Brief Report: Lysyl Oxidase Is a Potential Biomarker of Fibrosis in Systemic Sclerosis

(1) Background: Lysyl oxidase (LOX) plays a dual role in carcinogenesis and studies show a higher risk of cancer in LOX G473A variants. The present study evaluated the pattern of LOX G473A polymorphism (rs1800449) and serum LOX levels in ovarian cancer patients. (2) Methods: Serum LOX levels were estimated by enzyme linked immunosorbent assay (ELISA). A polymorphism of rs1800449 of LOX gene was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Selected samples were sequenced for external validation. (3) Results: A majority of study participants were from low socio-economic status. Serum LOX level was significantly higher in ovarian cancer patients as compared to control. Serum LOX level in early-stage ovarian cancer was significantly lower as compared to advanced stage (FIGO stage III & IV). Wild type GG genotype was used as reference. Genotypes AA were associated with a significant risk of epithelial ovarian cancer (OR 3.208; p value- 0.033). A allele of rs1800449 polymorphism of LOX gene, the odds ratio was 1.866 (95% Confidence Interval 1.112–3.16) p value = 0.017 (4) Conclusions: A allele of rs1800449 polymorphism of LOX gene presents an increased risk of ovarian cancer in East Indian population. Serum LOX levels could be a potential biomarker for the diagnosis and prognosis of ovarian cancer.

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Lysyl oxidase directly contributes to extracellular matrix production and fibrosis in systemic sclerosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00173.2020 ◽

2021 ◽

Vol 320 (1) ◽

pp. L29-L40

Author(s):

Xinh-Xinh Nguyen ◽

Tetsuya Nishimoto ◽

Takahisa Takihara ◽

Logan Mlakar ◽

Amy D. Bradshaw ◽

...

Keyword(s):

Extracellular Matrix ◽

Systemic Sclerosis ◽

Pulmonary Fibrosis ◽

Nuclear Localization ◽

Amine Oxidase ◽

Ex Vivo ◽

Lysyl Oxidase ◽

Lung Fibroblasts ◽

Transcriptional Level

Pulmonary fibrosis is one of the important causes of morbidity and mortality in fibroproliferative disorders such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Lysyl oxidase (LOX) is a copper-dependent amine oxidase whose primary function is the covalent crosslinking of collagens in the extracellular matrix (ECM). We investigated the role of LOX in the pathophysiology of SSc. LOX mRNA and protein levels were increased in lung fibroblasts of SSc patients compared with healthy controls and IPF patients. In vivo, bleomycin induced LOX mRNA expression in lung tissues, and LOX activity increased in the circulation of mice with pulmonary fibrosis, suggesting that circulating LOX parallels levels in lung tissues. Circulating levels of LOX were reduced upon amelioration of fibrosis with an antifibrotic peptide. LOX induced ECM production at the transcriptional level in lung fibroblasts, human lungs, and human skin maintained in organ culture. In vivo, LOX synergistically exacerbated fibrosis in bleomycin-treated mice. Further, LOX increased the production of interleukin (IL)-6, and the increase was mediated by LOX-induced c-Fos expression, the nuclear localization of c-Fos, and its engagement with the IL-6 promoter region. Our findings demonstrate that LOX expression and activity correlate with fibrosis in vitro, ex vivo, and in vivo. LOX induced ECM production via upregulation of IL-6 and nuclear localization of c-Fos. Thus, LOX has a direct pathogenic role in SSc-associated fibrosis that is independent of its crosslinking function. Our findings also suggest that measuring circulating LOX levels and activity can be used for monitoring response to antifibrotic therapy.

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Serum surfactant protein D is a potential biomarker of lung damage in systemic sclerosis

10.1183/13993003.congress-2016.pa4888 ◽

2016 ◽

Author(s):

Riccardo Messina ◽

Alida Benfante ◽

Daniela Castiglia ◽

Claudia I. Gruttad'Auria ◽

Nicola Scichilone

Keyword(s):

Systemic Sclerosis ◽

Surfactant Protein ◽

Lung Damage ◽

Surfactant Protein D ◽

Potential Biomarker

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Whole blood viscosity in systemic sclerosis: a potential biomarker of pulmonary hypertension?

