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

• Published in: Biochemical pharmacology Vol. 166; pp. 23 - 32
• Main Authors: Wang, Maofeng, Chao, Chia-Chia, Chen, Po-Chun, Liu, Po-I., Yang, Yi-Chen, Su, Chen-Ming, Huang, Wei-Chien, Tang, Chih-Hsin
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.08.2019
• Subjects: A549 Cells; Animals; Bone metastasis; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Bone Neoplasms - secondary; Humans; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Nude; miR-486-3p; Osteoclasts; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis - physiology; RANK Ligand - metabolism; RANK Ligand - pharmacology; RAW 264.7 Cells; Thrombospondin; Thrombospondins - deficiency; Thrombospondins - metabolism; Thrombospondins - pharmacology; Osteoclasts; Bone metastasis; Lung cancer; miR-486-3p; Thrombospondin
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2019.05.005

[Display omitted] 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.