CD146 Protein May Help Identify, Treat SSc
High levels of a form of the CD146 protein, normally found on endothelial cells — those that line blood vessel walls — may be a potential biomarker in identifying people with systemic sclerosis (SSc), a study suggests.
Certain forms of the protein are implicated in lung scarring (pulmonary fibrosis) and in controlling skin thickness, having potential as therapeutic targets.
The study, “Multiple variants of soluble CD146 are involved in Systemic Sclerosis: identification of a novel pro-fibrotic factor,” was published in the journal Arthritis & Rheumatology.
CD146 is involved in the formation of new blood vessels — a process called angiogenesis — inflammation, and controlling vascular permeability, or the capacity of certain cells and molecules to cross the vessel’s wall.
While the two major forms of CD146 are located in the cell’s membrane, the protein also can exist in a soluble form in the blood.
Recent research suggests that measuring the levels of this soluble form of CD146, known as sCD146, could serve as a biomarker of disease activity in SSc, also known as scleroderma. Moreover, data from an animal model of SSc showed that sCD146 injections reduced disease severity.
However, little is known about the mechanisms regulating sCD146 formation and whether different variants of the protein exist and play a role in SSc.
To answer this, an international team led by researchers at Aix-Marseille University, in France, conducted lab (in vitro) tests as well experiments in animal models of SSc.
The lab tests revealed that two forms of CD146 — a short and a longer form, both present at the membrane of endothelial cells — can generate a shed form of the soluble protein. The membrane proteins were cleaved by enzymes called metalloproteinases.
This process represented about 75% of the sCD146 production. The remaining 25% of the soluble protein was not dependent on the action of metalloproteinases.
The researchers went on to identify two new forms of sCD146 — called I5-13-sCD146 and I10-sCD146 — that arose as a result of alternative RNA splicing, a process that allows a single gene to produce a number of different messenger RNA (mRNA) sequences and as a consequence, different proteins. Of note, mRNAs are the molecules that carry genetic information to the sites where proteins are produced.
The levels of sCD146 variants in blood samples from 117 SSc patients were then measured and compared with those of 81 participants serving as controls.
Results showed that the sCD146 form that resulted from cleavage of the membrane protein and the splice variant I5-13-sCD146 had significantly higher levels in the blood of patients with SSc. The splice variant was particularly high in people with pulmonary fibrosis when compared with patients without lung disease. In contrast, levels of I10-sCD146 were decreased in SSc samples, as were those of cleaved sCD146 in participants with pulmonary hypertension, a disease associated with high blood pressure in the blood vessels that supply the lungs.
The scientists then tested the effects of the different sCD146 forms when injected under the skin (subcutaneously) in a mouse model of SSc.
Compared with control animals, sCD146 and I10-sCD146 reduced the thickness of the dermis, the thicker layer of the skin. Later experiments linked this effect with CD146’s role as a potentiator of blood vessels formation.
No such effects were seen with I5-13-sCD146. Instead, lab tests suggest that it plays a role in promoting fibrosis, which is in agreement with its levels being particularly high among SSc patients with pulmonary fibrosis.
Overall, these findings suggest that “variants of sCD146, and in particular the novel I5-13-sCD146 splice variant, could thus constitute novel biomarkers and/or molecular targets for the diagnosis and treatment of SSc, but also of other angiogenesis– or fibrosis-related pathologies [diseases],” the investigators concluded.