The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

Abstract

Human patients carrying PAPP‐A2 inactivating mutations have low bone mineral density. The underlying mechanisms for this reduced calcification are poorly understood. Using a zebrafish model, we report that Papp-aa regulates bone calcification by promoting Ca2+-transporting epithelial cell (ionocyte) quiescence-proliferation transition. Ionocytes, which are normally quiescent, re-enter the cell cycle under low [Ca2+] stress. Genetic deletion of Papp-aa, but not the closely related Papp-ab, abolished ionocyte proliferation and reduced calcified bone mass. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-Akt-Tor signaling in ionocytes. Under low Ca2+ stress, Papp-aa cleaved Igfbp5a. Under normal conditions, however, Papp-aa proteinase activity was suppressed and IGFs were sequestered in the IGF/Igfbp complex. Pharmacological disruption of the IGF/Igfbp complex or adding free IGF1 activated IGF signaling and promoted ionocyte proliferation. These findings suggest that Papp-aa-mediated local Igfbp5a cleavage functions as a [Ca2+]-regulated molecular switch linking IGF signaling to bone calcification by stimulating epithelial cell quiescence-proliferation transition under low Ca2+ stress.

Stanniocalcin 1a is a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca2+uptake

“…NaR cell reactivation is impaired in igfbp5a -/mutant fish (Liu et al, 2018). Likewise, genetic deletion and pharmacological inhibition of Papp-aa, the Igfbp5a proteinase, abolishes NaR cell reactivation and IGF signaling (Liu et al, 2020). The Papp-aa-mediated Igfbp5a proteolysis is suppressed by a [Ca 2+ ]-dependent mechanism (Liu et al, 2020).…”

“…Next, stc mRNA levels in trpv6 -/and papp-aa -/mutant fish were determined. Both mutant lines suffer from a severe body 6 calcium deficiency (Liu et al, 2020;Xin et al, 2019). The levels of stc1a mRNA, but not the other stc genes, were significantly reduced in the papp-aa -/mutant fish compared to the wildtype fish ( Figure 1E-H).…”

“…When subjected to low [Ca 2+ ] stress, these cells rapidly re-enter the cell cycle and proliferate due to elevated IGF-PI3 kinase-Akt-Tor signaling (Dai et al, 2014;Liu et al, 2017). Further studies suggested that IGF binding protein 5a (Igfbp5a), a secreted high-affinity IGF binding protein, and its major proteinase, pregnancyassociated plasma protein-a (Papp-aa), are highly expressed in NaR cells and indispensable in the low [Ca 2+ ] stress-induced activation of IGF signaling in these cells (Liu et al, 2020;Liu et al, 2018). Genetic deletion of igfbp5a, papp-aa, or perturbations of Papp-aa-mediated Igfbp5a proteolysis abolishes NaR cell reactivation (Liu et al, 2020;Liu et al, 2018).…”

“…Further studies suggested that IGF binding protein 5a (Igfbp5a), a secreted high-affinity IGF binding protein, and its major proteinase, pregnancyassociated plasma protein-a (Papp-aa), are highly expressed in NaR cells and indispensable in the low [Ca 2+ ] stress-induced activation of IGF signaling in these cells (Liu et al, 2020;Liu et al, 2018). Genetic deletion of igfbp5a, papp-aa, or perturbations of Papp-aa-mediated Igfbp5a proteolysis abolishes NaR cell reactivation (Liu et al, 2020;Liu et al, 2018). Interestingly, the Papp-aa-mediated Igfbp5a proteolytic cleavage is inhibited by an unknown post-transcriptional mechanism under normal [Ca 2+ ] conditions.…”

“…Interestingly, the Papp-aa-mediated Igfbp5a proteolytic cleavage is inhibited by an unknown post-transcriptional mechanism under normal [Ca 2+ ] conditions. Under low [Ca 2+ ] conditions, this suppression mechanism is removed, which liberates IGFs from the Igfbp5a/IGF complex to bind and activate the IGF1 receptor (Liu et al, 2020). The molecular nature of this [Ca 2+ ]-dependent mechanism, however, is unknown.…”