Fibroblast Growth Factor 23 Antibody Research Articles

Spectrum of PHEX Mutations and FGF23 Profiles in a Taiwanese Cohort With X-Linked Hypophosphatemia Including 102 Patients.

X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH. We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing. The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis. Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.

Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia

Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg−1 of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3–7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities.

Mineralized tissues in hypophosphatemic rickets.

Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.

FGF23 impairs peripheral microvascular function in renal failure.

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

Correlation of fibroblast growth factor 23 with adverse prognosis of chronic kidney disease and therapy strategy

Fibroblast growth factor 23 (FGF23) is a hormone secreted by the bone. It is not only involved in the pathophysiological process of chronic kidney disease (CKD), but also associated with the poor prognosis. In patients with CKD, serum FGF23 levels are elevated in early phase. The increased FGF23 levels gradually lead to myocardial hypertrophy, inflammatory, vascular calcification, and low level of vitamin D, which contribute to the progress of CKD, cardiovascular complications and even death. Presently, there are several ways to reduce FGF23 levels, including decrease of intake and block of phosphorus absorption, supplement of FGF23 antibody and pseudo calcium or renal transplantation.

FGF23: Mediator of poor prognosis in a sizeable subgroup of patients with castration-resistant prostate cancer presenting with severe hypophosphatemia?

Castration-resistant prostate cancer (CRPC) is an advanced and incurable stage of the second most frequently diagnosed malignancy in men globally. Current treatment options improve survival modestly but eventually fail due to intrinsic or acquired therapeutic resistance. A hypothesis is presented wherein circulating levels of fibroblast growth factor 23 (FGF23), an endocrine member of the fibroblast growth factor family with phosphaturic properties, are proposed as a prognostic and predictive marker to identify CRPC patients with poor prognosis that are amenable to FGF23 antibody therapy (FGF23i) or treatment with fibroblast growth factor receptor inhibitors (FGFRi). With respect to the latter, FGF23 may also serve as a pharmacodynamic marker enabling individualized FGFRi dosing.We recently discovered that the development of severe and sustained hypophosphatemia in CRPC patients undergoing zoledronic acid therapy for bone metastases was associated with markedly worse prognosis compared to patients without or with only mild and transient hypophosphatemia. Severe hypophosphatemia is a typical manifestation of tumor-induced hypophosphatemic osteomalacia (TIO), a paraneoplastic condition mediated by FGF23 overexpression in most instances. While the postulated tumor-promoting role of FGF23 in CRPC or other malignancies has not yet been studied, several lines of evidence suggest that FGF23 may mediate both severe hypophosphatemia (via its endocrine properties) and aggressive CRPC behavior (via autocrine and paracrine activities): (i) FGF23 and the necessary signalling machinery (i.e. members of the fibroblast growth factor receptor [FGFR] family and the essential co-receptor α-KLOTHO [KL]) are highly expressed in a sizeable subgroup of CRPC patients; (ii) FGF/FGFR signalling plays important roles in prostate cancer; (iii) FGF23 can induce its own expression via a positive autocrine feedback loop involving FGFR1; and (iv) this positive feedback loop may be triggered by bone-targeted therapies frequently used for the treatment of CRPC-associated bone metastases.While there is a lack of personalized treatment strategies in the management of CRPC to date, FGF23 targeted therapy has the potential to fill this unmet clinical need in the not-so-distant future. In fact, FGFRi are currently in advanced clinical testing for a number of malignancies such as kidney and lung cancer, but there is a lack of conclusive data on FGFRi therapy in patients selected for FGF/FGFR pathway activation.

