Functional interaction between Wnt and Bmp signaling in periosteal bone growth

Deye Song,Yu Shi,Guangxu He,Fanxin Long,Jiangdong Ni

doi:10.1038/s41598-021-90324-1

Abstract

Wnt and Bmp proteins are well known to regulate bone development and homeostasis. Although both signals are extensively studied, their potential interaction in vivo is less well understood. Previous studies have shown that deletion of Bmpr1a, a type I receptor for Bmp signaling, results in excessive trabecular bone formation while diminishing periosteal bone growth. Moreover, forced-expression of the Wnt antagonist Sost suppresses the overgrowth of trabecular bone caused by Bmpr1a deletion, thus implicating hyperactive Wnt signaling in the excessive trabecular bone formation. However, it remains uncertain whether Wnt and Bmp signaling interacts in regulating the periosteal bone growth. Here we show that multiple Wnt genes are markedly suppressed in the cortical bone without Bmpr1a. Importantly, overexpression of Wnt7b fully rescues periosteal bone growth in the Bmpr1a-deficient mice. Thus, pharmacological activation of Wnt signaling can restore normal bone size without intact Bmp signaling.

Highlights

IntroductionA family of secreted glycoproteins, have been shown to stimulate bone formation
Wnt proteins, a family of secreted glycoproteins, have been shown to stimulate bone formation
We have shown that deletion of Bmpr1a in osteoblasts and osteocytes notably suppressed the expression of multiple bone anabolic Wnt genes in the cortical bone

Summary

Introduction

A family of secreted glycoproteins, have been shown to stimulate bone formation. In the best studied mechanism, Wnt proteins signal through frizzled proteins and the low-density lipoprotein receptorrelated protein Lrp[5] or Lrp[6] to stabilize ß-catenin which in turn activates gene expression[18]. Besides β-catenin signaling, Wnt proteins activate mTORC1 signaling to stimulate bone formation[34]. Upon activation of mTORC1 signaling, Wnt has been shown to stimulate. To address the relationship between Bmp and Wnt signaling in vivo, we have previously shown that deletion of Bmpr1a by Dmp1-Cre leads to downregulation of Sost expression in osteocytes, and that forced-expression of Sost in the Bmpr1a-deficient mice partially corrected the hyperproliferation of preosteoblasts in trabecular bone[38]. Bmp signaling through Bmpr1a normally limits Wnt signaling via the induction of Sost to restrict preosteoblast proliferation during trabecular bone formation. The results support a model wherein Bmp signaling via Bmpr1a induces Wnt expression to promote periosteal bone growth

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Conclusion