A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling
Bromodomains are epigenetic readers that modulate gene expression linked to inflammation and cartilage degeneration. Emerging evidence suggests their dysregulation plays a pivotal role in osteoarthritis (OA) pathogenesis, making them promising therapeutic targets. We evaluated the therapeutic effica...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-07-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1633334/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849246027871158272 |
|---|---|
| author | Hyemi Lee Seong Jae Han Subin Ok Kwang Min Lee Seungseok Choi Injoo Yoon Somang Choi Jina Kim Serim Ryu Min-Hee Son In-Hyun Lee Chanmi Cho Siyoung Yang |
| author_facet | Hyemi Lee Seong Jae Han Subin Ok Kwang Min Lee Seungseok Choi Injoo Yoon Somang Choi Jina Kim Serim Ryu Min-Hee Son In-Hyun Lee Chanmi Cho Siyoung Yang |
| author_sort | Hyemi Lee |
| collection | DOAJ |
| description | Bromodomains are epigenetic readers that modulate gene expression linked to inflammation and cartilage degeneration. Emerging evidence suggests their dysregulation plays a pivotal role in osteoarthritis (OA) pathogenesis, making them promising therapeutic targets. We evaluated the therapeutic efficacy of a novel carboxamide derivative bromodomain inhibitor (NCD) as a potentially safer alternative for preventing OA progression. The inhibitory effects of NCD were assessed through both in vitro and in vivo models. In vitro, mouse primary chondrocytes were stimulated with IL-1β, and the effects of NCD treatment were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. In vivo, destabilization of the medial meniscus (DMM) surgery was performed in 12-week-old male C57BL/6 mice, followed by either oral administration or intra-articular (IA) NCD injection. Cartilage integrity was assessed by histology. We analyzed changes in the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways to elucidate the mechanism of NCD. NCD treatment significantly suppressed IL-1β-induced expression of matrix metalloproteinases (Mmp3 and Mmp13) and cyclooxygenase-2 (Cox2) in mouse chondrocytes. In the DMM mouse model, both oral IA administration of NCD alleviated OA-related cartilage destruction. Mechanistically, NCD inhibited IκB degradation and reduced Erk and Jnk phosphorylation, indicating suppression of the NF-κB and MAPK signaling pathways. This study demonstrates that targeting bromodomains with a novel carboxamide-based inhibitor effectively attenuates OA cartilage destruction by suppressing these signaling pathways. These findings support the therapeutic potential of epigenetic modulation in mitigating OA pathogenesis. |
| format | Article |
| id | doaj-art-c44de972c1bf47aabccf634deef7375e |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-c44de972c1bf47aabccf634deef7375e2025-08-20T03:58:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16333341633334A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signalingHyemi Lee0Seong Jae Han1Subin Ok2Kwang Min Lee3Seungseok Choi4Injoo Yoon5Somang Choi6Jina Kim7Serim Ryu8Min-Hee Son9In-Hyun Lee10Chanmi Cho11Siyoung Yang12Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of KoreaCentralBio Co., Ltd., Incheon, Republic of KoreaDepartment of Biological Sciences, Sungkyunkwan University, Suwon, Republic of KoreaDepartment of Life Science and Environmental Biochemistry, and Life and Industry Convergence Research Institute, Pusan National University, Miryang, Republic of KoreaDepartment of Biological Sciences, Sungkyunkwan University, Suwon, Republic of KoreaDepartment of Biological Sciences, Sungkyunkwan University, Suwon, Republic of KoreaDepartment of Biological Sciences, Sungkyunkwan University, Suwon, Republic of KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of KoreaBenobio Co., Ltd, Seongnam, Republic of KoreaBenobio Co., Ltd, Seongnam, Republic of KoreaBenobio Co., Ltd, Seongnam, Republic of KoreaDepartment of Biological Sciences, Sungkyunkwan University, Suwon, Republic of KoreaDepartment of Biological Sciences, Sungkyunkwan University, Suwon, Republic of KoreaBromodomains are epigenetic readers that modulate gene expression linked to inflammation and cartilage degeneration. Emerging evidence suggests their dysregulation plays a pivotal role in osteoarthritis (OA) pathogenesis, making them promising therapeutic targets. We evaluated the therapeutic efficacy of a novel carboxamide derivative bromodomain inhibitor (NCD) as a potentially safer alternative for preventing OA progression. The inhibitory effects of NCD were assessed through both in vitro and in vivo models. In vitro, mouse primary chondrocytes were stimulated with IL-1β, and the effects of NCD treatment were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. In vivo, destabilization of the medial meniscus (DMM) surgery was performed in 12-week-old male C57BL/6 mice, followed by either oral administration or intra-articular (IA) NCD injection. Cartilage integrity was assessed by histology. We analyzed changes in the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways to elucidate the mechanism of NCD. NCD treatment significantly suppressed IL-1β-induced expression of matrix metalloproteinases (Mmp3 and Mmp13) and cyclooxygenase-2 (Cox2) in mouse chondrocytes. In the DMM mouse model, both oral IA administration of NCD alleviated OA-related cartilage destruction. Mechanistically, NCD inhibited IκB degradation and reduced Erk and Jnk phosphorylation, indicating suppression of the NF-κB and MAPK signaling pathways. This study demonstrates that targeting bromodomains with a novel carboxamide-based inhibitor effectively attenuates OA cartilage destruction by suppressing these signaling pathways. These findings support the therapeutic potential of epigenetic modulation in mitigating OA pathogenesis.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1633334/fullbromodomainarthritiscarboxamide derivativemitogen-activated protein kinaseNF-κB |
| spellingShingle | Hyemi Lee Seong Jae Han Subin Ok Kwang Min Lee Seungseok Choi Injoo Yoon Somang Choi Jina Kim Serim Ryu Min-Hee Son In-Hyun Lee Chanmi Cho Siyoung Yang A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling Frontiers in Immunology bromodomain arthritis carboxamide derivative mitogen-activated protein kinase NF-κB |
| title | A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling |
| title_full | A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling |
| title_fullStr | A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling |
| title_full_unstemmed | A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling |
| title_short | A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling |
| title_sort | novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of nf κb and mapk signaling |
| topic | bromodomain arthritis carboxamide derivative mitogen-activated protein kinase NF-κB |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1633334/full |
| work_keys_str_mv | AT hyemilee anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT seongjaehan anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT subinok anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT kwangminlee anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT seungseokchoi anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT injooyoon anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT somangchoi anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT jinakim anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT serimryu anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT minheeson anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT inhyunlee anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT chanmicho anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT siyoungyang anovelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT hyemilee novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT seongjaehan novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT subinok novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT kwangminlee novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT seungseokchoi novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT injooyoon novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT somangchoi novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT jinakim novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT serimryu novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT minheeson novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT inhyunlee novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT chanmicho novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling AT siyoungyang novelcarboxamidebromodomaininhibitorattenuatesosteoarthritisviaepigeneticrepressionofnfkbandmapksignaling |