Critical Role of LMCD1 in Promoting Profibrotic Characteristics of Lung Myofibroblasts in Experimental and Scleroderma‐Associated Lung Fibrosis

Abstract

Objective Interstitial lung disease (ILD) is a serious complication and leading cause of mortality in patients with systemic sclerosis (SSc). In this study, we explored the role of LIM and cysteine‐rich domains protein 1 (LMCD1) as a novel factor in the pathogenesis of SSc‐related ILD (SSc‐ILD). Methods The expression and effects of LMCD1 were studied in lung tissue samples and fibroblasts from SSc‐ILD patients and control subjects as well as in lung tissue samples from animal models. Results LMCD1 was consistently elevated in lung tissue samples and in fibroblasts isolated from SSc‐ILD patients as compared to controls. Additionally, LMCD1 was found to be highly expressed in the lung in the fibroblast‐specific protein (FSP)–driven, constitutively active transforming growth factor β receptor type I (TGFβR1) transgenic mouse model of ILD and the bleomycin‐induced mouse model of ILD. In lung fibroblasts from SSc‐ILD patients, LMCD1 is an essential factor for the TGFβ‐induced generation of type I collagen, fibronectin, and α‐smooth muscle actin (α‐SMA). Depletion of LMCD1 by small interfering RNA reduced the expression of extracellular matrix proteins and lowered transcriptional activity and expression of α‐SMA, as well as decreased the proliferation and contractile activity of SSc‐ILD lung fibroblasts. In dense fibrotic areas of affected lung tissue, lung LMCD1 colocalized with α‐SMA. In cultured scleroderma lung fibroblasts, LMCD1 colocalized and interacted with serum response factor which mediates LMCD1‐induced contractile activity of lung fibroblasts. Conclusion Our study identifies LMCD1 as a profibrotic molecule contributing to the activation of myofibroblasts and the persistent fibroproliferation observed in SSc‐ILD. Thus, LMCD1 may be a potential novel therapeutic target for patients with SSc‐ILD.

Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease

“…In particular, in cases of systemic sclerosis-associated lung fibrosis, LMCD1 interacts with serum response factors in lung fibroblasts, which leads to increased contractile activity of lung myofibroblasts. This suggests that LMCD1 is a pro-fibrotic molecule that contributes to myofibroblast activation and sustained fibrotic proliferation ( Bogatkevich et al., 2023 ). Lung fibrosis and lung myofibroblasts also play important roles in the pathophysiology of COPD, and it is reasonable to hypothesize that LMCD1 could potentially contribute to lung tissue fibrosis, thereby increasing the risk of spirometry-defined COPD.…”

The Role of Vimentin in Human Corneal Fibroblast Spreading and Myofibroblast Transformation

“…Another protein that was highly expressed in both Vim KO and control cells was the LIM and cysteine rich domains 1, LMCD1, which is a transcription factor. Evidence suggests that LMCD1 may facilitate profibrotic gene expression and in tissue fibrosis, it is found to be consistently elevated in pulmonary and renal fibrosis [34,63]. Depletion of LMCD1 expression has been shown to reduce the expression of ECM proteins and αSMA.…”

“…Depletion of LMCD1 expression has been shown to reduce the expression of ECM proteins and αSMA. On the other hand, high levels of LMCD1 correlate with high levels of ECM and αSMA protein, features of tissue fibrosis [34].…”

“…Tumor protein P53 inducible protein 3 (TP53I3) provides apoptotic resistance to myofibroblasts during fibrosis [33]. LMCD1 has been shown to be highly up-regulated by myofibroblasts in order to increase expression of ECM proteins and maintain high levels of αsma [34]. Latent transforming growth factor binding proteins (LTBP2) are essential for securing TGFβ to the ECM through the latency-associated pro-peptide, LAP [35,36].…”

Unagi: Deep Generative Model for Deciphering Cellular Dynamics and In-Silico Drug Discovery in Complex Diseases

“…A notable observation from our snRNA-seq and proteomics data is that five of these overlapping dynamic markers are collagens (COL1A1, COL1A2, COL3A1, COL3A1, COL14A1), confirming that progressive matrix remodeling is intrinsically intertwined with the development of fibrosis 68 . Moreover, a majority of the overlapped dynamic markers have been previously associated with pulmonary fibrosis 54,[69][70][71] , including CCN5, CDH13, MYH10, PAPSS2, and LMCD. This proteomics data serves as a validation, confirming that the discovered dynamical genes play a crucial role in the progression of IPF.…”