gamma-Secretase-dependent cleavage of amyloid precursor protein regulates osteoblast behavior

TY - JOUR

T1 - gamma-Secretase-dependent cleavage of amyloid precursor protein regulates osteoblast behavior

AU - McLeod, Jane

AU - Curtis, Neil

AU - Lewis, Huw D.

AU - Good, Mark A.

AU - Fagan, Michael J.

AU - Genever, Paul G.

PY - 2009/9

Y1 - 2009/9

N2 - gamma-Secretase cleaves amyloid precursor protein (APP) to generate amyloid-beta (A beta) peptides, which aggregate in the brain in Alzheimer's disease (AD). gamma-Secretase also cleaves molecules that regulate osteoblast activity, such as Notch and ephrinB2. However, the role of APP in bone is unknown. In this study, the expression, cleavage, and function of APP were investigated during osteogenesis in vitro and in vivo. Expression of all gamma-secretase subunits was confirmed in human primary osteoprogenitors cells, and a significant increase in enzyme activity was observed during osteogenic differentiation using a specific fluorimetric assay. Application of selective inhibitors confirmed gamma-secretase-dependent cleavage of APP within osteogenic cells, and secretion of A beta by mature osteoblasts was demonstrated with the use of a chemiluminescent immunoassay. Osteoprogenitors showed a selective and significant increase in adhesion to extracellular matrices containing aged A beta plaques compared with nonaged A beta peptide controls. A beta on the endosteal and periosteal surfaces of adult rat ulnae were identified by immunohistochemistry. MicroCT analysis of vertebrae from an AD mouse model, Tg2576, identified a decrease in bone volume, surface area, and thickness compared with wild-type controls. These findings indicate that APP functions as a novel regulator of osteoblast activity and suggest that the mechanisms underlying the pathogenesis of AD may also influence bone.-McLeod, J., Curtis, N., Lewis, H. D., Good, M. A., Fagan, M. J., Genever, P. G. gamma-Secretase-dependent cleavage of amyloid precursor protein regulates osteoblast behavior. FASEB J. 23, 2942- 2955 (2009). www.fasebj.org

AB - gamma-Secretase cleaves amyloid precursor protein (APP) to generate amyloid-beta (A beta) peptides, which aggregate in the brain in Alzheimer's disease (AD). gamma-Secretase also cleaves molecules that regulate osteoblast activity, such as Notch and ephrinB2. However, the role of APP in bone is unknown. In this study, the expression, cleavage, and function of APP were investigated during osteogenesis in vitro and in vivo. Expression of all gamma-secretase subunits was confirmed in human primary osteoprogenitors cells, and a significant increase in enzyme activity was observed during osteogenic differentiation using a specific fluorimetric assay. Application of selective inhibitors confirmed gamma-secretase-dependent cleavage of APP within osteogenic cells, and secretion of A beta by mature osteoblasts was demonstrated with the use of a chemiluminescent immunoassay. Osteoprogenitors showed a selective and significant increase in adhesion to extracellular matrices containing aged A beta plaques compared with nonaged A beta peptide controls. A beta on the endosteal and periosteal surfaces of adult rat ulnae were identified by immunohistochemistry. MicroCT analysis of vertebrae from an AD mouse model, Tg2576, identified a decrease in bone volume, surface area, and thickness compared with wild-type controls. These findings indicate that APP functions as a novel regulator of osteoblast activity and suggest that the mechanisms underlying the pathogenesis of AD may also influence bone.-McLeod, J., Curtis, N., Lewis, H. D., Good, M. A., Fagan, M. J., Genever, P. G. gamma-Secretase-dependent cleavage of amyloid precursor protein regulates osteoblast behavior. FASEB J. 23, 2942- 2955 (2009). www.fasebj.org

KW - Alzheimer's disease

KW - mesenchymal stem cell

KW - MESENCHYMAL STEM-CELLS

KW - RECEPTOR-RELATED PROTEIN

KW - SMOOTH-MUSCLE-CELLS

KW - ALZHEIMERS-DISEASE

KW - TRANSGENIC MICE

KW - INTRACELLULAR DOMAIN

KW - BETA-PROTEIN

KW - A-BETA

KW - BASEMENT-MEMBRANE

KW - BONE HOMEOSTASIS

UR - http://www.scopus.com/inward/record.url?scp=70349304406&partnerID=8YFLogxK

U2 - 10.1096/fj.08-121657

DO - 10.1096/fj.08-121657

M3 - Article

SN - 0892-6638

VL - 23

SP - 2942

EP - 2955

JO - The FASEB Journal

JF - The FASEB Journal

IS - 9

ER -