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Biomed Res Int. 2017;2017:5316845. doi: 10.1155/2017/5316845. Epub 2017 Sep 10.

Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases.

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Department of Tumor Biology, Unit of Pharmacology, National Cancer Institute, Cairo University, Giza, Egypt.
Department of Pathology, Faculty of Medicine, University of Beni Suef, Beni Suef, Egypt.
Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, TX, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern Medical School, Houston, TX, USA.
Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Department of Pharmacy Practice, College of Clinical Pharmacy, University of Dammam, Dammam, Saudi Arabia.
Department of Pharmacology & Toxicology, Al-Azhar University, Cairo, Egypt.


The role of the extracellular matrix (ECM) in uterine fibroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stiffness and profoundly affect tumor progression. The aim of the current study was to investigate the relationship between ECM of UF, collagen and collagen cross-linking enzymes [lysyl hydroxylases (LH) and lysyl oxidases (LOX)], and the development and progression of UF. Our results indicated that hydroxyl lysine (Hyl) and HP cross-links are significantly higher in UF compared to the normal myometrial tissues accompanied by increased expression of LH (LH2b) and LOX. Also, increased resistance to matrix metalloproteinases (MMP) proteolytic degradation activity was observed. Furthermore, the extent of collagen cross-links was positively correlated with the expression of myofibroblast marker (α-SMA), growth-promoting markers (PCNA; pERK1/2; FAKpY397; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defines the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, differentiation, and resistance to MMP. These effects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF.

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