This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Byun, D. Articles by Qin, X. Search for Related Content PubMed PubMed Citation Articles by Byun, D. Articles by Qin, X.

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-4 in Vitro¹

Musculoskeletal Disease Center, J. L. Pettis Memorial Veterans Affairs Medical Center, and Loma Linda University (D.B., S.M., C.S., D.J.B., X.Q.), Loma Linda, California 92357; and Department of Endocrinology, SoonChunHyang University Hospital (M.Y.), Seoul, 140-743 Korea

Address all correspondence and requests for reprints to: Dr. Xuezhong Qin, Musculoskeletal Disease Center, J. L. Pettis Veterans Affairs Medical Center (151), 11201 Benton Street, Loma Linda, California 92357. E-mail: xuezhong.qin{at}med.va.gov

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.

This article has been cited by other articles:

				C. Ganeff, G. Chatel, C. Munaut, F. Frankenne, J.-M. Foidart, and R. Winkler The IGF system in in-vitro human decidualization Mol. Hum. Reprod., January 1, 2009; 15(1): 27 - 38. [Abstract] [Full Text] [PDF]

				Y. Ning, A. G. P. Schuller, C. A. Conover, and J. E. Pintar Insulin-Like Growth Factor (IGF) Binding Protein-4 Is Both a Positive and Negative Regulator of IGF Activity in Vivo Mol. Endocrinol., May 1, 2008; 22(5): 1213 - 1225. [Abstract] [Full Text] [PDF]

				C. A. Conover Insulin-like growth factor-binding proteins and bone metabolism Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E10 - E14. [Abstract] [Full Text] [PDF]

				M. Rehage, S. Mohan, J. E. Wergedal, B. Bonafede, K. Tran, D. Hou, D. Phang, A. Kumar, and X. Qin Transgenic Overexpression of Pregnancy-Associated Plasma Protein-A Increases the Somatic Growth and Skeletal Muscle Mass in Mice Endocrinology, December 1, 2007; 148(12): 6176 - 6185. [Abstract] [Full Text] [PDF]

				S. C. Harrington, R. D. Simari, and C. A. Conover Genetic Deletion of Pregnancy-Associated Plasma Protein-A Is Associated With Resistance to Atherosclerotic Lesion Development in Apolipoprotein E-Deficient Mice Challenged With a High-Fat Diet Circ. Res., June 22, 2007; 100(12): 1696 - 1702. [Abstract] [Full Text] [PDF]

				B. S Miller, J. T Bronk, T. Nishiyama, H. Yamagiwa, A. Srivastava, M. E Bolander, and C. A Conover Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice J. Endocrinol., March 1, 2007; 192(3): 505 - 513. [Abstract] [Full Text] [PDF]

				X. Qin, J. E. Wergedal, M. Rehage, K. Tran, J. Newton, P. Lam, D. J. Baylink, and S. Mohan Pregnancy-Associated Plasma Protein-A Increases Osteoblast Proliferation in Vitro and Bone Formation in Vivo Endocrinology, December 1, 2006; 147(12): 5653 - 5661. [Abstract] [Full Text] [PDF]

				Z. T. Resch, R. D. Simari, and C. A. Conover Targeted Disruption of the Pregnancy-Associated Plasma Protein-A Gene Is Associated with Diminished Smooth Muscle Cell Response to Insulin-like Growth Factor-I and Resistance to Neointimal Hyperplasia after Vascular Injury Endocrinology, December 1, 2006; 147(12): 5634 - 5640. [Abstract] [Full Text] [PDF]

				F. Prefumo, S. Canini, A. Crovo, D. Pastorino, P. L. Venturini, and P. De Biasio Correlation between first trimester fetal bone length and maternal serum pregnancy-associated plasma protein-A (PAPP-A) Hum. Reprod., November 1, 2006; 21(11): 3019 - 3021. [Abstract] [Full Text] [PDF]

				Z. T. Resch, C. Oxvig, L. K. Bale, and C. A. Conover Stress-Activated Signaling Pathways Mediate the Stimulation of Pregnancy-Associated Plasma Protein-A Expression in Cultured Human Fibroblasts Endocrinology, February 1, 2006; 147(2): 885 - 890. [Abstract] [Full Text] [PDF]

				C. A. Conover, L. K. Bale, S. C. Harrington, Z. T. Resch, M. T. Overgaard, and C. Oxvig Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells: inhibition by resveratrol Am J Physiol Cell Physiol, January 1, 2006; 290(1): C183 - C188. [Abstract] [Full Text] [PDF]

