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First published online 8 September 2009
doi: 10.1242/jcs.051904

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Axin2 controls bone remodeling through the β-catenin–BMP signaling pathway in adult mice

Ying Yan^1,*, Dezhi Tang^1,2,*, Mo Chen¹, Jian Huang¹, Rong Xie¹, Jennifer H. Jonason¹, Xiaohong Tan¹, Wei Hou^1,2, David Reynolds¹, Wei Hsu³, Stephen E. Harris⁴, J. Edward Puzas¹, Hani Awad^1,5, Regis J. O'Keefe¹, Brendan F. Boyce⁶ and Di Chen^1,

¹ Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, NY 14642, USA
³ Department of Biomedical Genetics, Center for Oral Biology, University of Rochester School of Medicine, Rochester, NY 14642, USA
⁵ Department of Biomedical Engineering, University of Rochester School of Medicine, Rochester, NY 14642, USA
⁶ Department of Pathology, University of Rochester School of Medicine, Rochester, NY 14642, USA
² Spine Research Institute, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
⁴ Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

Author for correspondence (di_chen{at}urmc.rochester.edu)

Accepted 26 July 2009

To investigate the role of Wnt–β-catenin signaling in bone remodeling, we analyzed the bone phenotype of female Axin2-lacZ knockout (KO) mice. We found that trabecular bone mass was significantly increased in 6- and 12-month-old Axin2 KO mice and that bone formation rates were also significantly increased in 6-month-old Axin2 KO mice compared with wild-type (WT) littermates. In vitro studies were performed using bone marrow stromal (BMS) cells isolated from 6-month-old WT and Axin2 KO mice. Osteoblast proliferation and differentiation were significantly increased and osteoclast formation was significantly reduced in Axin2 KO mice. Nuclear β-catenin protein levels were significantly increased in BMS cells derived from Axin2 KO mice. In vitro deletion of the β-catenin gene under Axin2 KO background significantly reversed the increased alkaline phosphatase activity and the expression of osteoblast marker genes observed in Axin2 KO BMS cells. We also found that mRNA expression of Bmp2 and Bmp4 and phosphorylated Smad1/5 protein levels were significantly increased in BMS cells derived from Axin2 KO mice. The chemical compound BIO, an inhibitor of glycogen synthase kinase 3β, was utilized for in vitro signaling studies in which upregulated Bmp2 and Bmp4 expression was measured in primary calvarial osteoblasts. Primary calvarial osteoblasts were isolated from Bmp2^fx/fx;Bmp4^fx/fx mice and infected with adenovirus-expressing Cre recombinase. BIO induced Osx, Col1, Alp and Oc mRNA expression in WT cells and these effects were significantly inhibited in Bmp2/4-deleted osteoblasts, suggesting that BIO-induced Osx and marker gene expression were Bmp2/4-dependent. We further demonstrated that BIO-induced osteoblast marker gene expression was significantly inhibited by Osx siRNA. Taken together, our findings demonstrate that Axin2 is a key negative regulator in bone remodeling in adult mice and regulates osteoblast differentiation through the β-catenin–BMP2/4–Osx signaling pathway in osteoblasts.

Key words: Axin2, β-catenin, BMP, Osteoblast, Bone remodeling

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JCS 2009 122: 1901. [Full Text]