Pregnancy-Associated Plasma Protein-A Accounts for the Insulin-Like Growth Factor (IGF)-Binding Protein-4 (IGFBP-4) Proteolytic Activity in Human Pregnancy Serum and Enhances the Mitogenic Activity of IGF by Degrading IGFBP-4in Vitro1 | Zendy

Dong Won Byun | Zendy; Subburaman Mohan | Zendy; Myung Hi Yoo | Zendy; Christopher Sexton | Zendy; David J. Baylink | Zendy; Xuezhong Qin | Zendy

Open Access

Pregnancy-Associated Plasma Protein-A Accounts for the Insulin-Like Growth Factor (IGF)-Binding Protein-4 (IGFBP-4) Proteolytic Activity in Human Pregnancy Serum and Enhances the Mitogenic Activity of IGF by Degrading IGFBP-4in Vitro¹

Author(s) -

Dong Won Byun,

Subburaman Mohan,

Myung Hi Yoo,

Christopher Sexton,

David J. Baylink,

Xuezhong Qin

Publication year - 2001

Publication title -

the journal of clinical endocrinology and metabolism

Language(s) - English

Resource type - Journals

eISSN - 1945-7197

pISSN - 0021-972X

DOI - 10.1210/jcem.86.2.7223

Subject(s) - proteolysis , protease , insulin like growth factor binding protein , growth factor , proteases , pregnancy associated plasma protein a , insulin like growth factor , in vitro , endocrinology , medicine , antibody , immunoprecipitation , metalloproteinase , biology , binding protein , microbiology and biotechnology , chemistry , matrix metalloproteinase , pregnancy , immunology , biochemistry , receptor , fetus , enzyme , gene , genetics , first trimester

Pregnancy-associated plasma protein-A (PAPP-A) has been identified as the insulin-like growth factor (IGF)-dependent IGF-binding protein-4 (IGFBP-4) protease produced by human fibroblasts. Recently, we found that serum proteases induced during human pregnancy cleaved IGFBP-4 in both an IGF-II-dependent and an IGF-II-independent fashion. This study sought to determine whether PAPP-A is the predominant IGFBP-4 protease in human pregnancy serum (PS) and to assess the in vitro role of serum PAPP-A. Immunoprecipitation with PAPP-A antibody effectively depleted PAPP-A from the PS and completely abolished both IGF-II-dependent and IGF-II-independent IGFBP-4 proteolytic activity in PS. Direct addition of PAPP-A antibody to PS completely blocked IGFBP-4 proteolysis and partially blocked IGFBP-5 proteolysis, but had no effect on IGFBP-3 proteolysis. To evaluate the role of serum PAPP-A, we tested whether PAPP-A in PS modulated the inhibitory activity of IGFBP-4 on IGF-II-induced cell proliferation in human osteosarcoma MG63 cells. The wild-type IGFBP-4 (WTBP-4; 200 ng/mL) failed to inhibit proliferation of the cells treated with PS (0.1% or 0.3%) alone or in combination with IGF-II (40 ng/mL), whereas the inhibitory effect of WTBP-4 was observed in the cells treated with nonpregnancy serum alone or in combination with IGF-II (P < 0.05). In contrast to WTBP-4, a protease-resistant IGFBP-4 was able to inhibit proliferation of the cells treated with PS alone or in combination with IGF-II (P < 0.05). In the presence of PAPP-A neutralizing antibody, the inhibitory effect of WTBP-4 on proliferation of the cells treated with IGF-II and PS was restored. In summary, these data demonstrate 1) that PAPP-A represents the predominant IGFBP-4 protease in PS; 2) that PAPP-A may in part contribute to IGFBP-5, but not IGFBP-3, proteolytic activity in PS; and 3) that PAPP-A enhances the bioactivity of IGFs in vitro by degrading IGFBP-4.

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