Background:The biological function and biochemical activity of mammalian stanniocalcin-2 are unknown. Results: Stanniocalcin-2 inhibits proteolytic release of insulin-like growth factor (IGF), and its ability to cause growth retardation upon transgenic overexpression in mice depends on its proteinase inhibitory function. Conclusion: Stanniocalcin-2 is a novel component of the IGF axis. Significance: Altered stanniocalcin-2 expression may affect IGF signaling under pathological conditions.

Background: The molecular mechanisms behind previously reported biological effects of stanniocalcin-1 are poorly understood. Results: Stanniocalcin-1 potently inhibits the proteolytic activity of the metzincin metalloproteinases PAPP-A and PAPP-A2, which promote insulin-like growth factor (IGF) activity in tissues. Conclusion: Stanniocalcin-1 is a novel proteinase inhibitor. Significance: Altered stanniocalcin-1 expression may affect IGF signaling in vivo under normal or pathological conditions.

This work was supported by grants from the Novo Nordisk Foundation, and the Danish Council for Independent Research. No competing interests declared.

Pregnancy-associated plasma protein-A2 (PAPP-A2, pappalysin-2) is a large metalloproteinase, known to be required for normal postnatal growth and bone development in mice. We here report the detection of zebrafish papp-a2 mRNA in chordamesoderm, notochord, and lower jaw of zebrafish (Danio rerio) embryos, and that papp-a2 knockdown embryos display broadened axial mesoderm, notochord bends, and severely reduced cranial cartilages. Genetic data link these phenotypes to insulin-like growth factor binding protein-3 (Igfbp-3) and Bmp signaling, and biochemical analysis show specific Igfbp-3 proteolysis by Papp-a2, implicating Papp-a2 in the modulation of Bmp signaling by Igfbp-3 proteolysis. Knockdown of papp-a2 additionally resulted in angiogenesis defects, strikingly similar to previous observations in embryos with mutations in components of the Notch system. Concordantly, we find that Notch signaling is modulated by Papp-a2 in vivo, and, furthermore, that PAPP-A2 is capable of modulating Notch signaling independently of its proteolytic activity in cell culture. Based on these results, we conclude that Papp-a2 modulates Bmp and Notch signaling by independent mechanisms in zebrafish embryos. In conclusion, these data link pappalysin function in zebrafish to two different signaling pathways outside the IGF system.

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