Reprogramming pathological secretory phenotype of chondrocytes inhibits neurovascular invasion for osteoarthritis treatment.
8 affiliations
- 1Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Basic Medical Sciences, Interdisciplinary Innovation Center for Nanomedicine, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Biomedical Basic Research Center of Jiangsu, Soochow University, Suzhou, Jiangsu, 215000, China.
- 2Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, 570100, China.
- 3Department of Orthopedic Surgery, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, Jiangsu, 214200, China.
- 4Department of Orthopaedics, The Second Affiliated Hospital of Wannan Medical University, Wuhu, Anhui, 241001, China.
- 5Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315000, China.
- 6Sanitation & Environment Technology Institute of Soochow University Ltd, Suzhou, Jiangsu, 215000, China.
- 7Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, China.
- 8Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215000, China.
Abstract
Pain severity in osteoarthritis (OA) often dissociates from the extent of cartilage structural damage, indicating that non-structural mechanisms contribute to symptom persistence. Here, we identify articular chondrocytes as active orchestrators of pathological neurovascular invasion through a pathogenic secretome, rather than merely passive victims of degeneration. Integrated human single-cell transcriptomic analysis reveals that OA chondrocytes undergo phenotypic reprogramming characterized by coordinated activation of angiogenic and neurotrophic programs. Functionally, inflammatory chondrocytes directly promote endothelial angiogenesis and sensory axon outgrowth, linking chondrocyte-derived signals to neurovascular invasion and sustained pain. To therapeutically target this upstream mechanism, we engineered MMP-13-responsive celecoxib-loaded hyaluronic acid methacrylate microspheres (HMPC) for disease-adaptive delivery to degenerative cartilage. HMPC suppresses chondrocyte COX-2 activity and remodels the pathological chondrocyte secretome through restoration of miR-339-5p_R-5 and miR-103-3p_R-2, thereby inhibiting angiopoietin-2 (Angpt2)-mediated angiogenesis and brain-derived neurotrophic factor (Bdnf)-driven sensory neurogenesis. In murine OA models, HMPC markedly alleviates pain-related behaviors, reduces neurovascular infiltration, and preserves joint structure. Collectively, this study supports a chondrocyte-centric framework in which reprogrammed chondrocytes govern neurovascular invasion through microRNA-dependent secretome regulation and introduces a smart biomaterial-enabled strategy with disease-modifying potential for OA pain intervention.
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BibTeX
@article{yuan2026reprogramming,
title = {{Reprogramming pathological secretory phenotype of chondrocytes inhibits neurovascular invasion for osteoarthritis treatment.}},
author = {Xiaonan Yuan and Yao Xiao and Cheng Chen and Youzhi Hong and Zhen Pan and Yang Zhang and Chao Wang and Jiale Chen and Yuan Chen and Feng Zhou and Liwei Yao and Lijie Wang and Haijiao Mao and Bin Li and Jiaying Li and Jinjin Ma},
journal = {Bioactive materials},
year = {2026},
month = oct,
doi = {10.1016/j.bioactmat.2026.09.035},
url = {https://europepmc.org/article/MED/42898573},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Reprogramming pathological secretory phenotype of chondrocytes inhibits neurovascular invasion for osteoarthritis treatment.
AU - Xiaonan Yuan
AU - Yao Xiao
AU - Cheng Chen
AU - Youzhi Hong
AU - Zhen Pan
AU - Yang Zhang
AU - Chao Wang
AU - Jiale Chen
AU - Yuan Chen
AU - Feng Zhou
AU - Liwei Yao
AU - Lijie Wang
AU - Haijiao Mao
AU - Bin Li
AU - Jiaying Li
AU - Jinjin Ma
PY - 2026
DA - 2026/10/10
JO - Bioactive materials
DO - 10.1016/j.bioactmat.2026.09.035
UR - https://europepmc.org/article/MED/42898573
AB - Pain severity in osteoarthritis (OA) often dissociates from the extent of cartilage structural damage, indicating that non-structural mechanisms contribute to symptom persistence. Here, we identify articular chondrocytes as active orchestrators of pathological neurovascular invasion through a pathogenic secretome, rather than merely passive victims of degeneration. Integrated human single-cell transcriptomic analysis reveals that OA chondrocytes undergo phenotypic reprogramming characterized by coordinated activation of angiogenic and neurotrophic programs. Functionally, inflammatory chondrocytes directly promote endothelial angiogenesis and sensory axon outgrowth, linking chondrocyte-derived signals to neurovascular invasion and sustained pain. To therapeutically target this upstream mechanism, we engineered MMP-13-responsive celecoxib-loaded hyaluronic acid methacrylate microspheres (HMPC) for disease-adaptive delivery to degenerative cartilage. HMPC suppresses chondrocyte COX-2 activity and remodels the pathological chondrocyte secretome through restoration of miR-339-5p_R-5 and miR-103-3p_R-2, thereby inhibiting angiopoietin-2 (Angpt2)-mediated angiogenesis and brain-derived neurotrophic factor (Bdnf)-driven sensory neurogenesis. In murine OA models, HMPC markedly alleviates pain-related behaviors, reduces neurovascular infiltration, and preserves joint structure. Collectively, this study supports a chondrocyte-centric framework in which reprogrammed chondrocytes govern neurovascular invasion through microRNA-dependent secretome regulation and introduces a smart biomaterial-enabled strategy with disease-modifying potential for OA pain intervention.
SN - 2452-199X
ER -