Targeting the CD248 molecule may be a good therapeutic option for patients with systemic sclerosis (SSc) due to the central role it seems to play in the development of fibrosis, a study reports.
Results of the study, “Blocking CD248 molecules in perivascular stromal cells of patients with systemic sclerosis strongly inhibits their differentiation toward myofibroblasts and proliferation: a new potential target for antifibrotic therapy,” were published in the journal Arthritis Research & Therapy.
CD248, also known as endosialin or tumor endothelial marker 1, is a receptor present on the surface of cells, which binds to collagen and fibronectin, two important proteins that make up the extracellular matrix surrounding cells.
CD248 also plays an important role during the early stages of development, from the embryonic stage. It is required for the proliferation and differentiation of two types of cells: pericytes and fibroblasts. In the adult stage, expression of CD248 normally decreases, but some studies have shown that during inflammation or cancer progression, CD248 expression increases again.
Its role in cancer prompted a first-in-human Phase 1 clinical trial (NCT00847054) with an antibody that targeted and inhibited CD248. This trial showed that the therapy is safe and effective in the treatment of different cancers.
Fibrosis is often seen in patients with SSc, characterized by the accumulation of proteins, namely collagen, in the extracellular matrix. Transforming growth factor-β (TGF-β) and platelet-derived growth factor BB (PDGF-BB) both contribute to fibrosis development. It is thought that after injury, pericytes and fibroblasts become a different type of cell — called myofibroblasts — that produce large amounts of collagen.
Because of the role CD248 plays in cell growth and differentiation and its possible links to TGF-β and PDGF-BB, the researchers in this study investigated how CD248 regulates fibrosis in SSc using both human samples and in vitro cell line models.
Skin biopsies were collected from 20 patients with SSc and 10 healthy individuals used as controls to evaluate the levels of CD248.
Researchers found that CD248 is overexpressed in SSc skin compared with healthy controls. CD248 expression is highest in early-onset SSc patients — in this context, early-onset refers to a subset of patients who are at a higher risk of developing fibrosis faster.
Bone marrow mesenchymal stem cells (MSCs) are a good surrogate for studying how pericytes differentiate into myofibroblasts. In MSCs of SSc patients, CD248 expression was also found to be higher than in those of healthy controls.
In these MSCs, the addition of TGF-β, but not PDGF-BB, could induce expression of CD248. Additionally, TGF-β decreased the proliferative capacity of MSCs from SSc patients and healthy controls. PDGF-BB, on the other hand, increased the proliferation of these cells.
When CD248 expression was silenced, the effects of TGF-β and PDGF-BB were inhibited, showing that both these pro-fibrotic molecules require CD248 for their function.
According to the team, this is the first study to show a connection between TGF-β, PDGF-BB, and CD248 in the fibrotic process of SSc.
“Our study shows that SSc perivascular cells overexpress CD248, which is involved in SSc pericyte transition toward myofibroblasts, and CD248 silencing may prevent pericyte-to-myofibroblast transition, proliferation, vascular instability, and tissue fibrosis,” the researchers wrote.
They concluded that the “data suggest that targeting CD248 expression may be considered a potential target in order to block tissue fibrosis … during SSc.”