Christians Lab
PAPP-A2 in bone
The ultimate goal of quantitative trait loci (QTL) studies is to identify the genes underlying quantitative phenotypic variation. We used a quantitative complementation test to show that a QTL affecting growth in mice is due to natural variation at the PAPP-A2 gene (Christians et al 2013). Subsequent studies by others have found that loss-of-function mutations in PAPP-A2 cause short stature in humans. We also showed that knocking out PAPP-A2 reduced the size of bones more than expected given the effect on mass (Christians et al 2013), which led us to focus on bone. We subsequently found that PAPP-A2 produced locally in bone is responsible for much, but not all, of its regulation of postnatal growth (Amiri and Christians 2015). While an earlier study by others found no effect of PAPP-A2 deletion on bone mineral density in mice, by systematically studying different ages and accounting for sex, we did discover effects on bone density (Christians et al 2019). Our results are guiding the treatment of humans with loss-of-function mutations (Rubio et al 2021).Relevant papers
Rubio L, Vargas A, Rivera P, López-Gambero AJ, Tovar R, Christians JK, Martín-de-las-Heras S, Rodríguez de Fonseca F, Chowen JA, Argente J, Suárez J. (2021) Recombinant IGF-1 Induces Sex-Specific Changes in Bone Composition and Remodeling in Adult Mice with Pappa2 Deficiency. International Journal of Molecular Sciences. 22:4048.Christians JK, Amiri N, Schipilow JD, Zhang SW, May-Rashke KI (2019) Pappa2 deletion has sex- and age-specific effects on bone in mice. Growth Horm IGF Res 44: 6–10.
Amiri N, Christians JK (2015) PAPP-A2 expression by osteoblasts is required for normal postnatal growth in mice. Growth Horm IGF Res 25:274–80.
Christians JK, de Zwaan DR, Fung SHY (2013) Pregnancy Associated Plasma Protein A2 (PAPP-A2) affects bone size and shape and contributes to natural variation in postnatal growth in mice. PLoS ONE 8: e56260.