rickets ◽  
Fgf 23

Phosphate homeostasis in humans is a complex phenomenon involving the interplay of several different organs and circulating hormones. Among the latter, parathyroid hormone (PTH), and vitamin D3 (Vit D3) were thought to be the main regulators of serum phosphate concentration since they mediated the intestinal, renal and bone responses that follow fluctuations in serum phosphate levels. The study of three rare disorders – tumor-induced osteomalacia (TIO), autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemic rickets (XLH) – has offered a completely new insight into phosphate metabolism by unraveling the role of a group of peptides that can directly affect serum phosphate concentration by increasing urinary phosphate excretion. Fibroblast growth factor-23 (FGF-23) is the most extensively studied “phosphatonin”. The production, mechanism of action, effects in various target tissues, and its role in common clinical disorders are the focus of this review.

scholarly journals Pathogenic role of Fgf23 in Dmp1-null mice

2008 ◽  
Vol 295 (2) ◽  
pp. E254-E261 ◽  
Author(s):  
Shiguang Liu ◽  
Jianping Zhou ◽  
Wen Tang ◽  
Rochelle Menard ◽  
Jian Q. Feng ◽  
...  
Keyword(s):  
Growth Retardation ◽  
Matrix Protein ◽  
Serum Levels ◽  
Serum Phosphate ◽  
Hypophosphatemic Rickets ◽  
Null Mouse ◽  
Matrix Mineralization ◽  
Severe Growth ◽  
Inactivating Mutations

Autosomal recessive hypophosphatemic rickets (ARHR), which is characterized by renal phosphate wasting, aberrant regulation of 1α-hydroxylase activity, and rickets/osteomalacia, is caused by inactivating mutations of dentin matrix protein 1 ( DMP1). ARHR resembles autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH), hereditary disorders respectively caused by cleavage-resistant mutations of the phosphaturic factor FGF23 and inactivating mutations of PHEX that lead to increased production of FGF23 by osteocytes in bone. Circulating levels of FGF23 are increased in ARHR and its Dmp1-null mouse homologue. To determine the causal role of FGF23 in ARHR, we transferred Fgf23 deficient/enhanced green fluorescent protein (eGFP) reporter mice onto Dmp1-null mice to create mice lacking both Fgf23 and Dmp1. Dmp1−/− mice displayed decreased serum phosphate concentrations, inappropriately normal 1,25(OH)2D levels, severe rickets, and a diffuse form of osteomalacia in association with elevated Fgf23 serum levels and expression in osteocytes. In contrast, Fgf23−/− mice had undetectable serum Fgf23 and elevated serum phosphate and 1,25(OH)2D levels along with severe growth retardation and focal form of osteomalacia. In combined Dmp1−/−/Fgf23−/−, circulating Fgf23 levels were also undetectable, and the serum levels of phosphate and 1,25(OH)2D levels were identical to Fgf23−/− mice. Rickets and diffuse osteomalacia in Dmp1-null mice were transformed to severe growth retardation and focal osteomalacia characteristic of Fgf23-null mice. These data suggest that the regulation of extracellular matrix mineralization by DMP1 is coupled to renal phosphate handling and vitamin D metabolism through a DMP1-dependent regulation of FGF23 production by osteocytes.

Calcium and vitamin D metabolism in acromegaly

1981 ◽  
Vol 96 (4) ◽  
pp. 444-450 ◽  
Author(s):  
Bjarne Lund ◽  
Peter Claes Eskildsen ◽  
Birger Lund ◽  
Anthony W. Norman ◽  
Ole Helmer Sørensen
Keyword(s):  
Growth Hormone ◽  
Serum Concentration ◽  
Urinary Excretion ◽  
Direct Action ◽  
Elevated Serum ◽  
Serum Levels ◽  
Calcium Excretion ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D ◽  
Free Cortisol

