Reduced Cathepsin L expression and secretion into the extracellular milieu contribute to lung fibrosis in systemic sclerosis

Mouawad, Joe E; Sharma, Shailza; Renaud, Ludivine; Pilewski, Joseph M.; Nadig, Satish N.; Feghali‐Bostwick, Carol

doi:10.1093/rheumatology/keac411

Cited by 10 publications

(7 citation statements)

References 48 publications

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“…Cathepsins degrade collagen via intracellular lysosomal degradation and secretion into the ECM [71]. Decreased CTSL expression has been reported in SSc and IPF lung tissues and fibroblasts, and TGFβ was shown to downregulate CTSL in fibroblasts [27,47]. Our data showing that IGF-II decreases CTSL expression in NL fibroblasts suggest that IGF-II limits the availability of this enzyme to reduce collagen breakdown, promoting collagen accumulation.…”

Section: The Igf System In Pulmonary Fibrosissupporting

confidence: 59%

“…Therefore, our goal was to provide mechanistic insights into the role of IGF-II in PF using primary human lung fibroblasts and tissues from healthy individuals (NL) and SSc patients. Based on our recent characterization of NL and SSc lung fibroblast transcriptomic signatures [26,27], we identified novel targets downstream of IGF-II that include collagen type III (COL3A1), several collagen posttranslational modification enzymes, and collagen degradation enzymes. In addition, we investigated SRY-box transcription factor 9 (SOX9) as a mediator of the IGF-II fibrotic response.…”

Section: Introductionmentioning

confidence: 99%

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The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis

Waldrep

Rodgers

Garrett

et al. 2023

IJMS

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Pulmonary fibrosis (PF) associated with systemic sclerosis (SSc) results in significant morbidity and mortality. We previously reported that insulin-like growth factor-II (IGF-II) is overexpressed in lung tissues and fibroblasts from SSc patients, and IGF-II fosters fibrosis by upregulating collagen type I, fibronectin, and TGFβ. We now show that IGF-II augments mRNA levels of profibrotic signaling molecules TGFβ2 (p ≤ 0.01) and TGFβ3 (p ≤ 0.05), collagen type III (p ≤ 0.01), and the collagen posttranslational modification enzymes P4HA2 (p ≤ 0.05), P3H2 (p ≤ 0.05), LOX (p = 0.065), LOXL2 (p ≤ 0.05), LOXL4 (p ≤ 0.05) in primary human lung fibroblasts. IGF-II increases protein levels of TGFβ2 (p ≤ 0.01), as well as COL3A1, P4HA2, P4Hβ, and LOXL4 (p ≤ 0.05). In contrast, IGF-II decreases mRNA levels of the collagen degradation enzymes cathepsin (CTS) K, CTSB, and CTSL and protein levels of CTSK (p ≤ 0.05). The SRY-box transcription factor 9 (SOX9) is overexpressed in SSc lung tissues at the mRNA (p ≤ 0.05) and protein (p ≤ 0.01) levels compared to healthy controls. IGF-II induces SOX9 in lung fibroblasts (p ≤ 0.05) via the IGF1R/IR hybrid receptor, and SOX9 regulates TGFβ2 (p ≤ 0.05), TGFβ3 (p ≤ 0.05), COL3A1 (p ≤ 0.01), and P4HA2 (p ≤ 0.001) downstream of IGF-II. Our results identify a novel IGF-II signaling axis and downstream targets that are regulated in a SOX9-dependent and -independent manner. Our findings provide novel insights on the role of IGF-II in promoting pulmonary fibrosis.

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Section: The Igf System In Pulmonary Fibrosissupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis

Waldrep

Rodgers

Garrett

et al. 2023

IJMS

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“…Mechanisms mediating a multi-system disease such as SSc are complex. Our study does not address the potential role of biologically active protein cleavage products such as matrikines [ 141 ] or the role of extracellular vesicles [ 142 , 143 ] in promoting cell-to-cell communication. However, our findings provide valuable insights into molecular alterations that differentiate fibroblasts from lung tissues of AA in health and disease.…”

Section: Discussionmentioning

confidence: 99%

First Characterization of the Transcriptome of Lung Fibroblasts of SSc Patients and Healthy Donors of African Ancestry

