Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice

Abstract Background: Fibroblast growth factor 23 (FGF23) decreases serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D level, thereby regulating phosphate metabolism. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by FGF23 overproduction by tumor tissue. Resecting the responsible tumor is a radical treatment for TIO. When the responsible tumor is undetectable, phosphate and active vitamin D administration is recommended. However, supplementation alone is frequently insufficient to maintain phosphate levels and it is difficult to prevent the complications associated with medical therapy, including hypercalciuria and nephrocalcinosis. Recently, burosumab, a human monoclonal anti-FGF23 antibody, has been approved in Japan as a therapeutic agent for FGF23-related hypophosphatemia. Here, we present a patient with TIO effectively treated with burosumab in the absence of identification of tumour location. Clinical case: A 47-year-old female developed pain and edema of the feet; however, the cause could not be determined at local hospitals. Afterwards, she developed marked bone atrophy in the feet and was referred to our hospital. Her age at symptom onset, hypophosphatemia (serum P, 1.9 mg/dl, 2.7 mg/dl < n < 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml < n < 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml < n < 60 pg/ml) indicated FGF23-related osteomalacia. She was not having any medication at the time of diagnosis, including saccharified iron oxide or iron polymaltose. Urinary phosphate excretion increased without renal tubular defect; therefore, hypophosphatemic osteomalacia was diagnosed. MRI showed high signal intensity in the talus, sacral, and L5 vertebral regions, indicating multiple pseudofractures. Comprehensive imaging studies, including systemic CT scan and 111In-pentetreotide scintigraphy, did not reveal any tumors despite the suspicion of TIO. Next, we performed systemic venous sampling, which revealed high FGF23 level in the left external iliac vein. Second venous sampling limited to the left lower limb exhibited high FGF23 level in the posterior tibial vein. However, an additional imaging study limited to the left foot could not identify any tumors. Genetic variation was negative for potentially responsible genes, including PHEX and FGF23. We decided to administer burosumab to normalize serum phosphate level without phosphate supplementation. Within 2 months, pain was relieved and the visual analog scale scores also improved from 10 to 6. Moreover, bone MRI showed improved pseudofractures. Conclusion: Burosumab administration was effective for TIO of unknown origin, and it improved not only laboratory findings but also clinical symptoms in this case.

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Serum Leptin, Parathyroid Hormone, 1,25-Dihydroxyvitamin D, Fibroblast Growth Factor 23, Bone Alkaline Phosphatase, and Sclerostin Relationships in Obesity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-2280 ◽

2012 ◽

Vol 97 (5) ◽

pp. 1655-1662 ◽

Cited By ~ 87

Author(s):

Elizabeth Grethen ◽

Kathleen M. Hill ◽

RoseMarie Jones ◽

Brenda M. Cacucci ◽

Christine E. Gupta ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Parathyroid Hormone ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Bone Alkaline Phosphatase ◽

Fibroblast Growth ◽

Serum Leptin ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

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Fibroblast Growth Factor 23 Regulation by Systemic and Local Osteoblast-Synthesized 1,25-Dihydroxyvitamin D

Journal of the American Society of Nephrology ◽

10.1681/asn.2016010066 ◽

2016 ◽

Vol 28 (2) ◽

pp. 586-597 ◽

Cited By ~ 32

Author(s):

Loan Nguyen-Yamamoto ◽

Andrew C. Karaplis ◽

Rene St–Arnaud ◽

David Goltzman

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

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PENGARUH PEMBERIAN 1,25 DIHYDROXYVITAMIN D (CALCITRIOL) TERHADAP KADAR FIBROBLAST GROWTH FACTOR-23 DAN ALBUMINURIA PADA PASIEN PENYAKIT GINJAL KRONIK STADIUM V YANG MENJALANI HEMODIALISIS

Biomedika ◽

10.23917/biomedika.v9i1.4344 ◽

2017 ◽

Vol 9 (1) ◽

Author(s):

