The authors state that they have no conflicts of interest.
Lrp6 Hypomorphic Mutation Affects Bone Mass Through Bone Resorption in Mice and Impairs Interaction With Mesd†
Article first published online: 19 MAY 2008
Copyright © 2008 ASBMR
Journal of Bone and Mineral Research
Volume 23, Issue 10, pages 1661–1671, October 2008
How to Cite
Kubota, T., Michigami, T., Sakaguchi, N., Kokubu, C., Suzuki, A., Namba, N., Sakai, N., Nakajima, S., Imai, K. and Ozono, K. (2008), Lrp6 Hypomorphic Mutation Affects Bone Mass Through Bone Resorption in Mice and Impairs Interaction With Mesd. J Bone Miner Res, 23: 1661–1671. doi: 10.1359/jbmr.080512
- Issue published online: 4 DEC 2009
- Article first published online: 19 MAY 2008
- Manuscript Accepted: 12 MAY 2008
- Manuscript Revised: 16 APR 2008
- Manuscript Received: 9 NOV 2007
- bone resorption;
- Wnt signaling;
Low-density lipoprotein receptor-related protein 5 (LRP5) regulates bone acquisition by controlling bone formation. Because roles of LRP6, another co-receptor for Wnts, in postnatal bone metabolism have not been fully elucidated, we studied bone phenotype in mice harboring an Lrp6 hypomorphic mutation, ringelschwanz (rs), and characterized the mutant protein. First, we performed pQCT, bone histomorphometry, and immunohistochemistry on tibias of Lrp6rs/rs and Lrp6+/+ mice and determined biochemical parameters for bone turnover. Lrp6rs/rs mice exhibited reduced trabecular BMD in pQCT. Bone histomorphometry showed low bone volume and decreased trabecular number, which were associated with increased eroded surface. Urinary deoxypyridinoline excretion was increased in Lrp6rs/rs mice, whereas levels of serum osteocalcin were comparable between Lrp6rs/rs mice and wildtype littermates. Increase in cell number and mineralization of calvariae-derived osteoblasts were not impaired in Lrp6rs/rs osteoblasts. Rankl expression was increased in Lrp6rs/rs osteoblasts both in vivo and in vitro, and osteoclastogenesis and bone-resorbing activity in vitro were accelerated in Lrp6rs/rs cells. Treatment with canonical Wnt suppressed Rankl expression in both in primary osteoblasts and ST2 cells. Overexpression of Lrp6 also suppressed Rankl expression, whereas the Lrp6 rs mutant protein did not. Functional analyses of the Lrp6 rs mutant showed decreased targeting to plasma membrane because of reduced interaction with Mesoderm development (Mesd), a chaperone for Lrp6, leading to impaired Wnt/β-catenin signaling. These results indicate that Lrp6-mediated signaling controls postnatal bone mass, at least partly through the regulation of bone resorption. It is also suggested that the interaction with Mesd is critical for Lrp6 to function.