Renaud

Waldrep

Silveira

et al. 2023

IJMS

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Systemic sclerosis (SSc) is a connective tissue disorder that results in fibrosis of the skin and visceral organs. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death amongst SSc patients. Racial disparity is noted in SSc as African Americans (AA) have a higher frequency and severity of disease than European Americans (EA). Using RNAseq, we determined differentially expressed genes (DEGs; q < 0.1, log2FC > |0.6|) in primary pulmonary fibroblasts from SSc lungs (SScL) and normal lungs (NL) of AA and EA patients to characterize the unique transcriptomic signatures of AA-NL and AA-SScL fibroblasts using systems-level analysis. We identified 69 DEGs in “AA-NL vs. EA-NL” and 384 DEGs in “AA-SScL vs. EA-SScL” analyses, and a comparison of disease mechanisms revealed that only 7.5% of DEGs were commonly deregulated in AA and EA patients. Surprisingly, we also identified an SSc-like signature in AA-NL fibroblasts. Our data highlight differences in disease mechanisms between AA and EA SScL fibroblasts and suggest that AA-NL fibroblasts are in a “pre-fibrosis” state, poised to respond to potential fibrotic triggers. The DEGs and pathways identified in our study provide a wealth of novel targets to better understand disease mechanisms leading to racial disparity in SSc-PF and develop more effective and personalized therapies.

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“…The mRNA expression of cathepsin B and L is decreased in the skin of bleomycin-induced mouse model. Catepshin L is also downregulated in lung tissue and lung fibroblasts in SSc and is thought to have an inhibitory effect on fibrosis [ 32 ]. Therefore, it is unlikely that the anti-fibrotic effect of ALLN in the present study is due to the inhibition of cathepsin B and/or L. Second, regarding the effect of ALLN on TGF-β1 signaling, we investigated only canonical Smad2/3 signaling rather than non-canonical signaling pathways such as PI3K/Akt signaling [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis

Kasamatsu,

Chino,

Hasegawa

et al. 2023

Arthritis Res Ther

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Background Systemic sclerosis (SSc) is a connective tissue disease that is characterized by fibrosis in the skin and internal organs, such as the lungs. Activated differentiation of progenitor cells, which are mainly resident fibroblasts, into myofibroblasts is considered a key mechanism underlying the overproduction of extracellular matrix and the resultant tissue fibrosis in SSc. Calpains are members of the Ca2+-dependent cysteine protease family, whose enzymatic activities participate in signal transduction and tissue remodeling, potentially contributing to fibrosis in various organs. However, the roles of calpain in the pathogenesis of SSc remain unknown. This study aimed to examine the anti-fibrotic properties of N-acetyl-Leu-Leu-norleucinal (ALLN), one of the cysteine proteinase inhibitors that primarily inhibit calpain, in vitro and in vivo, to optimally translate into the therapeutic utility in human SSc. Methods Normal human dermal and lung fibroblasts pretreated with ALLN were stimulated with recombinant transforming growth factor beta 1 (TGF-β1), followed by assessment of TGF-β1/Smad signaling and fibrogenic molecules. Results ALLN treatment significantly inhibited TGF-β1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-β1-dependent increases in α-smooth muscle actin (αSMA), collagen type I, fibronectin 1, and some mesenchymal transcription markers were attenuated by ALLN. Moreover, our findings suggest that ALLN inhibits TGF-β1-induced mesenchymal transition in human lung epithelial cells. Consistent with these in vitro findings, administering ALLN (3 mg/kg/day) three times a week intraperitoneally remarkably suppressed the development of skin and lung fibrosis in a SSc mouse model induced by daily subcutaneous bleomycin injection. The number of skin- and lung-infiltrating CD3+ T cells decreased in ALLN-treated mice compared with that in control-treated mice. Phosphorylation of Smad3 and/or an increase in αSMA-positive myofibroblasts was significantly inhibited by ALLN treatment on the skin and lungs. However, no adverse effects were observed. Conclusions Our results prove that calpains can be a novel therapeutic target for skin and lung fibrosis in SSc, considering its inhibitor ALLN.

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Reduced Cathepsin L expression and secretion into the extracellular milieu contribute to lung fibrosis in systemic sclerosis

Cited by 10 publications

References 48 publications

The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis

The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis

First Characterization of the Transcriptome of Lung Fibroblasts of SSc Patients and Healthy Donors of African Ancestry

A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis

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