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Pappa2 deletion has sex- and age-specific effects on bone in mice
Julian K Christians1, Neilab Amiri1, John D Schipilow2
1Department of Biological Sciences, Simon Fraser University, Burnaby, Canada.
Objective:
In humans, loss-of-function mutations in the gene encoding pregnancy-associated pregnancy protein-A2 cause short stature and slightly reduced bone density. The goal of this study was to determine the effects of Pappa2 deletion on bone in mice.
Design:
Pappa2 deletion mice and littermate controls were culled at 10, 19 or 30 weeks of age and femurs were analysed by micro-computed tomography. Serum markers of bone turnover and insulin-like growth factor binding protein 5 (IGFBP-5), a proteolytic target of PAPP-A2, were measured by ELISA.
Results:
At 10 and 19 weeks of age, Pappa2 deletion mice had slightly reduced trabecular parameters, but by 19 weeks of age, female deletion mice had increased cortical tissue mineral density, and this trait was increased by a small amount in deletion mice of both sexes at 30 weeks. Cortical area fraction was increased in Pappa2 deletion mice at all ages. Deletion of Pappa2 increased circulating IGFBP-5 levels and reduced markers of bone turnover (PINP and TRACP 5b).
Conclusions:
PAPP-A2 contributes to the regulation of bone structure and mass in mice, likely through control of IGFBP-5 levels. The net effect of changes in bone formation and resorption depend on sex and age, and differ between trabecular and cortical bone.
Insights
Pregnancy-associated plasma protein-A2 (PAPP-A2) influences bone structure and mass in mice. Pappa2 deletion alters bone density and turnover, with effects varying by sex and age, likely via IGFBP-5 regulation.
Area of Science:
- Biochemistry
- Bone Biology
- Genetics
Background:
- Loss-of-function mutations in the gene for pregnancy-associated plasma protein-A2 (PAPP-A2) in humans are associated with short stature and reduced bone density.
- PAPP-A2 is a metalloproteinase that cleaves insulin-like growth factor binding proteins (IGFBPs).
Purpose of the Study:
- To investigate the skeletal effects of Pappa2 deletion in a mouse model.
- To determine the role of PAPP-A2 in regulating bone structure, mass, and turnover.
Main Methods:
- Pappa2 deletion mice and wild-type littermate controls were analyzed at 10, 19, and 30 weeks of age.
- Femurs were analyzed using micro-computed tomography (micro-CT).
- Serum markers of bone turnover (PINP, TRACP 5b) and IGFBP-5 levels were measured using ELISA.
Main Results:
- Pappa2 deletion mice exhibited altered trabecular and cortical bone parameters compared to controls.
- Increased cortical tissue mineral density and cortical area fraction were observed in Pappa2 deletion mice.
- Circulating IGFBP-5 levels were elevated, while bone turnover markers were reduced in Pappa2 deletion mice.
Conclusions:
- PAPP-A2 plays a role in regulating bone structure and mass in mice, potentially through modulation of IGFBP-5.
- The impact of PAPP-A2 on bone turnover is complex, influenced by sex, age, and bone compartment (trabecular vs. cortical).
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