PAPP-A2 expression by osteoblasts is required for normal postnatal growth in mice

Objective: Pregnancy associated plasma protein-A2 (PAPP-A2) is a protease that cleaves insulin-like growth factor binding protein-5 (IGFBP-5), the most abundant IGFBP in bone. Deletion of Pappa2 reduces postnatal growth and bone length in mice. The aim of this study was to determine whether locally produced PAPP-A2 is required for normal bone growth. Design: We deleted Pappa2 primarily in osteoblasts by crossing conditional Pappa2 deletion mice with mice expressing Cre recombinase under the control of the Sp7 (Osterix) promoter. Effects of disrupting Pappa2 in Sp7-expressing cells were examined by measuring body mass and tail length at 3, 6, 10 and 12 weeks of age and bone dimensions at 12 weeks. Results: Body mass, tail length, and linear bone dimensions were significantly reduced at all ages by osteoblastspecific Pappa2 deletion. Mice homozygous for the conditional Pappa2 deletion allele and carrying the Cre transgene were smaller than controls carrying the Cre transgene, whereas mice homozygous for the conditional Pappa2 deletion allele were not smaller than controls when comparing mice not carrying the transgene. This result unambiguously demonstrates that PAPP-A2 produced by Sp7 expressing cells is required for normal growth. However, constitutive Pappa2 deletion had greater effects than osteoblast-specific Pappa2 deletion for many traits, indicating that post-natal growth is also affected by other sources of PAPP-A2. Immunohistochemistry revealed that PAPP-A2 localized in the epiphysis and metaphysis as well as osteoblasts, consistent with a role in bone growth. Conclusion: Locally-produced PAPP-A2 is required for normal bone growth. (C) 2015 Elsevier Ltd. All rights reserved.