Ito Nobuaki, Wijenayaka Asiri R, Prideaux Matthew, Kogawa Masakazu, Ormsby Renee T, Evdokiou Andreas, Bonewald Lynda F, Findlay David M, Atkins Gerald J
Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia.
Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, The University of Adelaide, Woodville, SA 5011, Australia.
Mol Cell Endocrinol. 2015 Jan 5;399:208-18. doi: 10.1016/j.mce.2014.10.007. Epub 2014 Oct 16.
Fibroblast growth factor-23 (FGF23), produced by osteocytes, is the key physiological regulator of phosphate homeostasis. Sepsis patients often experience transient hypophosphataemia, suggesting the regulation of FGF23 levels by pro-inflammatory factors. Here, we used the osteocyte-like cell line IDG-SW3 to investigate the effect of pro-inflammatory stimuli on FGF23 production. In differentiated IDG-SW3 cultures, basal Fgf23 mRNA was dose-dependently up-regulated by pro-inflammatory cytokines TNF, IL-1β and TWEAK, and bacterial LPS. Similar effects were observed in human bone samples. TNF- and IL-1β-induced Fgf23 expression was NF-κB-dependent. Conversely, mRNA encoding negative regulators of FGF23, Phex, Dmp1 and Enpp1, were suppressed by TNF, IL-1β, TWEAK and LPS, independent of NF-κβ signalling. Galnt3, the protein product of which protects intact FGF23 protein from furin/furin-like proprotein convertase cleavage, increased in response to these treatments. C-terminal FGF23 and intact FGF23 protein levels also increased, the latter only in the presence of Furin inhibitors, suggesting that enzymatic cleavage exerts critical control of active FGF23 secretion by osteocytes. Our results demonstrate in principle that pro-inflammatory stimuli are capable of increasing osteocyte secretion of FGF23, which may contribute to hypophosphataemia during sepsis and possibly other inflammatory conditions.
成骨细胞产生的成纤维细胞生长因子23（FGF23）是磷稳态的关键生理调节因子。脓毒症患者常出现短暂性低磷血症，提示促炎因子对FGF23水平有调节作用。在此，我们使用类成骨细胞系IDG-SW3来研究促炎刺激对FGF23产生的影响。在分化的IDG-SW3培养物中，促炎细胞因子TNF、IL-1β和TWEAK以及细菌脂多糖（LPS）可使基础Fgf23 mRNA呈剂量依赖性上调。在人类骨样本中也观察到了类似的效应。TNF和IL-1β诱导的Fgf23表达依赖于NF-κB。相反，编码FGF23负调节因子Phex、Dmp1和Enpp1的mRNA被TNF、IL-1β、TWEAK和LPS抑制，且与NF-κβ信号传导无关。Galnt3的蛋白产物可保护完整的FGF23蛋白不被弗林蛋白酶/类弗林蛋白酶前蛋白转化酶切割，其表达在这些处理后增加。C末端FGF23和完整FGF23蛋白水平也增加，后者仅在存在弗林蛋白酶抑制剂的情况下增加，这表明酶切对成骨细胞分泌活性FGF23起着关键控制作用。我们的结果原则上证明，促炎刺激能够增加成骨细胞分泌FGF23，这可能导致脓毒症及其他可能的炎症状态下的低磷血症。
