Research Article Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases Marwa Kamel, 1 Mohamed Wagih, 2 Gokhan S. Kilic, 3 Concepcion R. Diaz-Arrastia, 4 Mohamed A. Baraka, 5,6 and Salama A. Salama 7 1 Department of Tumor Biology, Unit of Pharmacology, National Cancer Institute, Cairo University, Giza, Egypt 2 Department of Pathology, Faculty of Medicine, University of Beni Suef, Beni Suef, Egypt 3 Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, TX, USA 4 Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern Medical School, Houston, TX, USA 5 Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt 6 Department of Pharmacy Practice, College of Clinical Pharmacy, University of Dammam, Dammam, Saudi Arabia 7 Department of Pharmacology & Toxicology, Al-Azhar University, Cairo, Egypt Correspondence should be addressed to Salama A. Salama; salamas@hotmail.com Received 6 June 2017; Accepted 20 July 2017; Published 10 September 2017 Academic Editor: Yury V. Popov Copyright © 2017 Marwa Kamel et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Te role of the extracellular matrix (ECM) in uterine fbroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stifness and profoundly afect tumor progression. Te 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 signifcantly 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 myofbroblast marker (-SMA), growth-promoting markers (PCNA; pERK1/2; FAK pY397 ; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defnes the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, diferentiation, and resistance to MMP. Tese efects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF. 1. Introduction Uterine fbroids (UF), also known as uterine leiomyomas, are benign smooth muscle neoplasms of the uterus found in almost 20–40% of women of reproductive age [1]. It is anticipated that up to 77% of women will develop UF in their life and 15 to 30% of these women sufer from sub- stantial symptoms, including pelvic discomfort, menorrha- gia, dysmenorrhea, anemia, urinary incontinence, recurrent pregnancy loss, preterm labor, and sometimes infertility [2]. Te annual public cost for fbroids is estimated to be up to 34 billion dollars, calculated through combined expenses for management of symptomatic fbroids, diagnosis, and dealing with obstetrical complications of fbroids [3]. Consequently, fnding efective therapeutic options is crucial for overcoming this major public health problem. An important step towards this goal is to explore the molecular basis of fbroids to under- stand and target the underlying specifc pathophysiological pathways. Moreover, future research can identify potential targets which may help the development of new nonsurgical noninvasive treatments. Te uterine myometrium consists mostly of smooth muscle cells that stain positive for -smooth muscle actin and desmin and are interspersed with interstitial collagens. Hindawi BioMed Research International Volume 2017, Article ID 5316845, 13 pages https://doi.org/10.1155/2017/5316845