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MON-LB087 Synthesis of Osteocyte-Derived Phosphaturic Hormone FGF23 via IP3/PKC Signaling Downstream of the Extra-Large Gα Subunit (XLαs)

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Abstract Dysregulated actions of the bone-derived phosphaturic hormone FGF23 result in several inherited diseases and contribute substantially to the morbidity and mortality in renal failure. Molecular mechanisms governing FGF23 production… Click to show full abstract

Abstract Dysregulated actions of the bone-derived phosphaturic hormone FGF23 result in several inherited diseases and contribute substantially to the morbidity and mortality in renal failure. Molecular mechanisms governing FGF23 production are poorly defined. Parathyroid hormone (PTH) can stimulate FGF23 production via the alpha-stimulatory G protein (Gsα) and cAMP generation. The extra-large Gα-subunit (XLαs) is partially identical to Gsα, can mimic the latter regarding cAMP generation, and can couple to the PTH receptor. However, it has been shown that XLαs acts as a Gq/11α-like protein in kidney and stimulates IP3/PKC signaling. We have found that early postnatal XLαs knockout (XLKO) mice exhibit hyperphosphatemia due to diminished FGF23 production. We aimed to elucidate the mechanism of XLαs-mediated FGF23 synthesis. 2-hour PTH injection (50nM/kg body weight) increased serum FGF23 (WT+vehicle: 520.9±9.7, WT+PTH: 2848. 5±94.0, p<0.001; XLKO+vehicle: 260.8±18.4; XLKO+PTH: 3269.3±124.6 pg/mL, p<0.001; n=9~11 per group) and skeletal FGF23 mRNA (3.2-fold in WT, p<0.01, vs 8.1-fold in XLKO, p<0.001, over baseline; n=8 per group) levels in both genotypes, with no evidence of an impaired response in XLKO. In contrast, the femurs of XLKO mice showed significantly lower PKCα and PKCδ levels than in WT femurs. Likewise, XLαs ablation in osteocytic Ocy454 cells did not impair PTH-induced cAMP generation but suppressed baseline IP3 generation and PKCα/PKCδ protein levels. XLKO Ocy454 cells showed diminished FGF23 mRNA levels, which was rescued by treating the cells with the PKC activator phorbol myristate acetate (PMA). PMA also augmented FGF23 expression in WT cells (4.1-fold over baseline; p<0.05; n=6 per group). Moreover, 24-hour PMA injection (500 ng/g body weight) into WT and XLKO littermates raised FGF23 levels (WT+vehicle: 499. 9±29.9 WT+PMA: 1750.4±316.0; XLKO+vehicle: 281.0±25.9; XLKO+PMA: 846.0±191.7 pg/mL; n=10-13 per group) and caused hypophosphatemia. We then crossed Ocn-Cre or Dmp1-Cre mice with Rosa26-floxed stop-GNAQQ209L (GNAQQ209L) mice, which expresses a constitutively active Gqα mutant and activates PKC signaling upon Cre-mediated recombination. FGF23 levels were significantly increased in both GNAQQ209L/Ocn-Cre (2790.5±221.0 vs 355.3±8.7 pg/mL in controls; p<0.001; n=11-15 per group) and GNAQQ209L/Dmp1-Cre mice (452.2±20.1 vs 266.2±6.4 pg/mL in controls; p<0.01; n=11-14 per group). These results indicate that, rather than affecting PTH/cAMP signaling, XLαs mediates FGF23 production via promoting IP3/PKC signaling, and that PKC activation, directly or by constitutively active Gqα, enhances FGF23 production. These findings identify the XLαs/PKC axis as a novel mechanism governing FGF23 synthesis and a new paradigm for modulating the levels of this hormone in disease. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Keywords: per group; pth; pkc; fgf23; pkc signaling; xlko

Journal Title: Journal of the Endocrine Society
Year Published: 2019

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