Roflumilast mitigates cartilage degeneration in osteoarthritis by activating CFTR-mediated anti-apoptotic signaling.
6 affiliations
- 1Department of Orthopedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, China.
- 2Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, School of Life Sciences, Nanjing Drum Tower Hospital, Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, PR China.
- 3Suzhou Medical College of Soochow University, Suzhou, China.
- 4Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, PR China.
- 5Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, School of Life Sciences, Nanjing Drum Tower Hospital, Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, PR China. [email protected].
- 6Department of Orthopedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, China. [email protected].
Abstract
Osteoarthritis (OA) is a chronic degenerative joint disorder marked by progressive cartilage loss, synovial inflammation, and remodeling of the subchondral bone. Although roflumilast, a selective phosphodiesterase-4 inhibitor, has shown clinical benefits in chronic inflammatory diseases, its potential role in OA has not been defined. Here, we examined whether roflumilast can protect chondrocytes against apoptosis and extracellular matrix (ECM) degradation under inflammatory stress. In IL-1β-stimulated primary chondrocytes, roflumilast pretreatment (20 µM) suppressed the expression of matrix-degrading enzymes MMP13 and ADAMTS5, while restoring collagen II and aggrecan, thereby maintaining ECM integrity. Transcriptomic profiling identified a strong upregulation of cystic fibrosis transmembrane conductance regulator (CFTR) alongside the suppression of apoptosis-related genes. Mechanistically, roflumilast activated the Akt/Bcl-2 signaling cascade, and either pharmacological blockade or siRNA silencing of CFTR abolished these protective effects, indicating a CFTR-dependent pathway. Consistently, human OA cartilage displayed a marked reduction in CFTR expression, underscoring the clinical relevance of this mechanism. In vivo, roflumilast treatment in the destabilization of the medial meniscus mouse model alleviated cartilage erosion, improved subchondral bone architecture, and reduced synovial inflammation. Behavioral and imaging assessments further confirmed enhanced locomotor performance and mitigated joint degeneration. Collectively, our findings identify CFTR as a crucial mediator of roflumilast-induced chondroprotection and highlight roflumilast as a promising candidate for disease modification in OA.
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BibTeX
@article{yang2026roflumilast,
title = {{Roflumilast mitigates cartilage degeneration in osteoarthritis by activating CFTR-mediated anti-apoptotic signaling.}},
author = {Haoyu Yang and Guihua Tan and Xunhao Wang and Nuo Xu and Wenli Gong and Ruiyang Jiang and Xiaoyu Jin and Chenfeng Qiao and Zhaofeng Zhang and Gang Zhao and Dongquan Shi and Jingyi Mi},
journal = {Arthritis research \& therapy},
year = {2026},
month = jul,
doi = {10.1186/s13075-026-03872-0},
url = {https://europepmc.org/article/MED/42897680},
note = {CC BY},
}
RIS
TY - JOUR
TI - Roflumilast mitigates cartilage degeneration in osteoarthritis by activating CFTR-mediated anti-apoptotic signaling.
AU - Haoyu Yang
AU - Guihua Tan
AU - Xunhao Wang
AU - Nuo Xu
AU - Wenli Gong
AU - Ruiyang Jiang
AU - Xiaoyu Jin
AU - Chenfeng Qiao
AU - Zhaofeng Zhang
AU - Gang Zhao
AU - Dongquan Shi
AU - Jingyi Mi
PY - 2026
DA - 2026/07/01
JO - Arthritis research & therapy
DO - 10.1186/s13075-026-03872-0
UR - https://europepmc.org/article/MED/42897680
AB - Osteoarthritis (OA) is a chronic degenerative joint disorder marked by progressive cartilage loss, synovial inflammation, and remodeling of the subchondral bone. Although roflumilast, a selective phosphodiesterase-4 inhibitor, has shown clinical benefits in chronic inflammatory diseases, its potential role in OA has not been defined. Here, we examined whether roflumilast can protect chondrocytes against apoptosis and extracellular matrix (ECM) degradation under inflammatory stress. In IL-1β-stimulated primary chondrocytes, roflumilast pretreatment (20 µM) suppressed the expression of matrix-degrading enzymes MMP13 and ADAMTS5, while restoring collagen II and aggrecan, thereby maintaining ECM integrity. Transcriptomic profiling identified a strong upregulation of cystic fibrosis transmembrane conductance regulator (CFTR) alongside the suppression of apoptosis-related genes. Mechanistically, roflumilast activated the Akt/Bcl-2 signaling cascade, and either pharmacological blockade or siRNA silencing of CFTR abolished these protective effects, indicating a CFTR-dependent pathway. Consistently, human OA cartilage displayed a marked reduction in CFTR expression, underscoring the clinical relevance of this mechanism. In vivo, roflumilast treatment in the destabilization of the medial meniscus mouse model alleviated cartilage erosion, improved subchondral bone architecture, and reduced synovial inflammation. Behavioral and imaging assessments further confirmed enhanced locomotor performance and mitigated joint degeneration. Collectively, our findings identify CFTR as a crucial mediator of roflumilast-induced chondroprotection and highlight roflumilast as a promising candidate for disease modification in OA.
SN - 1478-6354
SN - 1478-6362
ER -