Abstract. Acromegalic subjects were found to have elevated serum levels of both 1,25-dihydroxyvitamin D (1,25-(OH)2D), (67 ± 22 (sd) pg/ml) and 24,25-dihydroxyvitamin D (24,25-(OH)2D), (6.9 ± 1.5 (sd) ng/ml). The serum concentration of 1,25-(OH)2D correlated positively (P < 0.02, R = 0.56) to the 24 h urinary excretion of growth hormone, but not to the serum levels of parathyroid hormone, prolactin, thyroid hormones or the urinary excretion of free cortisol. Fourteen patients were treated with bromocriptine at doses from 15–45 mg/day for a period of about 6 months. This was accompanied by a significant decrease in the urinary excretion of growth hormone and calcium and in the serum concentrations of 1,25-(OH)2D and 24,25-(OH)2D. A relationship was demonstrated between the decrease in urinary calcium excretion and the decrease in serum 1,25-(OH)2D (P < 0.02, R = 0.64). It is concluded that the serum concentration of 1,25-(OH)2D is elevated in acromegaly, perhaps as a consequence of a direct action of growth hormone on the renal lα-hydroxylase activity.

Multiplex Analysis of Serum Cytokine Levels in Waldenström Macroglobulinemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2616-2616
Author(s):  
Sherine F. Elsawa ◽  
Anne J. Novak ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Vincent Rajkumar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Elevated Serum ◽  
Fold Increase ◽  
Serum Levels ◽  
Healthy Controls ◽  
Β2 Microglobulin ◽  
Healthy Donors ◽  
Cytokine Levels

Abstract Waldenström macroglobulinemia (WM) is a monoclonal B cell disorder characterized by a circulating monoclonal IgM protein that may lead to serum hyperviscosity in association with an infiltration of lymphoplasmacytic cells into the bone marrow. Although proinflammatory and chemotactic cytokines can profoundly affect tumor cells and the tumor microenvironment, and many cytokines have been shown to have potent therapeutic efficacy in preclinical cancer models, the role of cytokine networks in WM is not fully understood. In this study, we used a high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) to simultaneously test 30 cytokines, chemokines, angiogenic factors as well as growth factors and soluble receptors in the sera of WM patients and compared them with other B cell malignancies including IgM monoclonal gammopathy of undetermined significance (MGUS), follicular lymphoma, chronic lymphocytic leukemia (CLL) as well as healthy controls. Using a Mann-Whitney U test to analyze the differences between the groups, 15 of the 30 cytokines tested had significantly different levels in WM compared to healthy controls. Of those 15 cytokines, 11 were elevated in WM patients and 4 were decreased. Cytokines were grouped into 3 groups; those with &lt; 2-fold difference, 2–8 fold difference and those having &gt; 8-fold difference in their cytokine levels compared to healthy donors. There was a greater than 8-fold increase in the serum levels of Rantes, G-CSF and IL-2R (p&lt;0.0001) in WM patients. Furthermore, 3 cytokines had between 2–8-fold increase in WM patients including IL-4 (p&lt;0.0001), IL-6 (p&lt;0.0019) and IP-10 (p&lt;0.0006). Five cytokines had statistically elevated levels in WM patients compared to healthy controls, however the fold increase was &lt; 2 including HGF (p&lt;0.0185), IL-10 (p&lt;0.0002), MIP-1α (P&lt;0.0484), IL-2 (P&lt;0.0130) and IL-12 (P&lt;0.0155). Of the cytokines that had significantly lower levels in the sera of WM patients, IL-8 (p&lt;0.0001) and EGF (p&lt;0.0001) were &gt; 8-fold decreased, MCP-1 (p&lt;0.0001) was 2–8 fold lower and Eotaxin (p&lt;0.0004) was &lt; 2-fold lower in WM patients. All of the cytokines that had the greatest fold difference (&gt; 8-fold) in WM patients compared to healthy donors also differed significantly from the MGUS patients. Rantes, G-CSF, IL-2R and EGF had significantly different levels compared to other B cell malignancies. We tested for a correlation between the cytokines that had &gt; 2-fold difference between the WM group and control group with clinical features of the disease and found the cytokines IL-6 and IL-2R had a significant correlation with β2-microglobulin levels (p&lt;0.01). We analyzed cytokine levels in the bone marrow plasma of the same patients and found that high levels of IL-2R in the bone marrow microenvironment significantly correlated with anemia and elevated serum β2-microglobulin (p&lt;0.01). In conclusion, we have simultaneously analyzed sera from WM patients for 30 cytokines and found the most significantly elevated cytokines are Rantes, G-CSF and IL-2R and the most significantly downregulated cytokines are IL-8 and EGF. Furthermore, we found that elevated serum levels of IL-6 and IL-2R correlated with β2-microglobulin levels, a measure of disease activity. Further analysis of the biological role of these cytokines in WM may offer insight into disease pathogenesis and provide a basis for novel targeted therapies.

