TY - JOUR
T1 - Endothelial Dysfunction Contributes to Chondrocyte Senescence Associated With Insulin-Like Growth Factor-Binding Protein-6 in a Spontaneously Hypertensive Rat Model
AU - Zhang, Yuqi
AU - Ching, Karen
AU - Zhang, Lanlan
AU - Zhu, Lin
AU - Yip, Siu Ling
AU - Lu, Xuan
AU - Liu, Zhongyu
AU - Cai, ZongWei
AU - Au, Man Ting
AU - Wen, Chunyi
N1 - This work was supported by Health and Medical Research Fund Scheme (16172691#), Research Grants Council of Hong Kong General Research Fund (PolyU15100821M), National Natural Science Foundation of China/Research Grants Council Collaborative Research Scheme (N_PolyU 520/20) and the Hong Kong Polytechnic University Project of Strategic Importance (ZE2C). Natural Science Foundation of Guangdong Province (Grant No. 2020A1515010451), and Science and Technology Program of Guangzhou (Grant No. 202201010913). The authors would also like to thank the Hong Kong Polytechnic University, Hong Kong Baptist University, and The Third Affiliated Hospital of Sun Yat‐sen University for providing equipment and technical and financial support.
Publisher Copyright:
© 2025 The Author(s).
PY - 2025/12/17
Y1 - 2025/12/17
N2 - BACKGROUND: Given an epidemiological association between hypertension and osteoarthritis, we aim to elucidate how vascular pathology triggers avascular articular cartilage loss by comparing vascular and joint phenotypes between spontaneously hypertensive rats and normotensive Wistar Kyoto rats at tissue, cellular, and molecular levels.METHODS: Systemic and local endothelial function were assessed via blood pressure monitoring and photoacoustic imaging of knee joints, respectively (n=5-6). Tissue and cellular damages in articular cartilage, subchondral bone, and synovium were systemically evaluated by radiological and histological examination (n=6). Endothelial transcriptional changes were delineated via bulk RNA-seq (n=3). The secretome of human endothelial cells under oxidative stress was analyzed via proteomics to identify key factors in chondrocyte senescence (n=4). Captopril, an antihypertensive medication, was adopted as a tool to rescue chondrocyte senescence and osteoarthritis both in vitro (n=3) and in vivo (n=6).RESULTS: Compared with Wistar Kyoto rats, spontaneously hypertensive rats exhibited higher blood pressure and local joint hypoxia with increased endothelial oxidative stress as early as 3 months old. Notably, these endothelial dysfunctions preceded the onset of structural joint damage. By 9 months of age, spontaneously hypertensive rats developed osteoarthritis-like pathology characterized by senescent chondrocyte accumulation and cartilage degradation, which could be mitigated by captopril. Transcriptomic and proteomic analyses of rat and human endothelial cells revealed upregulated IGFBPs (insulin-like growth factor-binding proteins). Among them, IGFBP6 was identified to induce chondrocyte senescence in vitro. This effect can be modified by captopril treatment.CONCLUSIONS: Systemic vascular dysfunction may induce local joint damage with upregulation of endothelial IGFBPs secretion such as IGFBP6. This study highlights a potential therapeutic target for preventing joint structural damage by addressing endothelial dysfunction.
AB - BACKGROUND: Given an epidemiological association between hypertension and osteoarthritis, we aim to elucidate how vascular pathology triggers avascular articular cartilage loss by comparing vascular and joint phenotypes between spontaneously hypertensive rats and normotensive Wistar Kyoto rats at tissue, cellular, and molecular levels.METHODS: Systemic and local endothelial function were assessed via blood pressure monitoring and photoacoustic imaging of knee joints, respectively (n=5-6). Tissue and cellular damages in articular cartilage, subchondral bone, and synovium were systemically evaluated by radiological and histological examination (n=6). Endothelial transcriptional changes were delineated via bulk RNA-seq (n=3). The secretome of human endothelial cells under oxidative stress was analyzed via proteomics to identify key factors in chondrocyte senescence (n=4). Captopril, an antihypertensive medication, was adopted as a tool to rescue chondrocyte senescence and osteoarthritis both in vitro (n=3) and in vivo (n=6).RESULTS: Compared with Wistar Kyoto rats, spontaneously hypertensive rats exhibited higher blood pressure and local joint hypoxia with increased endothelial oxidative stress as early as 3 months old. Notably, these endothelial dysfunctions preceded the onset of structural joint damage. By 9 months of age, spontaneously hypertensive rats developed osteoarthritis-like pathology characterized by senescent chondrocyte accumulation and cartilage degradation, which could be mitigated by captopril. Transcriptomic and proteomic analyses of rat and human endothelial cells revealed upregulated IGFBPs (insulin-like growth factor-binding proteins). Among them, IGFBP6 was identified to induce chondrocyte senescence in vitro. This effect can be modified by captopril treatment.CONCLUSIONS: Systemic vascular dysfunction may induce local joint damage with upregulation of endothelial IGFBPs secretion such as IGFBP6. This study highlights a potential therapeutic target for preventing joint structural damage by addressing endothelial dysfunction.
KW - articular chondrocytes
KW - cellular senescence
KW - endothelium
KW - hypertension
KW - insulin-like growth factor-binding protein
UR - https://www.scopus.com/pages/publications/105027223258
U2 - 10.1161/JAHA.124.042132
DO - 10.1161/JAHA.124.042132
M3 - Journal article
C2 - 41404752
SN - 2047-9980
VL - 14
SP - e042132
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 1
M1 - e042132
ER -