Berberine attenuates CCN2-induced IL-1β expression and prevents cartilage degradation in a rat model of osteoarthritis.
Connective tissue growth factor (CTGF; also known as CCN2) is an inflammatory mediator that is abundantly expressed in osteoarthritis (OA). Interleukin-1β (IL-1β) plays a pivotal role in OA pathogenesis. Berberine exhibits an anti-inflammatory effect, but the mechanisms by which it modulates CCN2-induced IL-1β expression in OA synovial fibroblasts (OASFs) remain unknown. We showed that CCN2-induced IL-1β expression is mediated by the activation of αvβ3/αvβ5 integrin-dependent reactive oxygen species (ROS) generation, and subsequent activation of apoptosis signal-regulating kinase 1 (ASK1), p38/JNK, and nuclear factor-κB (NF-κB) signaling pathways. This IL-1β expression in OASFs is attenuated by N-acetylcysteine (NAC), inhibitors of ASK1, p38, or JNK, or treatment with berberine. Furthermore, berberine also reverses cartilage damage in an experimental model of collagenase-induced OA (CIOA). We observed that CCN2 increased IL-1β expression via αvβ3/αvβ5 integrins, ROS, and ASK1, p38/JNK, and NF-κB signaling pathways. Berberine was found to inhibit these signaling components in OASFs in vitro and prevent cartilage degradation in vivo. We suggest a novel therapeutic strategy of using berberine for managing OA.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Shan-Chi
SC
Liu
Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.
Hsiang-Ping
HP
Lee
Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yun-Lin County, Taiwan.
Chun-Yin
CY
Hung
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
Chun-Hao
CH
Tsai
School of Chinese Medicine, China Medical University, Taichung, Taiwan.
Te-Mao
TM
Li
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. Electronic address: chtang@mail.cmu.edu.tw.
Chih-Hsin
CH
Tang
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000494:pharmacology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C526317:CCN2 protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C064660:integrin alphaVbeta5; D001599:Berberine; D055513:Connective Tissue Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D000111:Acetylcysteine
Anti-inflammation; Berberine; CCN2; Osteoarthritis