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

Abstract

Objective. Fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc). Levels of lysyl oxidase (LOX), an extracellular enzyme that stabilizes collagen fibrils, have been found to be elevated in the skin of SSc patients, but have not been evaluated in the serum or correlated with the clinical parameters. We undertook this study to evaluate serum LOX levels in SSc patients and to correlate these levels with clinical parameters of SSc.Methods. SSc patients were evaluated for demographic features, clinical manifestations, routine laboratory tests, serum autoantibodies, serum LOX concentrations, and nailfold capillaroscopy patterns. They underwent pulmonary function testing, echocardiography, and high-resolution computed tomography scans of the lung, assessment of skin fibrosis by the modified Rodnan skin thickness score (MRSS), and assessment of disease severity and activity by the Medsger severity scale and the Valentini activity index.Results. Twenty-six SSc patients were evaluated and compared with 25 healthy controls and with 9 disease control patients with primary myelofibrosis. Almost 62% of the SSc patients (16 of 26) had limited cutaneous SSc (lcSSc), while 38% had diffuse cutaneous SSc (dcSSc) (10 of 26); 31% of the patients (8 of 26) had lung involvement. The LOX concentration in SSc patients was higher than that in healthy controls and similar to that in disease controls (P < 0.0001), and it was significantly higher in patients with dcSSc than in those with lcSSc (P ‫؍‬ 0.006). The LOX concentration correlated with the MRSS in patients without lung fibrosis.Conclusion. This study is the first to demonstrate high serum LOX levels in SSc patients that correlate specifically with skin fibrosis. These correlations suggest that LOX levels may serve as a novel biomarker of fibrosis. Future studies are warranted to determine whether LOX is a potential therapeutic target in SSc.Fibrosis is the main complication of systemic sclerosis (SSc) and its pathophysiology is complex. Despite our growing understanding of this process and the many targets available, our therapeutic success in ameliorating fibrosis in SSc is minimal (1). Moreover, even today, assessment of skin fibrosis is usually determined by the modified Rodnan skin thickness score (MRSS) (2), which is based on clinical inspection of 17 parts of the body, has significant interobserver variability, and is rather subjective (3). This is why other objective and specific markers for assessing fibrosis are needed.Type I collagen is the most abundant structural protein of the connective tissues, such as the skin. The formation of collagen is an active process that reflects a balance between degradation and synthesis and involves bone morphogenetic protein 1 (BMP-1), a disintegrin and metalloproteinase. Under physiologic conditions, the chemical crosslinking of collagen molecules incorporated in collagen fibrils is critical for the mechanical stability of these fibrils. Moreover, the presence of chemical crosslinks makes fibril-incorporated ...

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

“…3 Two reports have since corroborated our findings by demonstrating higher levels of LOX in the bone marrow and sera of patients with MPNs and other types of fibrosis. 4,5 Philadelphia chromosome-negative MPNs 6 are a group of disorders characterized by proliferation of dysmorphic megakaryocytes and myelofibrosis in the bone marrow. In 1951, William Dameshek proposed that polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis share a common pathogenesis, based on similarities observed in clinical and bone marrow morphologic findings.…”

Anti-Fibrotic Effects of Astragaloside IV in Systemic Sclerosis

“…There is currently no effective cure for this disease. However, since fibrosis is a major cause of morbidity and mortality in SSc [3], studies suggest that the therapeutic targeting of fibrosis may be one of the potential options in treating SSc [4]. The transforming growth factor β (TGF-β), associated with the Smad pathway, plays a fundamental role in pathological fibrogenesis in SSc.…”

Lysyl Oxidase Isoforms and Potential Therapeutic Opportunities for Fibrosis and Cancer

“…Thus, if BAPN appears to not inhibit a LOX isoform in vivo, then it is likely that (1) either BAPN has been metabolized, or (2) that the activity in question occurs as a result of a non-enzymatic function of LOX or LOX isoform. Data consistently show LOX up-regulated in a variety of fibrotic conditions, sometimes accompanied by additional LOX isoforms, including lung- 49-53 , liver- 43, 54-56 , and heart- 57, 58 , and skin- 59-61 fibrosis, and hypertension 47, 58 . One notable exception is phenytoin-induced gingival overgrowth which appears to be accompanied by LOXL2 elevations and not LOX 62, 63 .…”