Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
Shuang Li
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States; College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
Pernille Rimmer Noer
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
Kasper Kjaer-Sorensen
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
Anna Karina Juhl
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
Allison Goldstein
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
Caihuan Ke
College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
Claus Oxvig
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
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.
