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Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone.

Significance statement

Bone anabolic stimuli activate canonical Wnt/βcatenin signaling and human mutations of this pathway underscore its essential role in bone accrual. However, the cell responsible for orchestrating these actions has remained elusive. This study identifies osteocytes as mediators of the anabolic effect of canonical Wnt/βcatenin signaling in bone; and, further, it dissects desired (bone gain) from undesired (decreased resorption and leukemia) outcomes by selective activation of canonical Wnt/βcatenin signaling in osteocytes versus osteoblasts. Long-lived osteocytes constitute more than 90% of bone cells, thus representing more logical and effective target cells to induce bone anabolism than scarce, short-lived osteoblasts. These findings pave the way towards the development of better treatments for osteoporosis and other bone related disorders targeting osteocytic Wnt/βcatenin signaling.

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Tu X1, Delgado-Calle J2, Condon KW3, Maycas M3, Zhang H4, Carlesso N4, Taketo MM5, Burr DB3, Plotkin LI2, Bellido T6. Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):E478-86.

Show Affiliations

1Department of Anatomy and Cell Biology and [email protected] [email protected]

2Department of Anatomy and Cell Biology and Roudebush Veterans Administration Medical Center.

3Department of Anatomy and Cell Biology.

4Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46022; and.

5Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.and

6Department of Anatomy and Cell Biology and Roudebush Veterans Administration Medical Center and Division of Endocrinology, Department of Medicine, Indiana University School of Medicine; [email protected] [email protected]

 

Abstract

Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical  Wnt  signaling  exclusively in osteocytes [dominant active (da)βcat(Ot) mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat(Ot) mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat(Ot) mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat(Ot) mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bonegain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.

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