Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation.
Human and mouse genetic and in vitro evidence has shown that canonical Wnt signaling promotes bone formation, but we found that mice lacking the canonical Wnt antagonist Dickkopf2 (Dkk2) were osteopenic. We reaffirmed the finding that canonical Wnt signaling stimulates osteogenesis, including the differentiation from preosteoblasts to osteoblasts, in cultured osteoblast differentiation models, but we also found that canonical Wnts upregulated the expression of Dkk2 in osteoblasts. Although exogenous overexpression of Dkk before the expression of endogenous canonical Wnt (Wnt7b) suppressed osteogenesis in cultures, its expression after peak Wnt7b expression induced a phenotype resembling terminal osteoblast differentiation leading to mineralization. In addition, osteoblasts from Dkk2-null mice were poorly mineralized upon osteogenic induction in cultures, and Dkk2 deficiency led to attenuation of the expression of osteogenic markers, which could be partially reversed by exogenous expression of Dkk2. Taken together with the finding that Dkk2-null mice have increased numbers of osteoids, these data indicate that Dkk2 has a role in late stages of osteoblast differentiation into mineralized matrices. Because expression of another Wnt antagonist, FRP3, differs from Dkk2 expression in rescuing Dkk2 deficiency and regulating osteoblast differentiation, the effects of Dkk2 on terminal osteoblast differentiation may not be entirely mediated by its Wnt signaling antagonistic activity.
Li
Xiaofeng
X
Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, Connecticut 06030, USA.
Liu
Peng
P
Liu
Wenzhong
W
Maye
Peter
P
Zhang
Jianghong
J
Zhang
Yazhou
Y
Hurley
Marja
M
Guo
Caiying
C
Boskey
Adele
A
Sun
Le
L
Harris
Stephen E
SE
Rowe
David W
DW
Ke
Hua Zhu
HZ
Wu
Dianqing
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002113:Calcification, Physiologic; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D002479:Inclusion Bodies; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051153:Wnt Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C405060:Dkk2 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C455624:MYOZ3 protein, human; D009124:Muscle Proteins; C499200:Myoz3 protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C095937:Wnt7b protein, mouse