Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.
Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.
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分泌型卷曲相关蛋白 4 是一种有效的肿瘤源性磷酸盐制剂。
DOI：
10.1172/jci18563
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Kumar,Rajiv
中科院分区：
文献类型：
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作者：
Berndt,Theresa;Craig,TheodoreA;Bowe,AnnE;Vassiliadis,John;Reczek,David;Finnegan,Richard;JanDeBeur,SuzanneM;Schiavi,SusanC;Kumar,Rajiv
与骨软化症相关的肿瘤阐述了新的因子，磷酸激素，其通过cAMP非依赖性途径引起磷酸盐尿和低磷酸盐血症。我们发现，分泌型卷曲相关蛋白-4（sFRP-4），一种在此类肿瘤中高度表达的蛋白质，是一种循环磷酸尿因子，可拮抗肾Wnt信号传导。在培养的负鼠肾上皮细胞中，sFRP-4特异性抑制钠依赖性磷酸盐转运。在正常大鼠中输注sFRP-4超过2小时，特异性地使肾无机磷酸盐排泄分数（FEPi）从14% ± 2%增加至34% ± 5%（平均值± SEM，P< 0.01）。尿cAMP和钙排泄无变化。在甲状腺-甲状旁腺切除大鼠中，sFRP-4使FEPi从0.7% ± 0.2%增加至3.8% ± 1.2%（P< 0.05），表明sFRP-4通过PTH非依赖性机制抑制肾脏无机磷重吸收。对完整大鼠给予sFRP-4 8小时以上可增加FEPi，降低血清磷（1.95 ± 0.1至1.53 ± 0.09 mmol/l，P< 0.05），但未改变血清1α，25-二羟维生素D、肾25-羟维生素D 1α-羟化酶细胞色素P450和钠-磷酸盐协同转运蛋白mRNA浓度。输注sFRP-4拮抗Wnt作用，如通过肾β-连环蛋白减少和磷酸化β-连环蛋白浓度增加所证明的。sFRP-4可在正常人血清和肿瘤诱导的骨软化症患者的血清中检测到。因此，sFRP-4显示出磷酸化酶样性质，因为它是一种循环蛋白，可促进磷酸盐尿和低磷酸盐血症，并减弱1α，25-二羟基维生素D的代偿性增加。
Tumors associated with osteomalacia elaborate the novel factor(s), phosphatonin(s), which causes phosphaturia and hypophosphatemia by cAMP-independent pathways. We show that secreted frizzled-related protein-4 (sFRP-4), a protein highly expressed in such tumors, is a circulating phosphaturic factor that antagonizes renal Wnt-signaling. In cultured opossum renal epithelial cells, sFRP-4 specifically inhibited sodium-dependent phosphate transport. Infusions of sFRP-4 in normal rats over 2 hours specifically increased renal fractional excretion of inorganic phosphate (FEPi) from 14% ± 2% to 34% ± 5% (mean ± SEM,P< 0.01). Urinary cAMP and calcium excretion were unchanged. In thyro-parathyroidectomized rats, sFRP-4 increased FEPifrom 0.7% ± 0.2% to 3.8% ± 1.2% (P< 0.05), demonstrating that sFRP-4 inhibits renal inorganic phosphate reabsorption by PTH-independent mechanisms. Administration of sFRP-4 to intact rats over 8 hours increased FEPi, decreased serum phosphate (1.95 ± 0.1 to 1.53 ± 0.09 mmol/l,P< 0.05) but did not alter serum 1α, 25-dihydroxyvitamin D, renal 25-hydroxyvitamin D 1α-hydroxylase cytochrome P450, and sodium-phosphate cotransporter mRNA concentrations. Infusion of sFRP-4 antagonizes Wnt action as demonstrated by reduced renal β-catenin and increased phosphorylated β-catenin concentrations. The sFRP-4 is detectable in normal human serum and in the serum of a patient with tumor-induced osteomalacia. Thus, sFRP-4 displays phosphatonin-like properties, because it is a circulating protein that promotes phosphaturia and hypophosphatemia and blunts compensatory increases in 1α, 25-dihydroxyvitamin D.