FGF23 antagonism: the thin line between adaptation and maladaptation in chronic kidney disease

For more than 10 years, we have been convinced by overwhelming epidemiological evidence with a high biological plausibility that hyperphosphataemia imposes one of the most sustained cardiovascular and mortality risks on patients suffering from chronic kidney disease (CKD). With the discovery of the fibroblast growth factor-23 (FGF23)/klotho axis, we not only gained a new and mechanistic understanding of phosphate handling of the body, we also felt that novel therapeutic strategies may arise counteracting the deleterious consequences of phosphate retention, dysregulation and maldistribution. Two recent experimental studies shed additional and important light on what we can expect from such new insights. Faul et al. showed us that FGF23 excess may directly induce left ventricular hypertrophy (LVH) and that FGF-receptor antagonism ameliorates CKD-induced LVH in rats. Shalhoub et al. demonstrated that FGF23 antibodies successfully ameliorated the development and progression of most features of secondary hyperparathyroidism in a rat model of CKD, however, at the expense of hyperphosphataemia, progressive vascular calcification and death. Such studies not only help to continuously improve our understanding, but also especially sharpen our perception of how thin the line may be between adaptation and maladaptation in chronic disease scenarios.

Oncostatin M Induces FGF23 Expression in Cardiomyocytes

Background: It is well-known that elevated levels of Fibroblast Growth Factor-23 (FGF23), a bone derived hormone, in circulation are associated with renal failure. Recent studies emphasize the correlation between Heart Failure (HF) and FGF23, but the ability of cardiomyocytes themselves to express and secrete this phosphatonin is yet unknown. A further factor involved in HF is the cytokine oncostatin M (OSM). The aims of our study were: 1) to analyze the myocardium of HF patients in terms of FGF23 expression in cardiomyocytes and 2) to assess whether OSM is able to induce FGF23 production in cardiomyocytes. Methods: Cultures of adult cardiomyocytes were treated with OSM and screened for the expression of FGF23 transcripts. FGF23 secretion was determined by Western blot and ELISA of cell culture supernatants. Heart explants of HF patients with Dilated Cardiomyopathy (DCM), Ischemic Cardiomyopathy (ICM) and myocarditis (Myo) were analyzed by immunofluorescence using FGF23 antibodies and compared with healthy controls. FGF23 levels were also determined in mice with a cardiac restricted overexpression of Monocyte Chemotactic Protein-1 (MCP1), which developed an “inflammatory” Heart Failure (iHF) due to macrophage infiltration. Results: OSM massively induced the expression and secretion of FGF23 in cultured adult cardiomyocytes. Confocal microscopy revealed high amounts of FGF23 positive cardiomyocytes in the myocardium of patients with ischemic heart disease (IHD), myocarditis, dilated cardiomyopathy (DCM) and in mice with iHF. Conclusions: The presence of FGF23 in the myocardium of patients with different types of HF and in mice with “inflammatory” HF suggests that macrophages are responsible for the FGF23 expression in cardiomyocytes via OSM. Whether FGF23 acts as a regeneration promoting factor and/or potentially serves as a HF/transplantation marker has to be clarified.

Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice

Fibroblast growth factor 23 (FGF-23) plays causative roles in the development of several hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia. Patients with hypophosphatemic rickets/osteomalacia often complain of muscle weakness and bone pain that severely affect daily activities of these patients. The purpose of this study was to examine whether anti-FGF-23 antibodies, which have been shown to improve hypophosphatemia and rachitic changes of juvenile Hyp mice in a murine model of XLH, also ameliorate hypophosphatemic osteomalacia and affect muscle force and spontaneous motor activity in adult Hyp mice. Repeated injections of anti-FGF-23 antibodies increased serum phosphate and 1,25-dihydroxyvitmain D levels and enhanced mineralization of osteoid in adult Hyp mice, whereas bone length did not change. We found that grip strength was weaker and that spontaneous movement was less in adult Hyp mice than in wild-type mice. In addition, FGF-23 antibodies increased grip strength and spontaneous movement. These results suggest that the inhibition of excess FGF-23 action not only ameliorates hypophosphatemia and impaired mineralization of bone but also improves muscle weakness and daily activities of patients with FGF-23-related hypophosphatemic rickets/osteomalacia.

Therapeutic Effects of Anti-FGF23 Antibodies in Hypophosphatemic Rickets/Osteomalacia

X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.

