Targeted overexpression of Dkk1 in osteoblasts reduces bone mass but does not impair the anabolic response to intermittent PTH treatment in mice.
Parathyroid hormone (PTH) is a potent anabolic agent, but the cellular mechanisms by which it increases bone mass are not fully understood. Dickkopf 1 (Dkk1) is an endogenous inhibitor of Wnt signaling and suppresses bone formation in vivo. We sought to determine if Dkk1 and anabolic PTH treatment interact in regulating bone mass. PTH treatment of primary murine osteoblasts for 24 h reduced Dkk1 expression by 90% as quantified by real-time PCR, whereas PTH treatment in vivo reduced Dkk1 expression by 30% when given as a single daily subcutaneous dose. To directly determine whether Dkk1 modulates the anabolic response of PTH in vivo, we engineered transgenic (TG) mice expressing murine Dkk1 under the control of the 2.3-kb rat collagen alpha-1 promoter. TG mice had significantly reduced bone mass, which was accompanied by reduced histomorphometric parameters of bone formation (reduced OV/TV, ObS/OS, and NOb/TAR). Treatment of TG mice and wild-type (WT) littermates with 95 ng/g body weight of human (1-34) PTH daily for 34 days resulted in comparable increases in bone mass at all skeletal sites. Histomorphometric analyses indicated that PTH treatment increased the numbers of both osteoblasts and osteoclasts in WT mice but only increased the numbers of osteoblasts in TG mice. We conclude that overexpression of Dkk1 does not attenuate the anabolic response to PTH in vivo.
Yao
Gang-Qing
GQ
Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8016, USA. gang-qing.yao@yale.edu
Wu
Jian-Jun
JJ
Troiano
Nancy
N
Insogna
Karl
K
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D010281:Parathyroid Hormone