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Endocrine Research Unit, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic College of Medicine, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905, USA
(Requests for offprints should be addressed to C A Conover; Email: Conover.Cheryl{at}mayo.edu)
Pregnancy-associated plasma protein-A (PAPP-A), an insulin-like growth factor-binding protein (IGFBP) protease, increases insulin-like growth factor (IGF) activity through cleavage of inhibitory IGFBP-4 and the consequent release of IGF peptide for receptor activation. Mice homozygous for targeted disruption of the PAPP-A gene are born as proportional dwarfs and exhibit retarded bone ossification during fetal development. Phenotype and in vitro data support a model in which decreased IGF-II bioavailability during embryogenesis results in growth retardation and reduction in overall body size. To test the hypothesis that an increase in IGF-II during embryogenesis would overcome the growth deficiencies, PAPP-A-null mice were crossed with 
H19 mutant mice, which have increased IGF-II expression and fetal overgrowth due to disruption of IgfII imprinting. H19 mutant mice were 126% and PAPP-A-null mice were 74% the size of controls at birth. These size differences were evident at embryonic day 16.5. Importantly, double mutants were indistinguishable from controls both in terms of size and skeletal development. Body size programmed during embryo development persisted post-natally. Thus, disruption of IgfII imprinting and consequent elevation in IGF-II during fetal development was associated with rescue of the dwarf phenotype and ossification defects of PAPP-A-null mice. These data provide strong genetic evidence that PAPP-A plays an essential role in determining IGF-II bioavailability for optimal fetal growth and development.
This article has been cited by other articles:
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  C. A Conover, M. A Mason, J. A Levine, and C. M Novak Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype J. Endocrinol., September 1, 2008; 198(3): 599 - 605. [Abstract] [Full Text] [PDF]
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 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]
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 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]
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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]
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 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]
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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]
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