LMCD1 Protein May Have Treatment Potential in SSc-ILD Cases
LMCD1 helps lung fibroblasts develop into myofibroblasts, lab study shows
A protein called LMCD1 is present at higher levels in the lungs of patients with interstitial lung disease (ILD) linked to systemic sclerosis (SSc) than in healthy individuals, and may be a candidate target for the treatment of the disease, a small study suggests.
Researchers found that the protein helps lung fibroblasts grow in number and develop into myofibroblasts, which can tighten (contract) in a way similar to muscle cells. Fibroblasts are cells that make too much collagen during scarring, which is what causes tissues to thicken and harden in patients with scleroderma.
These findings suggest that “LMCD1 may be a potential novel therapeutic target for patients with SSc-ILD,” the researchers wrote.
The study, “Increased expression of LMCD1 in scleroderma-associated interstitial lung disease is critical for profibrotic characteristics of lung myofibroblasts,” was published in the journal Arthritis & Rheumatology.
Systemic scleroderma, also called SSc, is a type of scleroderma that results in thickened, hardened skin and scarring around the blood vessels and the body’s internal organs. When this happens in the lungs, it can make it difficult to breathe and get oxygen out into the bloodstream.
Scarring occurs when there is a buildup of large amounts of collagen-rich extracellular matrix (ECM). The ECM is a mesh-like scaffold that holds cells and gives structure to tissues; it also helps them repair from damage. But abnormal changes to the ECM may make cells grow out of control.
Members of the LIM family of proteins play a role in helping cells grow. They work as transcription factors, which are proteins that tell how much of certain genes are to be copied into RNA on the way to making the proteins they code. Too much of these LIM-domain proteins may cause an overgrowth of heart and tumor tissue.
One particular member of this family, LMCD1, has been linked to scarring. However, exactly how the protein works is unknown. To know more, a team of researchers in the U.S. looked at samples of postmortem tissues taken from the lungs of five patients with late-stage SSc-ILD.
Compared with samples of healthy lungs, those of patients with SSc-ILD had more than six times as many LMCD1-positive cells (64.8% vs. 10.4%). Many of these cells were in highly scarred areas, and nearly all also were positive for smooth muscle actin (SMA), a marker of cells called myofibroblasts that are responsible for the synthesis and buildup of scar tissue.
When the researchers grew lung fibroblasts in the lab together with either transforming growth factor beta or thrombin, two proteins involved in fibrosis, they saw an increase in the levels of LMCD1 RNA. This was true both for fibroblasts from patients or healthy individuals.
Next, the researchers used siRNA — a type of RNA — to tone down the levels of LMCD1 in the lab-grown fibroblasts. When they did this, the fibroblasts did not grow as much in number and did not make as much of collagen. Moreover, their levels of SMA were about halved.
To determine how this translated into the ability to contract, the researchers mixed the lab-grown fibroblasts into a collagen-rich lattice and watched for changes in its diameter. Compared with a scrambled (control) siRNA, toning down the levels of LMCD1 resulted in less shrinking (4.02 vs. 9.32 mm).
When the researchers looked more closely at the molecular levels, they found that LMCD1 interacted with serum response factor (SRF), a transcription factor that helps control how some cells grow and contract. Delivering SRF into the lab-grown fibroblasts in which LMCD1 had been toned down restored their ability to make a collagen-rich lattice shrink. This means that LMCD1 may need SRF to get the myofibroblasts to contract.
“As multiple networks of numerous molecules and cells control the complex processes of tissue injury, repair and remodeling in SSc-ILD, LMCD1 might serve as a driver of the underlying transcriptional mechanisms [conversion of DNA into RNA] leading to the development of the activated myofibroblasts and producing an overabundance of ECM proteins leading to lung fibrosis,” the researchers wrote.
This means that “LMCD1 may be a potential target for much needed novel therapy for SSc-ILD as well as other fibrosing lung diseases.”