Connexin 43 promotes ossification of the posterior longitudinal ligament through activation of the ERK1/2 and p38 MAPK pathways.
Although cervical ossification of the posterior longitudinal ligament (OPLL) is one of the most common spinal diseases, the pathogenic mechanism is still not fully understood. Abnormal mechanical stress distribution is believed to be one of the main causes of OPLL. We have previously found that mechanical stress can up-regulate connexin 43 (Cx43) expression in ligament fibroblasts; this transduces mechanical signals to promote osteoblastic differentiation. In the present study, in order to explore further the intracellular mechanisms of Cx43-induced osteoblast differentiation of ligament fibroblasts, we investigate the potential roles of the osteogenic signaling pathway components ERK1/2, p38 MAPK and JNK in Cx43-mediated mechanical signal transduction. We first confirm higher Cx43 levels in both in vivo ligament tissue from OPLL patients and in vitro cultured OPLL cells. We find that ERK1/2, p38 MAPK and the JNK pathway are all activated both in vivo and in vitro. The activation of these signals was dependent upon Cx43, as its knock-down resulted in diminished mechanical effects and reduced signaling. Moreover, its knock-down almost reversed the osteogenic effect of mechanical stress on ligament fibroblasts and the blocking of the ERK1/2 and p38 MAPK pathways but not the JNK pathway, partly diminished this effect. Therefore, Cx43, which is up-regulated by mechanical stress, seems to function partly via the activation of ERK1/2 and p38 MAPK signals to promote the osteoblastic differentiation of ligament fibroblasts.
Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China.
Dechun
D
Chen
Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China.
Yang
Y
Liu
Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China.
Haisong
H
Yang
Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China.
Deyu
D
Chen
The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200025, People's Republic of China. xlzhang@sibs.ac.cn.
Xiaoling
X
Zhang
Orthopaedics Research Laboratory, Research Center, Sacré-Coeur Hospital, University of Montreal, Quebec, H4J 1C5, Canada.
Julio C
JC
Fermandes
Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China. chenspine@126.com.
Yu
Y
Chen
D000328:Adult; D001696:Biomechanical Phenomena; D018031:Connexin 43 / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D017846:Longitudinal Ligaments / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D017887:Ossification of Posterior Longitudinal Ligament / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010012:Osteogenesis; D034741:RNA, Small Interfering / Q000378:metabolism; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018031:Connexin 43; D034741:RNA, Small Interfering; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases
Connexin 43; ERK, p38, and JNK signaling pathways; Human; Mechanical stress; Ossification; Osteoblastic differentiation; Posterior longitudinal ligament