ZFIN ID: ZDB-PUB-200422-126
The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition
Liu, C., Li, S., Noer, P.R., Kjaer-Sorensen, K., Juhl, A.K., Goldstein, A., Ke, C., Oxvig, C., Duan, C.
Date: 2020
Source: eLIFE   9: (Journal)
Registered Authors: Duan, Cunming, Li, Shuang
Keywords: developmental biology, zebrafish
MeSH Terms:
  • Animals
  • Calcification, Physiologic/physiology*
  • Cell Proliferation/physiology
  • Epithelial Cells/metabolism*
  • Insulin-Like Growth Factor Binding Protein 5/metabolism*
  • Metalloendopeptidases/metabolism*
  • Zebrafish
  • Zebrafish Proteins/metabolism*
PubMed: 32293560 Full text @ Elife
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.