scholarly journals Clinical Significance of FGF-23 in Patients with CKD

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Domenico Russo ◽  
Yuri Battaglia
Keyword(s):  
Ventricular Hypertrophy ◽  
Vascular Dysfunction ◽  
Left Ventricular ◽  
Vitamin D Metabolism ◽  
Fgf Receptor ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Phosphate Retention ◽  
Fgf 23

FGF23 is a bone-derived hormone that plays an important role in the regulation of phosphate and 1,25-dihydroxy vitamin D metabolism. FGF23 principally acts in the kidney to induce urinary phosphate excretion and suppress 1,25-dihydroxyvitamin D synthesis in the presence of FGF receptor 1 (FGFR1) and its coreceptor Klotho. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively increased to compensate for persistent phosphate retention, but this results in reduced renal production of 1,25-dihydroxyvitamin D and leads to hypersecretion of parathyroid hormone. Furthermore, FGF23 is associated with vascular dysfunction, atherosclerosis, and left ventricular hypertrophy. This paper summarizes the role of FGF23 in the pathogenesis of mineral, bone, and cadiovascular disorders in CKD.

scholarly journals Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties

2012 ◽  
Vol 446 (1) ◽  
pp. 149-157 ◽  
Author(s):  
Marianne Schimpl ◽  
Christina L. Rush ◽  
Marie Betou ◽  
Ian M. Eggleston ◽  
Anneliese D. Recklies ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Active Site ◽  
Elevated Serum ◽  
Serum Levels ◽  
Chitinase Activity ◽  
Active Site Residues ◽  
Binding Properties ◽  
Binding Partners ◽  
Tryptophan Residues

The chitinase-like proteins YKL-39 (chitinase 3-like-2) and YKL-40 (chitinase 3-like-1) are highly expressed in a number of human cells independent of their origin (mesenchymal, epithelial or haemapoietic). Elevated serum levels of YKL-40 have been associated with a negative outcome in a number of diseases ranging from cancer to inflammation and asthma. YKL-39 expression has been associated with osteoarthritis. However, despite the reported association with disease, the physiological or pathological role of these proteins is still very poorly understood. Although YKL-39 is homologous to the two family 18 chitinases in the human genome, it has been reported to lack any chitinase activity. In the present study, we show that human YKL-39 possesses a chitinase-like fold, but lacks key active-site residues required for catalysis. A glycan screen identified oligomers of N-acetylglucosamine as preferred binding partners. YKL-39 binds chitooligosaccharides and a newly synthesized derivative of the bisdionin chitinase-inhibitor class with micromolar affinity, through a number of conserved tryptophan residues. Strikingly, the chitinase activity of YKL-39 was recovered by reverting two non-conservative substitutions in the active site to those found in the active enzymes, suggesting that YKL-39 is a pseudo-chitinase with retention of chitinase-like ligand-binding properties.

Prognostic role of serum beta 2-microglobulin in Hodgkin's disease.

1993 ◽  
Vol 11 (6) ◽  
pp. 1108-1111 ◽  
Author(s):  
M A Dimopoulos ◽  
F Cabanillas ◽  
J J Lee ◽  
F Swan ◽  
L Fuller ◽  
...  
Keyword(s):  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Elevated Serum ◽  
Serum Levels ◽  
Tumor Stage ◽  
Stage Disease ◽  
Lower Response Rate ◽  
Beta 2 ◽  
Beta 2 Microglobulin

PURPOSE To evaluate the role of serum beta 2-microglobulin (beta 2M) in the prognosis of patients with Hodgkin's disease. PATIENTS AND METHODS One hundred sixty previously untreated patients with Hodgkin's disease had serum beta 2M levels determined before initiation of treatment. Serum beta 2M was tested for its correlation with known prognostic factors for patients with Hodgkin's disease. These variables, including beta 2M, were correlated with complete remission (CR) rate and time to treatment failure (TTF). Univariate and multivariate analyses were performed. RESULTS Serum beta 2M levels greater than 2.5 mg/L were found in 29% of patients. Such elevation was more common in patients with more advanced-stage disease. Elevated serum beta 2M was an independent and powerful factor in the prediction of lower response rate and shorter TTF. Its impact appeared to be more significant in patients with advanced disease. CONCLUSION Serum beta 2M appears to correlate with tumor stage in patients with Hodgkin's disease and elevated serum levels of this polypeptide predict a less favorable prognosis.

