Open Access Highly Accessed Research article

Dose-dependent regulation of cell proliferation and collagen degradation by estradiol on ligamentum flavum

Mei-Hsiu Chen1, Chao-Kai Hu23, Pei-Ru Chen4, Yu-Shan Chen5, Jui-Sheng Sun6 and Ming-Hong Chen457*

Author Affiliations

1 Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan

2 Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan

3 Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu City, Taiwan

4 Department of Biomedical Engineering, Ming Chuan University, Taoyuan, Taiwan

5 Department of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan

6 Department of Orthopedics, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu City, Taiwan

7 Department of Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu City, Taiwan

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BMC Musculoskeletal Disorders 2014, 15:238  doi:10.1186/1471-2474-15-238

Published: 15 July 2014



Estradiol plays an important role in the regulation of collagen metabolism. Deficiency of estradiol has been reported to be associated with the degeneration of many connective tissues. However, the association of estradiol and hypertrophy of the ligamentum flavum was seldom explored. Therefore, we studied the effects of estradiol on cultured cells from the ligamentum flavum.


Primary cultures of human ligamentum flavum cells obtained from surgical specimens of 14 patients undergoing spinal surgery were used to investigate the effect of estradiol on cell proliferation and the expression of collagen, elastin, and matrix metalloproteinases. Downstream pathways of estrogen receptor underlying the regulation of metalloproteinases were also investigated.


In our study, we revealed the existence of estrogen receptors on both female and male ligamentum flavum cells with a gender difference. 17β-estradiol increased early (24 hours) proliferation of ligamentum flavum cells in a dose dependent manner and the effect could not be seen when the cell density increased. Estradiol with a concentration of 10-9 M decreased collagen levels and increased the expression of MMP-13. Adding an antagonist of PI3K downstream pathway could reverse the expression of MMP-13 caused by estradiol.


The results implied estradiol regulated the expression of MMP-13 via PI3K pathway and contributed to the homeostasis of extracellular matrix in the ligamentum flavum.

Estradiol; Ligamentum flavum; Matrix metalloproteinases; Collagen; Elastin