Twenty-five years after it was identified as a circulating protein of unknown function derived from the placenta, pregnancy-associated plasma protein-A (PAPP-A) was discovered to be a novel zinc metalloproteinase expressed by a variety of cell types. Great progress has been made in understanding the biology of PAPP-A and its regulation during recent years, especially in regard to physiological and pathophysiological inflammatory injury responses. However, much remains to be learned about this complex protein and its potential clinical implications outside pregnancy. In this article we address some of the outstanding questions about PAPP-A, in particular about its newly emerging role in the insulin-like growth factor (IGF) system.
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