The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

Human patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca2+]-dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca2+]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.