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

Kamel, Marwa; Wagih, Mohamed; Kılıç, Gökhan; Diaz-Arrastia, Concepcion; Baraka, Mohamed; Salama, Salama A.

doi:10.1155/2017/5316845

Cited by 17 publications

(15 citation statements)

References 73 publications

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“…Previously, we and others have reported on the abundant extracellular matrix, especially collagen and glycosaminoglycans content in fibroids and their contribution to mechanical signaling mechanisms and fibroid stiffness [7, 8, 10–13, 15]. In this paper, our observations provide novel evidence that fibroid structural properties and collagen content vary widely.…”

Section: Discussionsupporting

confidence: 65%

“…It has been shown by different techniques that uterine fibroids are two to four-fold stiffer than myometrium [6–9]. The stiffness of fibroids results from their abundant extracellular matrix (ECM) which includes large amounts of glycosaminoglycans and more importantly large amounts of disordered, highly cross-linked interstitial collagens [7, 8, 10–15]. In addition, studies have linked the increased stiffness to altered biomechanical signaling in the tumors.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of biomechanical and collagen heterogeneity in uterine fibroids

et al. 2019

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Objective Uterine fibroids (leiomyomas) are common benign tumors of the myometrium but their molecular pathobiology remains elusive. These stiff and often large tumors contain abundant extracellular matrix (ECM), including large amounts of collagen, and can lead to significant morbidities. After observing structural multiformities of uterine fibroids, we aimed to explore this heterogeneity by focusing on collagen and tissue stiffness. Methods For 19 fibroids, ranging in size from 3 to 11 centimeters, from eight women we documented gross appearance and evaluated collagen content by Masson trichrome staining. Collagen types were determined in additional samples by serial extraction and gel electrophoresis. Biomechanical stiffness was evaluated by rheometry. Results Fibroid slices displayed different gross morphology and some fibroids had characteristics of two or more patterns: classical whorled (n = 8); nodular (n = 9); interweaving trabecular (n = 9); other (n = 1). All examined fibroids contained at least 37% collagen. Tested samples included type I, III, and V collagen of different proportions. Fibroid stiffness was not correlated with the overall collagen content (correlation coefficient 0.22). Neither stiffness nor collagen content was correlated with fibroid size. Stiffness among fibroids ranged from 3028 to 14180 Pa (CV 36.7%; p<0.001, one-way ANOVA). Stiffness within individual fibroids was also not uniform and variability ranged from CV 1.6 to 42.9%. Conclusions The observed heterogeneity in structure, collagen content, and stiffness highlights that fibroid regions differ in architectural status. These differences might be associated with variations in local pressure, biomechanical signaling, and altered growth. We conclude the design of all fibroid studies should account for such heterogeneity because samples from different regions have different characteristics. Our understanding of fibroid pathophysiology will greatly increase through the investigation of the complexity of the chemical and biochemical signaling in fibroid development, the correlation of collagen content and mechanical properties in uterine fibroids, and the mechanical forces involved in fibroid development as affected by the various components of the ECM.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Evidence of biomechanical and collagen heterogeneity in uterine fibroids

et al. 2019

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“…Increased production and accumulation of abnormal ECM results in further tumor volume gain [13,14,110]. MMPs are the enzymes which are responsible for matrix lysis and remodeling [29,111,112,113]. They are regulated by tissue inhibitors of metalloproteinases (TIMPs) [38].…”

Section: Discussionmentioning

confidence: 99%

The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms

Ciebiera

Włodarczyk

Zgliczyńska

et al. 2018

IJMS

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Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. The incidence of UFs has been estimated at 25–80% depending on selected population. The pathophysiology of UFs remains poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is the main component of all pathways leading to UF tumor formation and tumor necrosis factor α (TNF-α) is believed to be one of the key factors in this field. TNF-α is a cell signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. This publication presents current data about the role of tumor necrosis factor α in the biology of UFs and the related symptoms. TNF-α is an extremely important cytokine associated with the biology of UFs, UF-related symptoms and complaints. Its concentration has been proven to be elevated in women with clinically symptomatic UFs. The presented data suggest the presence of an “inflammation-like” state in women with UFs where TNF-α is a potent inflammation inducer. The origin of numerous symptoms reported by women with UFs can be traced back to the TNF-α influence. Nevertheless, our knowledge on this subject remains limited and TNF-α dependent pathways in UF pathophysiology should be investigated further.

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“…Given that overhydroxylation of lysine is a consequence of increases in the levels of lysyl hydroxylase, 42,[46][47][48] it is conceivable that availability of lysyl hydroxylases dictates the pattern of crosslinking during disease.…”

Section: Inhibition Of Heart Fibrosis By Pxs-5153amentioning

confidence: 99%

The lysyl oxidase like 2/3 enzymatic inhibitor, PXS‐5153A, reduces crosslinks and ameliorates fibrosis

Schilter

Findlay

Perryman

et al. 2018

J Cellular Molecular Medi

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Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε‐amino group of lysine or hydroxylysine on collagen side‐chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS‐5153A, a novel mechanism based, fast‐acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS‐5153A dose‐dependently reduced LOXL2‐mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet‐induced, PXS‐5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS‐5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.

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

Cited by 17 publications

References 73 publications

Evidence of biomechanical and collagen heterogeneity in uterine fibroids

Evidence of biomechanical and collagen heterogeneity in uterine fibroids

The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms

The lysyl oxidase like 2/3 enzymatic inhibitor, PXS‐5153A, reduces crosslinks and ameliorates fibrosis

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