FGF23 signalling and physiology

Abstract

Fibroblast growth factor 23 (FGF23) is a phosphotropic hormone that belongs to a subfamily of endocrine FGFs with evolutionarily conserved functions in C. elegans and fruit flies. FAM20C phosphorylates FGF23 post-translationally, targeting to proteolysis through subtilisin-like proprotein convertase FURIN, resulting in secretion of FGF23 fragments. O-glycosylation of FGF23 through GALNT3 appears to prevent proteolysis, resulting in secretion of biologically active intact FGF23. In the circulation, FGF23 may undergo further processing by plasminogen activators. Crystal structures show the ectodomain of the cognate FGF23 receptor FGFR1c binds with the ectodomain of the co-receptor alpha-KLOTHO. The KLOTHO-FGFR1c double heterodimer creates a high-affinity binding site for the FGF23 C-terminus. The topology of FGF23 deviates from that of paracrine FGFs, resulting in poor affinity for heparan sulfate, which may explain why FGF23 diffuses freely in the bone matrix to enter the bloodstream following its secretion by cells of osteoblastic lineage. Intact FGF23 signalling by this canonical pathway activates FRS2/RAS/RAF/MEK/ERK1/2. It reduces serum phosphate by inhibiting 1,25-Dihydroxyvitamin D synthesis, suppressing intestinal phosphate absorption, and by downregulating the transporters NPT2a and NPT2c, suppressing phosphate reabsorption in the proximal tubules. The physiological role of FGF23 fragments, which may be inhibitory, remains unclear. Pharmacological and genetic activation of canonical FGF23 signalling causes hypophosphatemic disorders, while its inhibition results in hyperphosphatemic disorders. Non-canonical FGF23 signalling through binding and activation of FGFR3/FGFR4/calcineurin/NFAT in an alpha-KLOTHO-independent fashion mainly occurs at extremely elevated circulating FGF23 levels and may contribute to mortality due to cardiovascular disease and left ventricular hypertrophy in chronic kidney disease.

Diagnostic utility of FGF-23 in mineral bone disorder during chronic kidney disease

“…The increase in FGF-23 concentration may be caused by the abnormal stimulation of its secretion exerted by substances released from the damaged renal parenchyma or by the effects exerted by the uremic state on bone mineralization processes. Other shreds of evidence, instead, suggest the crucial role that phosphorus plays in the uncontrolled stimulation of FGF-23 secretion ( 3 ). Limitation of our study is the distribution of samples by disease stage.…”

“…FGF-23 is a glycoprotein of 252 amino acids (32 kDa), encoded by the homonymous gene located on chromosome 12. FGF-23 exerts its biological activity through interaction with one of four specific receptors (FGFR 1-4) by a paracrine mechanism ( 3 ). FGF-23 is metabolized to its inactive C-terminal and N-terminal fragments and intact FGF-23 (iFGF-23) represents its biologically active form ( 4 ).…”

The Saga of Endocrine FGFs

“…This crystal structure supports the notion that FGF23 binds to FGFRs (FGFR 1c, 3c, and 4) in the presence of a co-receptor, KLA [ 68 , 210 ]. Furthermore, the KLA crystal structure shows that there are 2 extracellular domains, KL1 (E34 to F506) and KL2 (L515 to S950), in KLA [ 211 ]. The N-terminus of FGF23 binds to the KL2 domain of KLA, which in turn interacts with the D1 receptor of FGFR, and the C-terminus of FGF23 forms an active ternary receptor complex by binding to a pocket created by the KL1 and KL2 domains [ 210 , 212 ].…”

Effect of different phosphate binders on fibroblast growth factor 23 levels in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials

“…Currently, many clinical observations and animal experiments show that serum intact fibroblast growth factor 23 (FGF23) is a sensitive biomarker for CKD for it rises earlier than most other serum parameters, including serum creatinine and creatine phosphate (6,7). Phosphaturic hormone FGF23, derived and secreted primarily by bone osteocytes, is a 32-kDa glycoprotein (8). The key role of intact FGF23 is to maintain phosphate homeostasis (9).…”