Inactivation of insulin-like-growth factors diminished the anabolic effects of pregnancy-associated plasma protein-A (PAPP-A) on bone in mice.
In vivo studies have provided ubiquitous evidence that pregnancy-associated plasma protein-A (PAPP-A) functions as a potent anabolic factor. While some evidence supports the prediction that increasing IGF bioavailability contributes to the anabolic effects of PAPP-A, definitive evidence has been lacking. This important issue has been addressed in this study using a unique mouse model in which PAPP-A was overexpressed in bone either alone or together with a protease-resistant IGFBP-4 analog (PRBP-4) which serves as an IGF inhibitor. PAPP-A transgenic mice exhibited a 25% increase in skull bone mineral density (BMD) whereas PRBP-4 transgenic mice showed a 20-25% decrease in this parameter at an age of 3months. Femur/tibia size-related parameters were significantly increased in PAPP-A transgenic mice but decreased in PRBP-4 transgenic mice. This data clearly demonstrates that PAPP-A transgenic mice exhibit opposite phenotypes in both flat bone and long bone compared to PRBP-4 transgenic mice which have reduced IGF bioavailability in bone. Importantly, PRBP-4 and PRBP-4/PAPP-A double transgenic mice shared essentially identical phenotypes in both flat and long bones. Calvarial thickness, skull BMD and long bone parameters were reduced to similar degrees in PRBP-4 and PRBP-4/PAPP-A transgenic mice relative to wild-type littermates. Our findings provide compelling evidence that PAPP-A increases bone formation primarily by increasing IGF bioavailability and that other alternative pathways may play a negligible role in mediating the anabolic effect of PAPPA in bone. This clear definition of PAPP-A's mechanism of action is critical for future translational studies on the therapeutic application of PAPP-A.
Musculoskeletal Disease Center, Loma Linda University, Loma Linda, CA 92354, United States.
David
D
Phang
Mark
M
Rehage
Blake
B
Bonafede
Diana
D
Hou
Weirong
W
Xing
Subburaman
S
Mohan
Jon E
JE
Wergedal
Xuezhong
X
Qin
D000818:Animals; D001846:Bone Development / Q000187:drug effects / Q000235:genetics; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D041722:Genes, Transgenic, Suicide; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008660:Metabolism / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D013002:Somatomedins / Q000235:genetics* / Q000378:metabolism
D018974:Insulin-Like Growth Factor Binding Protein 4; D013002:Somatomedins; D011266:Pregnancy-Associated Plasma Protein-A