Osterix is a key target for mechanical signals in human thoracic ligament flavum cells.
Mechanical stress is considered to be an important factor in the progression of thoracic ossification of the ligament flavum (TOLF). To elucidate the mechanism underlying mechanical stress-induced TOLF, we investigated the effect of stretching on cultured flavum ligament cells derived from TOLF and non-TOLF patients. We found that the mRNA expression of alkaline phosphatase (ALP), osteocalcin, Runx2, and osterix, but not that of Dlx5 and Msx2, was significantly increased by stretching in TOLF cells. In addition, the effect seems to be finely tuned by stretching-triggered activation of distinct mitogen-activated protein kinase cascades. Specifically, a p38 specific inhibitor, SB203580, significantly inhibited stretching-induced osterix expression as well as ALP activity, whereas a specific inhibitor of ERK1/2, U0126, prevented stretching-induced Runx2 expression. We showed that overexpression of osterix resulted in a significant increase of ALP activity in TOLF cells, and osterix-specific RNAi completely abrogated the stretching-induced ALP activity, indicating that osterix plays a key role in stretching-stimulated osteogenic effect in TOLF cells. These results suggest that mechanical stress plays important roles in the progression of TOLF through induction of osteogenic differentiation of TOLF cells, and our findings support that osterix functions as a molecular link between mechanostressing and osteogenic differentiation.
Fan
Dongwei
D
Department of Orthopedics, Peking University Third Hospital, Beijing, China.
Chen
Zhongqiang
Z
Wang
Dan
D
Guo
Zhaoqing
Z
Qiang
Qi
Q
Shang
Yongfeng
Y
D000469:Alkaline Phosphatase / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D017843:Ligamentum Flavum / Q000166:cytology* / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D009999:Ossification, Heterotopic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010011:Osteocytes / Q000166:cytology; D034741:RNA, Small Interfering; D000076182:Sp7 Transcription Factor; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D034741:RNA, Small Interfering; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000469:Alkaline Phosphatase