硬化蛋白(SOST)由骨细胞产生,被称为骨稳态的负调节剂。甲状旁腺激素(PTH)调节钙,磷酸盐和维生素D的代谢,是体内外SOST合成的强抑制剂。PTH具有两个可被氧化的甲硫氨酸氨基酸(位置8和18)。在Met18氧化的PTH(Met18(ox)-PTH)继续具有生物活性,而PTH在Met8氧化(Met8(ox)-PTH)或PTH在Met8和Met18氧化(Met8,Met18(di-ox)-PTH)具有较小的生物活性。非氧化PTH(n-oxPTH)和氧化形式的PTH如何作用于硬化素合成是未知的。在UMR106成骨细胞样细胞中评估了n-oxPTH和PTH的氧化形式对SOST基因表达的影响。此外,我们分析了516例稳定肾移植受者中SOST与n-oxPTH和所有形式的oxPTH的关系,该系统可以在临床样本中区分n-oxPTH和所有氧化PTH形式的总和(Met8(ox)-PTH,Met18(ox)-PTH,和Met8,Met18(di-ox)-PTH。我们发现,n-oxPTH和Met18(ox)-PTH在1、3、20和30nmol/L的剂量下均显着抑制SOST基因的表达,而Met8(ox)-PTH和Met8,Met18(di-ox)-PTH对SOST基因表达的抑制作用较弱。在临床队列中,多元线性回归表明,只有n-oxPTH,但不是完整的PTH(iPTH)或oxPTH,在调整已知的混杂因素后,与循环SOST独立相关。总之,只有生物活性PTH形式,如n-oxPTH和Met18(ox)-PTH,抑制SOST合成。
Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized.
PTH oxidized at Met18 (Met18(ox)-
PTH) continues to be bioactive, whereas
PTH oxidized at Met8 (Met8(ox)-
PTH) or
PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-
PTH) has minor bioactivity. How non-oxidized
PTH (n-oxPTH) and oxidized forms of
PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-
PTH, Met18(ox)-
PTH, and Met8, Met18(di-ox)-
PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive
PTH forms such as n-oxPTH and Met18(ox)-
PTH, inhibit SOST synthesis.