A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways
Abstract Bromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in v...
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2021-06-01
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doaj-a11124e00feb407488c3fd6c0ac4f23b2021-06-27T11:05:05ZengNature Publishing GroupCell Death and Disease2041-48892021-06-0112711110.1038/s41419-021-03939-7A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathwaysYing Liu0Wenjie Liu1Ziqiang Yu2Yan Zhang3Yinghua Li4Dantao Xie5Gang Xie6Li Fan7Shipeng He8Institute of Translational Medicine, Shanghai UniversityDepartment of Orthopedics, The Second Affiliated Hospital, Shantou University Medical CollegeInstitute of Translational Medicine, Shanghai UniversityInstitute of Translational Medicine, Shanghai UniversityInstitute of Translational Medicine, Shanghai UniversityDepartment of Orthopedics, The Second Affiliated Hospital, Shantou University Medical CollegeDepartment of Orthopedics, The Second Affiliated Hospital, Shantou University Medical CollegeSchool of Pharmacy, Naval Medical UniversityInstitute of Translational Medicine, Shanghai UniversityAbstract Bromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.https://doi.org/10.1038/s41419-021-03939-7 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ying Liu Wenjie Liu Ziqiang Yu Yan Zhang Yinghua Li Dantao Xie Gang Xie Li Fan Shipeng He |
spellingShingle |
Ying Liu Wenjie Liu Ziqiang Yu Yan Zhang Yinghua Li Dantao Xie Gang Xie Li Fan Shipeng He A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways Cell Death and Disease |
author_facet |
Ying Liu Wenjie Liu Ziqiang Yu Yan Zhang Yinghua Li Dantao Xie Gang Xie Li Fan Shipeng He |
author_sort |
Ying Liu |
title |
A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways |
title_short |
A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways |
title_full |
A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways |
title_fullStr |
A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways |
title_full_unstemmed |
A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways |
title_sort |
novel brd4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking rankl-mediated mapk and nf-κb pathways |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-06-01 |
description |
Abstract Bromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment. |
url |
https://doi.org/10.1038/s41419-021-03939-7 |
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