Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

Muruganandam, Maheswari; Ariza-Hutchinson, Angie; Patel, Rosemina A; Sibbitt Jr, Wilmer L

doi:10.2147/jir.s379815

Cited by 10 publications

(2 citation statements)

References 281 publications

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“…Over the past decade several studies have provided evidence that LRG1 is involved in various inflammatory and autoimmune diseases, and may act as a useful clinical and diagnostic biomarker (23,(167)(168)(169)(170)(171)(172)(173)(174). In such conditions, levels of LRG1 are upregulated at the site of inflammation, with expression induced by proinflammatory cytokines secreted by various cell types, followed by the initiation of a series of downstream vascular events.…”

Section: Lrg1 and Inflammation-associated Diseasementioning

confidence: 99%

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Dritsoula,

Camilli,

Moss

et al. 2024

Front. Cardiovasc. Med.

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The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-β signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.

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Section: Lrg1 and Inflammation-associated Diseasementioning

confidence: 99%

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Dritsoula,

Camilli,

Moss

et al. 2024

Front. Cardiovasc. Med.

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“…Over the years, several circulating elements including proangiogenic molecules (e.g., VEGF, endoglin, and ET-1), antiangiogenic factors (e.g., VEGF165b, endostatin, and pentraxin-3), cell adhesion molecules, neurovascular guidance molecules, and sirtuins have been associated with SSc clinical features of impaired angiogenesis and proposed as vascular biomarkers [ 44 , 45 ]. Moreover, disease vasculopathy has been correlated with both the number of circulating angiogenic cells and the presence of specific autoantibodies [ 8 , 44 ].…”

Section: Circulating Factors and Cells Involved In Ssc Defective Angi...mentioning

confidence: 99%

Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis

Romano,

Rosa,

Fioretto

et al. 2024

Biomedicines

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In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial cells with different outcomes. Indeed, once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts, or acquire a senescence-associated secretory phenotype characterized by the release of exosomes and several profibrotic and proinflammatory mediators. In this narrative review, we aimed to give a comprehensive overview of recent studies dealing with the cellular and molecular mechanisms underlying SSc defective angiogenesis and the related endothelial cell dysfunctions, mainly the endothelial-to-mesenchymal transition process. We also discussed potential novel vascular treatment strategies able to restore the angiogenic process and reduce the endothelial-to-mesenchymal transition in this complex disease.

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Interleukin-17A is a potential therapeutic target predicted by proteomics for systemic sclerosis patients at high risk of pulmonary arterial hypertension

Ono,

Mogami,

Saito

et al. 2024

Sci Rep

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We explored effective therapeutic targets for systemic sclerosis (SSc) patients with high risk for pulmonary arterial hypertension (PAH) by plasma proteomics analysis. A total of fifty-seven patients with SSc were enrolled in the study and the prevalence of PAH was 19.3%. On the other hand, 75.4% of SSc patients showed the ratio of forced vital capacity percentage/diffusing capacity of the lungs for carbon monoxide percentage> 1.6 and met criteria for high risk of PAH. Identification of elevated plasma proteins in SSc patients with high risk of PAH, followed by upstream regulator analysis, predicted interleukin (IL)-17A as a major upstream molecule. Furthermore, we performed in vitro neutralization study using MT-6194, a bispecific antibody targeting both IL-17A and IL-6 receptor. We found that MT-6194 broadly suppressed the increased expression of downstream molecules of IL-17A including IL-17A-related cytokines/chemokines, IL-17A-driven NF$$\kappa$$B pathway and IL-6-driven JAK/STAT pathway which were shown to be increased in SSc patients with high risk of PAH by the proteomics. Consequently, it is revealed that IL-17A is a promising target for early intervention in SSc patients with high risk for PAH.

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Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

Cited by 10 publications

References 281 publications

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis

Interleukin-17A is a potential therapeutic target predicted by proteomics for systemic sclerosis patients at high risk of pulmonary arterial hypertension

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