Elevated Fibroblast Growth Factor 23 in Women With Malignant Ovarian Tumors

OBJECTIVE To determine whether fibroblast growth factor 23 (FGF23) concentrations are altered in women with ovarian cancers in which FGF physiology is known to be abnormal. PATIENTS AND METHODS Between May 2002 and September 2003 at the Mayo Clinic in Rochester, Minn, plasma or serum FGF23 concentrations were measured in 39 healthy women and in 14 with benign ovarian tumors, 14 with early-stage ovarian cancer, and 13 with advanced-stage ovarian cancer. Immunohistochemistry using anti-human FGF23 antibodies was performed on tissue from benign masses and advanced-stage tumors. RESULTS Serum or plasma FGF23 concentrations were significantly higher in women with advanced-stage ovarian cancer compared with concentrations in women with early-stage ovarian cancer or benign disease or in healthy women. A significant positive correlation was seen between serum iFGF23 and cFGF23 concentrations and stage of disease. Serum iFGF23 and cFGF23 concentrations were positively correlated with serum phosphorus among women with ovarian cancer. No patients with elevated iFGF23 or cFGF23 concentrations had hypophosphatemia. Immunohistochemistry detected FGF23 tissue staining in malignant ovarian cancer cells. CONCLUSION Serum or plasma FGF23 concentrations are elevated in patients with advanced-stage epithelial ovarian cancer without reductions in serum phosphate concentrations. The presence of elevated FGF23 concentrations in patients with an ovarian mass should suggest advanced-stage disease. To determine whether fibroblast growth factor 23 (FGF23) concentrations are altered in women with ovarian cancers in which FGF physiology is known to be abnormal. Between May 2002 and September 2003 at the Mayo Clinic in Rochester, Minn, plasma or serum FGF23 concentrations were measured in 39 healthy women and in 14 with benign ovarian tumors, 14 with early-stage ovarian cancer, and 13 with advanced-stage ovarian cancer. Immunohistochemistry using anti-human FGF23 antibodies was performed on tissue from benign masses and advanced-stage tumors. Serum or plasma FGF23 concentrations were significantly higher in women with advanced-stage ovarian cancer compared with concentrations in women with early-stage ovarian cancer or benign disease or in healthy women. A significant positive correlation was seen between serum iFGF23 and cFGF23 concentrations and stage of disease. Serum iFGF23 and cFGF23 concentrations were positively correlated with serum phosphorus among women with ovarian cancer. No patients with elevated iFGF23 or cFGF23 concentrations had hypophosphatemia. Immunohistochemistry detected FGF23 tissue staining in malignant ovarian cancer cells. Serum or plasma FGF23 concentrations are elevated in patients with advanced-stage epithelial ovarian cancer without reductions in serum phosphate concentrations. The presence of elevated FGF23 concentrations in patients with an ovarian mass should suggest advanced-stage disease.

Elevated Fibroblast Growth Factor 23 in Women With Malignant Ovarian Tumors

To determine whether fibroblast growth factor 23 (FGF23) concentrations are altered in women with ovarian cancers in which FGF physiology is known to be abnormal. Between May 2002 and September 2003 at the Mayo Clinic in Rochester, Minn, plasma or serum FGF23 concentrations were measured in 39 healthy women and in 14 with benign ovarian tumors, 14 with early-stage ovarian cancer, and 13 with advanced-stage ovarian cancer. Immunohistochemistry using anti-human FGF23 antibodies was performed on tissue from benign masses and advanced-stage tumors. Serum or plasma FGF23 concentrations were significantly higher in women with advanced-stage ovarian cancer compared with concentrations in women with early-stage ovarian cancer or benign disease or in healthy women. A significant positive correlation was seen between serum iFGF23 and cFGF23 concentrations and stage of disease. Serum iFGF23 and cFGF23 concentrations were positively correlated with serum phosphorus among women with ovarian cancer. No patients with elevated iFGF23 or cFGF23 concentrations had hypophosphatemia. Immunohistochemistry detected FGF23 tissue staining in malignant ovarian cancer cells. Serum or plasma FGF23 concentrations are elevated in patients with advanced-stage epithellal ovarian cancer without reductions in serum phosphate concentrations. The presence of elevated FGF23 concentrations in patients with an ovarian mass should suggest advanced-stage disease.