Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia.
The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bo...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3579827?pdf=render |
| _version_ | 1828486948645240832 |
|---|---|
| author | Ai-Luen Wu Bo Feng Mark Z Chen Ganesh Kolumam Jose Zavala-Solorio Shelby K Wyatt Vineela D Gandham Richard A D Carano Junichiro Sonoda |
| author_facet | Ai-Luen Wu Bo Feng Mark Z Chen Ganesh Kolumam Jose Zavala-Solorio Shelby K Wyatt Vineela D Gandham Richard A D Carano Junichiro Sonoda |
| author_sort | Ai-Luen Wu |
| collection | DOAJ |
| description | The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders. |
| first_indexed | 2024-12-11T09:42:14Z |
| format | Article |
| id | doaj.art-7746b2c7b71048fbbf201ac0ccb024f6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T09:42:14Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7746b2c7b71048fbbf201ac0ccb024f62022-12-22T01:12:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5732210.1371/journal.pone.0057322Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia.Ai-Luen WuBo FengMark Z ChenGanesh KolumamJose Zavala-SolorioShelby K WyattVineela D GandhamRichard A D CaranoJunichiro SonodaThe phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders.http://europepmc.org/articles/PMC3579827?pdf=render |
| spellingShingle | Ai-Luen Wu Bo Feng Mark Z Chen Ganesh Kolumam Jose Zavala-Solorio Shelby K Wyatt Vineela D Gandham Richard A D Carano Junichiro Sonoda Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. PLoS ONE |
| title | Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. |
| title_full | Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. |
| title_fullStr | Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. |
| title_full_unstemmed | Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. |
| title_short | Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. |
| title_sort | antibody mediated activation of fgfr1 induces fgf23 production and hypophosphatemia |
| url | http://europepmc.org/articles/PMC3579827?pdf=render |
| work_keys_str_mv | AT ailuenwu antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT bofeng antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT markzchen antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT ganeshkolumam antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT josezavalasolorio antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT shelbykwyatt antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT vineeladgandham antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT richardadcarano antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia AT junichirosonoda antibodymediatedactivationoffgfr1inducesfgf23productionandhypophosphatemia |