Intan Herlina ◽

Bambang Purwanto ◽

Sugiarto Sugiarto

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Drop Out ◽

Fibroblast Growth ◽

Angiotensin I ◽

Chi Square ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Fgf 23

Penyebab utama morbiditas dan mortalitas pada pasien Penyakit Ginjal Kronik adalah insiden kardiovaskuler yang didasari oleh proses aterosklerosis yang menyebabkan meningkatnya morbiditas dan mortalitas. Ginjal merupakan tempat utama sintesa 1,25 Dihydroxyvitamin D (Calcitriol), sehingga dengan adanya kerusakan ginjal menyebabkan defisiensi 1,25 Dihydroxyvitamin D (Calcitriol). Pada pasien Penyakit Ginjal Kronik terjadi peningkatan Fibroblast Growth Factor-23 dan Albuminuria akibat dari aktifitas Renin Angiotensin Aldosteron Sistem. Aktifitas RAAS mempengaruhi 1,25 Dihydroxy vitamin D (Calcitriol), Fibroblast Growth Factor-23 melalui Angiotensin 2 dengan cara menghambat reseptor Angiotensin I (AT1) melalui Nicotinmide Adenine Dinucleotide Phosphate Oxidase (NADPH Oksidase) dan Stress Oxidativ. Beberapa penelitian menyimpulkan pemberian 1,25 Dihydroxyvitamin D (Calcitriol) mempunyai efek renoprotektif, anti inflamasi dan antiproteinuric dengan cara menghambat reseptor Angoitensin I (AT1) sehingga mengakibatkan menurunnya albuminuria. Tujuan Penelitian ini adalah untuk membuktikan pemberian 1,25 Dihydroxyvitamin D (Calcitriol) dapat menurunkan kadar Fibroblas Growth Factor-23 dan albuminuria pada pasien Penyakit Ginjal Kronik stadium V yang menjalani hemodialisis. Penelitian ini merupakan penelitian eksperimen dengan randomisasi, subyek penelitian 30 orang, dibagi dalam dua kelompok sampel, kelompok plasebo 15 orang dan kelompok perlakuan 15 orang. Dalam perjalanan, kelompok placebo drop out 4 pasien karena keluarga pasien tidak menyetujui untuk melanjutkan penelitian dan satu lagi mengalami perburukan, sehingga jumlah sampel menjadi 26 orang, terbagi menjadi kelompok placebo sebanyak 11 orang yang diberi placebo dan kelompok perlakuan 15 orang diberi calcitriol 1x0,5 μg peroral selama 4 minggu. Karakteristik penelitian yang berupa variabel kualitatif, uji homogenitas dilakukan menggunakan uji Chi Square. Uji beda dua Rerata menggunakan uji t pada p<0.005. Pada kelompok plasebo (n=11) ; Kadar Fibroblast Growth Factor-23 sebelum dan sesudah perlakuan (876,24±795,93 RU/mL vs 1235,69±791,71 RU/mL; p=0,059) dan Albuminuria (72,30±195,06 μg/ mg vs 320,14±208,90 μg/mg; p=0,001). Pada kelompok perlakuan (n=15); Kadar Fibroblast Growth Factor-23 sebelum dan sesudah perlakuan (1210,96±845,97 RU/mL vs 612,33±487,32 RU/mL; p=0,002) dan Albuminuria (206,63±327,25 μg/mg vs 192,89±316,00 μg/mg; p=0,001). Terdapat perbedaan yang bermakna pada selisih ratarata kadar Fibroblast Growth Factor-23 (Delta-FGF-23) sebelum dan sesudah perlakuan pada kelompok placebo vs kelompok perlakuan (-359,45±560,23 RU/mL vs 598,63±608,27 RU/mL; p=0,001) dan selisih rata-rata Albuminuria (Delta-albuminuria) sebelum dan sesudah perlakuan pada kelompok placebo vs kelompok perlakuan (-247,84±189,48 μg/mg vs 13,73±23,15μg/mg;p=0,001. Pemberian suplementasi 1,25 Dihydroxyvitamin D (calcitriol) menurunkan kadar FGF-23 albuminuria secara bermakna pada pasien penyakit ginjal kronik stadium V yang menjalani hemodialisisKata Kunci: Penyakit Ginjal Kronis Stadium V, 1,25 Dihydroxyvitamin D (Calcitriol), Fibroblast Growth Factor-23, Albuminuria

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