Acute Parathyroid Hormone Injection Increases C-Terminal but Not Intact Fibroblast Growth Factor 23 Levels

Abstract

The acute effects of parathyroid hormone (PTH) on fibroblast growth factor 23 (FGF23) in vivo are not well understood. After a single subcutaneous PTH (1-34) injection (50 nmol/kg) in mice, FGF23 levels were assessed in plasma using assays that measure either intact alone (iFGF23) or intact/C-terminal FGF23 (cFGF23). Furthermore, FGF23 messenger RNA (mRNA) and protein levels were assessed in bone. In addition, we examined the effects of PTH treatment on FGF23 production in vitro using differentiated calvarial osteocyte-like cells. cFGF23 levels increased by three- to fivefold within 2 hours following PTH injection, which returned to baseline by 4 hours. In contrast, iFGF23 levels remained unchanged for the first 2 hours, yet declined to ∼60% by 6 hours and remained suppressed before returning to baseline after 24 hours. Using homozygous mice for an autosomal dominant hypophosphatemic rickets-FGF23 mutation or animals treated with a furin inhibitor, we showed that cFGF23 and iFGF23 levels increased equivalently after PTH injection. These findings are consistent with increased FGF23 production in bone, yet rapid cleavage of the secreted intact protein. Using primary osteocyte-like cell cultures, we showed that PTH increased FGF23 mRNA expression through cyclic adenosine monophosphate/protein kinase A, but not inositol triphosphate/protein kinase C signaling; PTH also increased furin protein levels. In conclusion, PTH injection rapidly increases FGF23 production in bone in vivo and in vitro. However, iFGF23 is rapidly degraded. At later time points through an unidentified mechanism, a sustained decrease in FGF23 production occurs.

A Novel Distal Enhancer Mediates Inflammation‐, PTH‐, and Early Onset Murine Kidney Disease‐Induced Expression of the Mouse Fgf23 Gene

“…B ). However, in line with a recent report from Knab and colleagues, in our experiment acute single PTH injection did not increase plasma iFGF23 levels in WT or Fgf23 −16KO mice (Fig. C ), providing another example of discordance between transcriptional regulation and processing.…”

“…Previous studies have shown that inflammation and calciotropic hormones increase Fgf23 transcription . However, the molecular mechanisms underpinning the transcriptional regulation of Fgf23 in response to inflammation and PTH in bone or non‐osseous tissues are unknown.…”

“…Both inflammation and PTH have been shown to increase Fgf23 production and therefore may be potential inducers of Fgf23 expression in CKD. Herein, we show that lack of the −16kb enhancer of Fgf23 prevented early onset kidney disease‐induced increases in renal, thymic, and skeletal Fgf23 expression in a diet‐induced CKD model.…”

A G protein–coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23

“…Based on our PTH injection experiments, the novel FGF23 synthesis mechanism involving G protein/PKC activation does not mediate the action of PTH. This is consistent with previous studies showing that PTH-induced FGF23 production occurs via cAMP-mediated mechanisms (15)(16)(17)(18)55). In contrast, 1,25(OH) 2 D-and phosphate-induced FGF23 production may depend, at least partly, on the G protein/PKC pathway, given that the significantly elevated 1,25(OH) 2 D and phosphate levels in XLKO pups were insufficient to maintain the normal level of FGF23.…”

Interactions of Phosphate Metabolism With Serious Injury, Including Burns

“…Therefore, something was suppressing FGF23 in both groups. This something is possibly PTH suppression inasmuch as PTH is proposed to affect FGF23 concentration in serum and calvarium in a mouse model of hyperparathyroidism, although the intact FGF23 molecule is rapidly degraded, as shown in a more recent mouse model . Others, however, have concluded that it is not PTH but 1,25‐dihydroxyvitamin D that stimulates FGF23 production, whereas still others feel that PTH suppresses FGF23 production, at least acutely .…”