				A. Kumar, S. Mohan, J. Newton, M. Rehage, K. Tran, D. J. Baylink, and X. Qin Pregnancy-associated Plasma Protein-A Regulates Myoblast Proliferation and Differentiation through an Insulin-like Growth Factor-dependent Mechanism J. Biol. Chem., November 11, 2005; 280(45): 37782 - 37789. [Abstract] [Full Text] [PDF]

				L. K Bale and C. A Conover Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A J. Endocrinol., August 1, 2005; 186(2): 325 - 331. [Abstract] [Full Text] [PDF]

				S. Oesterreicher, W. F. Blum, B. Schmidt, T. Braulke, and B. Kubler Interaction of Insulin-like Growth Factor II (IGF-II) with Multiple Plasma Proteins: HIGH AFFINITY BINDING OF PLASMINOGEN TO IGF-II AND IGF-BINDING PROTEIN-3 J. Biol. Chem., March 18, 2005; 280(11): 9994 - 10000. [Abstract] [Full Text] [PDF]

				M. Matsui, B. Sonntag, S. S. Hwang, T. Byerly, A. Hourvitz, E. Y. Adashi, S. Shimasaki, and G. F. Erickson Pregnancy-Associated Plasma Protein-A Production in Rat Granulosa Cells: Stimulation by Follicle-Stimulating Hormone and Inhibition by the Oocyte-Derived Bone Morphogenetic Protein-15 Endocrinology, August 1, 2004; 145(8): 3686 - 3695. [Abstract] [Full Text] [PDF]

				C. A. Conover, L. K. Bale, M. T. Overgaard, E. W. Johnstone, U. H. Laursen, E.-M. Fuchtbauer, C. Oxvig, and J. van Deursen Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development Development, March 1, 2004; 131(5): 1187 - 1194. [Abstract] [Full Text] [PDF]

				Z. T. Resch, B.-K. Chen, L. K. Bale, C. Oxvig, M. T. Overgaard, and C. A. Conover Pregnancy-Associated Plasma Protein A Gene Expression as a Target of Inflammatory Cytokines Endocrinology, March 1, 2004; 145(3): 1124 - 1129. [Abstract] [Full Text] [PDF]

				G. M. Rivera and J. E. Fortune Selection of the Dominant Follicle and Insulin-Like Growth Factor (IGF)-Binding Proteins: Evidence that Pregnancy-Associated Plasma Protein A Contributes to Proteolysis of IGF-Binding Protein 5 in Bovine Follicular Fluid Endocrinology, February 1, 2003; 144(2): 437 - 446. [Abstract] [Full Text] [PDF]

				I. Y. C. Sun, M. T. Overgaard, C. Oxvig, and L. C. Giudice Pregnancy-Associated Plasma Protein A Proteolytic Activity Is Associated with the Human Placental Trophoblast Cell Membrane J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5235 - 5240. [Abstract] [Full Text] [PDF]

				M. Zhang, E. P. Smith, H. Kuroda, W. Banach, S. D. Chernausek, and J. A. Fagin Targeted Expression of a Protease-resistant IGFBP-4 Mutant in Smooth Muscle of Transgenic Mice Results in IGFBP-4 Stabilization and Smooth Muscle Hypotrophy J. Biol. Chem., June 7, 2002; 277(24): 21285 - 21290. [Abstract] [Full Text] [PDF]

				L. C. Giudice, C. A. Conover, L. Bale, G. H. Faessen, K. Ilg, I. Sun, B. Imani, L.-F. Suen, J. C. Irwin, M. Christiansen, et al. Identification and Regulation of the IGFBP-4 Protease and Its Physiological Inhibitor in Human Trophoblasts and Endometrial Stroma: Evidence for Paracrine Regulation of IGF-II Bioavailability in the Placental Bed during Human Implantation J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2359 - 2366. [Abstract] [Full Text] [PDF]

				N. Miyakoshi, X. Qin, Y. Kasukawa, C. Richman, A. K. Srivastava, D. J. Baylink, and S. Mohan Systemic Administration of Insulin-Like Growth Factor (IGF)-Binding Protein-4 (IGFBP-4) Increases Bone Formation Parameters in Mice by Increasing IGF Bioavailability via an IGFBP-4 Protease-Dependent Mechanism Endocrinology, June 1, 2001; 142(6): 2641 - 2648. [Abstract] [Full Text] [PDF]