Human patients carrying PAPP-A2 inactivating mutations display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report that Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation and proliferation. Ionocyte, normally quiescent, proliferate in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and reduced calcified bone mass. Loss of Papp-aa resulted in diminished IGF1 receptor-mediated Akt-Tor signaling in ionocytes. Re-expression of Papp-aa or a constitutively active Akt in ionocytes rescued the reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. The Papp-aa-mediated Igfbp5a proteolysis was suppressed under normal [Ca2+] conditions. Forced release of IGFs from the Igfbp5a/IGF complex was sufficient to activate 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.

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