Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis

Maofeng Wang; Chia-Chia Chao; Po-Chun Chen; Po-I Liu; Yi-Chen Yang; Chen-Ming Su; Wei-Chien Huang; Chih-Hsin Tang

doi:10.1016/j.bcp.2019.05.005

Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis

Biochem Pharmacol. 2019 Aug:166:23-32. doi: 10.1016/j.bcp.2019.05.005. Epub 2019 May 7.

Authors

Maofeng Wang¹, Chia-Chia Chao², Po-Chun Chen³, Po-I Liu⁴, Yi-Chen Yang⁵, Chen-Ming Su¹, Wei-Chien Huang⁶, Chih-Hsin Tang⁷

Affiliations

¹ Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China.
² Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei City, Taiwan.
³ Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
⁴ Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan; Department of Thoracic Surgery, Changhua Christian Hospital, Changhua, Taiwan.
⁵ Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan.
⁶ Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.
⁷ Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung, Taiwan; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. Electronic address: chtang@mail.cmu.edu.tw.

PMID: 31075265
DOI: 10.1016/j.bcp.2019.05.005

Abstract

Lung cancers have a predilection for metastasizing to bone. The matricellular glycoprotein thrombospondin (TSP)-2 regulates multiple biological functions and has a critical role in tumor development and metastasis, although its effects are uncertain in lung cancer bone metastasis. This study demonstrates that TSP-2 expression is highly correlated with lung cancer tumor stage and that the TSP-2 neutralizing antibody reduces osteoclast formation in conditioned medium obtained from lung cancer cells. We also found that TSP-2 promotes osteoclastogenesis through the RANKL-dependent pathway and that TSP-2-mediated osteoclastogenesis involves the transactivation of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) via the inhibition of miR-486-3p expression. Osteoblasts played a critical role in osteoclast differentiation and incubation of osteoblasts with TSP-2 altered the RANKL:OPG ratio. Furthermore, TSP-2 knockdown inhibited lung cancer osteolytic metastasis in vivo. TSP-2 appears to be worth targeting for the prevention of bone metastasis in lung cancer.

Keywords: Bone metastasis; Lung cancer; Osteoclasts; Thrombospondin; miR-486-3p.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Bone Neoplasms / metabolism*
Bone Neoplasms / pathology
Bone Neoplasms / secondary
Humans
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
Mice
Mice, Nude
Osteoclasts / metabolism*
Osteoclasts / pathology
Osteogenesis / physiology*
RANK Ligand / metabolism*
RANK Ligand / pharmacology
RAW 264.7 Cells
Thrombospondins / deficiency
Thrombospondins / metabolism*
Thrombospondins / pharmacology

Substances

RANK Ligand
TNFSF11 protein, human
Thrombospondins
thrombospondin 2