Sclerostin expression in trabecular bone is downregulated by osteoclasts

Masanori Koide,Toshiaki Ara,Keigo Nakamura,Josef M Penninger,Hisataka Yasuda,Naoyuki Takahashi,Teruhito Yamashita,Yasuhiro Kobayashi,Kohei Murakami,Mai Matsushita,Midori Nakamura,Nobuyuki Udagawa,Shunsuke Uehara

doi:10.1038/s41598-020-70817-1

Abstract

Bone tissues have trabecular bone with a high bone turnover and cortical bone with a low turnover. The mechanisms by which the turnover rate of these bone tissues is determined remain unclear. Osteocytes secrete sclerostin, a Wnt/β-catenin signaling antagonist, and inhibit bone formation. We found that sclerostin expression in cortical bone is more marked than in trabecular bone in Sost reporter mice. Leukemia inhibitory factor (LIF) secreted from osteoclasts reportedly suppressed sclerostin expression and promoted bone formation. Here, we report that osteoclasts downregulate sclerostin expression in trabecular bone and promote bone turnover. Treatment of C57BL/6 mice with an anti-RANKL antibody eliminated the number of osteoclasts and LIF-positive cells in trabecular bone. The number of sclerostin-positive cells was increased in trabecular bone, while the number of β-catenin-positive cells and bone formation were decreased in trabecular bone. Besides, Tnfsf11 heterozygous (Rankl+/−) mice exhibited a decreased number of LIF-positive cells and increased number of sclerostin-positive cells in trabecular bone. Rankl+/− mice exhibited a decreased number of β-catenin-positive cells and reduced bone formation in trabecular bone. Furthermore, in cultured osteoclasts, RANKL stimulation increased Lif mRNA expression, suggesting that RANKL signal increased LIF expression. In conclusion, osteoclasts downregulate sclerostin expression and promote trabecular bone turnover.

Highlights

Increase bone mass with increased bone formation[16,17]
We previously reported that leukemia inhibitory factor (LIF) derived from osteoclasts suppressed sclerostin expression in osteocytes[8]
In order to evaluate whether LIF expression is suppressed by the elimination of bone resorption, we examined the LIF expression in trabecular bone of C57BL/6 male mice injected with the anti-RANKL antibody

Summary

Introduction

Increase bone mass with increased bone formation[16,17]. These findings indicate that the reduction of sclerostin expression increases bone formation. We demonstrated that osteoclast-secreted LIF suppressed sclerostin expression and accelerated bone formation in vitro and in vivo[8]. The trabecular bone was remodeled at a high turnover rate that was likely affected by alterations in the Wnt/β-catenin signaling pathway[26]. It is unclear how bone turnover is controlled. We found that the treatment of C57BL/6 mice with an anti-RANKL antibody upregulated sclerostin expression in trabecular bone and reduced the number of osteoclasts. Treatment with the anti-RANKL antibody reduced the number of β-catenin-positive cells and bone formation in trabecular bone. Tnfsf[11] heterozygous (Rankl+/−) mice, in which bone resorption is suppressed, exhibited increased numbers of sclerostin-positive cells in trabecular bone. The suppression of sclerostin expression by osteoclasts plays a critical role in bone formation in trabecular bone

Methods

Results

Conclusion