Sclerostin expression in trabecular bone is downregulated by osteoclasts

Koide, Masanori<sup>1</sup>; Yamashita, Teruhito<sup>1</sup>; Murakami, Kohei<sup>2</sup>; Uehara, Shunsuke<sup>2</sup>; Nakamura, Keigo<sup>1</sup>; Nakamura, Midori<sup>2</sup>; Matsushita, Mai<sup>1</sup>; Ara, Toshiaki<sup>3</sup>; Yasuda, Hisataka<sup>4</sup>; Penninger, Josef M.<sup>5,6</sup>; Takahashi, Naoyuki<sup>1</sup>; Udagawa, Nobuyuki<sup>1,2</sup>; Kobayashi, Yasuhiro<sup>1</sup>

Affiliations

¹Division of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro‑oka, Shiojiri, Nagano 399‑0781, Japan

²Department of Biochemistry, Matsumoto Dental University, 1780 Gobara, Hiro‑oka, Shiojiri, Nagano 399‑0781, Japan

³Department of Pharmacology, Matsumoto Dental University, 1780 Gobara, Hiro‑oka, Shiojiri, Nagano 399‑0781, Japan

⁴Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., 50 Kano‑cho, Nagahama, Shiga 526‑0804, Japan

⁵Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna Biocentre, Vienna, Austria

⁶Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, Canada

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.

Links

DOI: 10.1038/s41598-020-70817-1

PubMed: 32792620

WoS: 000563547400029

History

Received: 2020-04-08

Accepted: 2020-07-30

Online: 2020-08-13

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