Fowlkes J L, Suzuki K, Nagase H, Thrailkill K M
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710.
Endocrinology. 1994 Dec;135(6):2810-3. doi: 10.1210/endo.135.6.7527335.
Insulin-like growth factor binding protein-3 (IGFBP-3) is degraded by a cation-dependent protease(s) present in the serum of late gestation rats. Proteolysis of IGFBP-3 results in an increase in IGF-I clearance and possibly in IGF bioavailability. Based on our previous findings that matrix metalloproteinases (MMPs) degrade IGFBP-3 in fibroblast conditioned media, we hypothesized that MMPs might be involved in the degradation of IGFBP-3 by rat pregnancy serum. In the present study, we demonstrate that tissue inhibitor of metalloproteinases (TIMP-1), a specific inhibitor of all MMPs, inhibited significantly the degradation of 125I-rhIGFBP-3 by both rat pregnancy serum and rat placental extracts. Purified human MMPs (principally MMP-1 and MMP-3) degraded IGFBP-3 in solution; MMP-3 produced a pattern of IGFBP-3 degradation products identical in size to the fragments produced by pregnancy serum. Furthermore, the combined addition of antihuman MMP-1 IgG and anti-human MMP-3 IgG to rat pregnancy serum blocked almost completely the degradation of 125I-rhIGFBP-3, suggesting that these two MMPs are the principal MMPs involved in IGFBP-3 degradation in rat pregnancy serum. Together, these data suggest that MMPs function as IGFBP-3-degrading proteases in the serum of late gestational pregnant rats.
胰岛素样生长因子结合蛋白3（IGFBP - 3）可被妊娠晚期大鼠血清中存在的一种阳离子依赖性蛋白酶降解。IGFBP - 3的蛋白水解导致IGF - I清除率增加，可能还会影响IGF的生物利用度。基于我们之前的发现，即基质金属蛋白酶（MMPs）可在成纤维细胞条件培养基中降解IGFBP - 3，我们推测MMPs可能参与了大鼠妊娠血清对IGFBP - 3的降解。在本研究中，我们证明金属蛋白酶组织抑制剂（TIMP - 1），一种所有MMPs的特异性抑制剂，可显著抑制大鼠妊娠血清和大鼠胎盘提取物对125I - rhIGFBP - 3的降解。纯化的人MMPs（主要是MMP - 1和MMP - 3）可在溶液中降解IGFBP - 3；MMP - 3产生的IGFBP - 3降解产物模式在大小上与妊娠血清产生的片段相同。此外，将抗人MMP - 1 IgG和抗人MMP - 3 IgG联合添加到大鼠妊娠血清中，几乎完全阻断了125I - rhIGFBP - 3的降解，这表明这两种MMPs是参与大鼠妊娠血清中IGFBP - 3降解的主要MMPs。总之，这些数据表明MMPs在妊娠晚期大鼠血清中作为IGFBP - 3降解蛋白酶发挥作用。