Clinical Rheumatology ◽

10.1007/s10067-019-04603-4 ◽

2019 ◽

Vol 39 (1) ◽

pp. 49-56 ◽

Cited By ~ 2

Author(s):

Bihter Senturk ◽

Bahri Akdeniz ◽

Mehmet Birhan Yilmaz ◽

Buse Ozcan Kahraman ◽

Burak Acar ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Systemic Sclerosis ◽

Blood Viscosity ◽

Whole Blood ◽

Whole Blood Viscosity ◽

Potential Biomarker

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Exhaled Nitric Oxide in Systemic Sclerosis Lung Disease

Canadian Respiratory Journal ◽

10.1155/2017/6736239 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Natalie K. Kozij ◽

John T. Granton ◽

Philip E. Silkoff ◽

John Thenganatt ◽

Shobha Chakravorty ◽

...

Keyword(s):

Nitric Oxide ◽

Systemic Sclerosis ◽

Lung Disease ◽

Lupus Erythematosus ◽

Exhaled Nitric Oxide ◽

Discriminative Validity ◽

Axial Diffusion ◽

Conducting Airway ◽

Potential Biomarker ◽

Model Control

Background. Exhaled nitric oxide (eNO) is a potential biomarker to distinguish systemic sclerosis (SSc) associated pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). We evaluated the discriminative validity, feasibility, methods of eNO measurement, and magnitude of differences across lung diseases, disease-subsets (SSc, systemic lupus erythematosus), and healthy-controls.Methods. Consecutive subjects in the UHN Pulmonary Hypertension Programme were recruited. Exhaled nitric oxide was measured at 50 mL/s intervals using chemiluminescent detection. Alveolar and conducting airway NO were partitioned using a two-compartment model of axial diffusion (CMAD) and the trumpet model of axial diffusion (TMAD).Results. Sixty subjects were evaluated. Using the CMAD model, control subjects had lower median (IQR) alveolar NO than all PAH subjects (2.0 (1.5, 2.5) versus 3.14 ppb (2.3, 4.0),p=0.008). SSc-ILD had significantly lower median conducting airway NO compared to controls (1009.5 versus 1342.1 ml⁎ppb/s,p=0.04). SSc-PAH had increased median (IQR) alveolar NO compared to controls (3.3 (3.0, 5.7) versus 2.0 ppb (1.5, 2.5),p=0.01). SSc-PAH conducting airway NO inversely correlated with DLCO (r−0.88 (95% CI −0.99, −0.26)).Conclusion. We have demonstrated feasibility, identified that CMAD modeling is preferred in SSc, and reported the magnitude of differences across cases and controls. Our data supports discriminative validity of eNO in SSc lung disease.

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Pan-lysyl oxidase inhibitor PXS-5505 ameliorates multiple-organ fibrosis by inhibiting collagen crosslinks in rodent models of systemic sclerosis

10.22541/au.163847931.19877269/v1 ◽

2021 ◽

Author(s):

Yimin Yao ◽

Alison Findlay ◽

Jessica Stolp ◽

Benjamin Rayner ◽

Kjetil Ask ◽

...

Keyword(s):

Systemic Sclerosis ◽

Lysyl Oxidase ◽

Multiple Organ ◽

Oxidase Inhibitor ◽

Lung Model ◽

Rodent Models ◽

Collagen Crosslinks ◽

Fibrotic Liver ◽

Lysyl Oxidases ◽

Organ Fibrosis

Background/Purpose: Systemic sclerosis (SSc) is characterised by progressive multiple-organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. Experimental Approach: Lysyl oxidases are upregulated in preclinical models of fibrosis in skin, lung, heart, kidney and liver. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for bone fibrosis treatment was evaluated in in vivo rodent models resembling the fibrotic conditions in SSc. Key Results: Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression was elevated in the skin and lung of SSc patients. Once-a-day oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin compared to the disease controls. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced tissue fibrosis toward normal levels. The anti-fibrotic efficacy of PXS-5505 in the bleomycin exposed lungs was mediated by its ability to normalise collagen/elastin crosslink formation, a direct consequence of lysyl oxidase inhibition. PXS-5505 also reduced area of fibrosis in rodent models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney and the CCl4-induced fibrotic liver. Conclusion/Implication: PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.

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