期刊
JCI INSIGHT
卷 4, 期 17, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.125007
关键词
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资金
- NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK073911]
- NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [5K08AR067285, R01DK116716, R01AR05965]
- NIH/National Institute of Dental and Craniofacial Research [R01DE13686]
- NIH/NIDDK [T32DK007028]
- Boehringer Ingelheim Fonds MD fellowship
- NIH/NIAMS [P30AR066261]
Dysregulated actions of bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) result in several inherited diseases, such as X-linked hypophosphatemia (XLH), and contribute substantially to the mortality in kidney failure. Mechanisms governing FGF23 production are poorly defined. We herein found that ablation of the G(q/n )alpha-like, extralarge C alpha subunit (XL alpha s), a product of GNAS, exhibits FGF23 deficiency and hyperphosphatemia in early postnatal mice (XLKO). FGF23 elevation in response to parathyroid hormone, a stimulator of FGF23 production via cAMP, was intact in XLKO mice, while skeletal levels of protein kinase C isoforms alpha and delta (PKC alpha and PKC alpha) were diminished. XL alpha s ablation in osteocyte-like Ocy454 cells suppressed the levels of FGF23 mRNA, inositol 1,4,5-trisphosphate (IP3), and PKC alpha/PKC delta proteins. PKC activation in vivo via injecting phorbol myristate acetate (PMA) or by constitutively active Gq alpha-Q209L in osteocytes and osteoblasts promoted FGF23 production. Molecular studies showed that the PKC activation-induced FGF23 elevation was dependent on MAPK signaling. The baseline PKC activity was elevated in bones of Hyp mice, a model of XLH. XL alpha s ablation significantly, but modestly. reduced serum FGF23 and elevated serum phosphate in Hyp mice. These findings reveal a potentially hithertounknown mechanism of FGF23 synthesis involving a G protein-coupled IP3/PKC pathway, which may be targeted to fine-tune FGF23 levels.
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