Elevated Serum IL-12 Levels Attenuate Tumor Immunity Via the TIM-3/Gal-9 Axis and Worsen Patient Prognosis in Follicular B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2668-2668
Author(s):  
Zhi-Zhang Yang ◽  
Steven C. Ziesmer ◽  
Anne J. Novak ◽  
Toshiro Niki ◽  
Mitsuomi Hirashima ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Elevated Serum ◽  
B Cell Lymphoma ◽  
Serum Levels

Abstract Abstract 2668 Poster Board II-644 Interleukin-12 (IL-12) has been demonstrated to induce IFN-g production by T and NK cells and thereby contribute to anti-tumor immunity. However, the administration of IL-12 to boost anti-tumor immunity in B-cell lymphoma has shown no clinical benefit. In fact, clinical trials of IL-12 in combination with rituximab in follicular B-cell lymphoma (FL) showed a lower response rate in patients treated with the combination than in patients treated with rituximab alone (Clin Cancer Res. 2006 15; 12:6056-63). The goal of this study was therefore to determine the role of IL-12 in the antitumor response in B-cell NHL. First, we measured serum levels of IL-12 in patients with untreated FL before treatment with rituximab and normal healthy controls. We found that serum IL-12 levels were elevated in FL patients compared to healthy individuals (median: 0.50 ng/ml, n=30 vs 0.32 ng/ml, n=22; p= 0.03) and that elevated serum IL-12 levels were associated with a poor outcome in these patients when treated with rituximab alone as initial therapy. Using 0.56 ng/ml as a cutoff, patients with serum IL-12 levels of greater than 0.56 ng/ml had a significantly shorter time to progression than patients with IL-12 levels less than 0.56 ng/ml (12 months versus 40 months; p=0.001). To determine the mechanism by which IL-12 may contribute to a poor prognosis, we investigated the role of IL-12 on induction of immune tolerance. First, we found that TIM-3, a member of the T cell immunoglobulin and mucin domain-containing protein (TIM) family that functions to terminate TH1-mediated immunity and promote tolerance, was constitutively expressed on a subset of intratumoral T cells accounting for approximately 15% and 25% of the intratumoral CD4+ and CD8+ T cells, respectively. In contrast, less than 2% of T cells from peripheral blood of normal individuals expressed TIM-3. TIM-3-expressing T cells were distinct from regulatory T cells since CD25+ and Foxp3+ T cells lacked TIM-3 expression. Secondly, we found that TIM-3-expressing CD4+ cells were unable to produce cytokines such as IL-2, IFN-g or IL-17 and that TIM-3-expressing CD8+ T cells failed to produce Granzyme B, IFN-g or IL-2. We also observed that TIM-3-expressing T cells lost the capacity to proliferate in response to TCR activation. These results suggest that TIM-3 expressing CD4+ and CD8+ T cells are functionally exhausted. Thirdly, we observed that TIM-3 expression on T cells could be induced by activation and that IL-12 was the strongest stimulus to induce TIM-3 expression on CD4+ and CD8+ T cells. Finally, we found by immunohistochemistry (IHC) that Galectin-9 (Gal-9), a ligand for TIM-3, was abundantly expressed on lymphoma B cells. In vitro incubation with a stable form of Gal-9 induced apoptosis of CD4+ and CD8+ T cells in a dose dependent fashion. Gal-9-mediated apoptosis of T cells was attenuated by a TIM-3 Fc protein and isolated TIM-3+ T cells exhibited a significantly higher apoptosis rate than TIM-3− T cells in response to Gal-9. These results indicate that, in contrast to the observations in vitro or in vivo in mice, IL-12 actually plays a detrimental role in lymphoma patients. Given the findings that IL-12 strongly induces TIM-3 expression on effector T cells and that the TIM-3/Gal-9 pathway impairs the immune response, we conclude that increased serum levels of IL-12 suppress anti-tumor immunity in follicular lymphoma patients and is associated with a poor prognosis. Disclosures: Witzig: Novartis: Research Funding.

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