Abstract:
:Long-term glucocorticoid treatment impairs the survival and bone formation of osteogenic cells, leading to bone mass loss. The Wnt inhibitor Dickkopf-1 (DKK1) acts as a potent bone-remodeling factor that mediates several types of skeletal disorders. Whereas excess glucocorticoid is known to disturb Wnt signaling in osteogenic cells, modulation of the skeletally deleterious effects of DKK1 to alleviate glucocorticoid induction of bone loss has not been tested. In this study, knockdown of DKK1 expression by end-capped phosphorothioate DKK1 antisense oligonucleotide (DKK1-AS) abrogated dexamethasone suppression of alkaline phosphatase activity and osteocalcin expression in MC3T3-E1 preosteoblasts. Exogenous DKK1-AS treatment alleviated dexamethasone suppression of mineral density, trabecular bone volume, osteoblast surface, and bone formation rate in bone tissue and ex vivo osteogenesis of primary bone-marrow mesenchymal cells. The DKK1-AS inhibited adipocyte volume in the marrow cavity of steroid-treated bone tissue. Immunohistochemical observation revealed that DKK1-AS abrogated dexamethasone-induced DKK1 expression and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling of osteoblasts adjacent to trabecular bone. Knocking down DKK1 abrogated dexamethasone-modulated expression of nuclear beta-catenin and phosphorylated Ser(473)-Akt and survival of osteoblasts and adipocytic differentiation of mesenchymal progenitor cell cultures. Taken together, knocking down DKK1 alleviated the deleterious effect of glucocorticoid on bone microstructure. The DKK1-AS treatment appeared to protect bone tissue by modulating beta-catenin and Akt-mediated survival as well as the osteogenic and adipogenic activities of glucocorticoid-stressed osteoprogenitor cells. Interference with the osteogenesis-inhibitory action of DKK1 has therapeutic potential for preventing glucocorticoid induction of osteopenia.
journal_name
Endocrinologyjournal_title
Endocrinologyauthors
Wang FS,Ko JY,Yeh DW,Ke HC,Wu HLdoi
10.1210/en.2007-0910subject
Has Abstractpub_date
2008-04-01 00:00:00pages
1793-801issue
4eissn
0013-7227issn
1945-7170pii
en.2007-0910journal_volume
149pub_type
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