Scientists have found that the growth factor TGF-beta may play a role in the formation of posterior capsule opacification (PCO), suggesting a new direction for research.
“Preventing posterior capsule opacification would spare thousands of people from needing laser capsulotomy, a procedure with potential risks that costs the U.S. more than $150 million annually,” said Houmam Araj, PhD, lens and cataract program director at NEI. “In addition to shedding light on how secondary cataracts form, these findings present some exciting insights into the growth factor TGF-beta that have implications far beyond the eye.”
The team’s work was published online last month in Molecular Biology of the Cell.
Residual lens epithelial cells can differentiate into 1 of 2 distinct cell types: lens fiber cells and myofibroblasts. Both cell types cause PCO through differing mechanisms. Lens fiber cells become bloated crystallins causes them to scatter light as it passes through the lens, while myofibroblasts generate large amounts of extracellular matrix proteins that causes the lens capsule to wrinkle.
To better understand the molecular mechanisms responsible for directing lens epithelial cell differentiation, Linda S. Musil, PhD, of Oregon Health & Science University and her team used cultured purified embryonic lens cells from a chick.
They found that adding active TGF-beta to their in vitro cultures induced the lens epithelial cells to differentiate into either myofibroblasts or lens fiber cells, while adding a TGF-beta inhibitor reduced differentiation. Other growth factors failed to induce similar cell differentiation.
Both cell types were found in the same cultures, often right next to each other, as previously reported in people with secondary cataract. In addition, the presence of TGF-beta was associated with the migration of lens cells, a requirement for accumulation at the back of the lens capsule and secondary cataract.
Next, they assessed whether TGF-beta has a direct effect on lens epithelial cell differentiation, or if it is indirectly enabled through cell signaling downstream of TGF-beta activation. They found that blocking the downstream p38 kinase pathway with an inhibitor, prevented myofibroblast formation. Similarly, inhibiting the MTOR pathway prevented the formation of lens fiber cells.
The team used their lens culture system to test drugs for their ability to block PCO. They found that the multikinase inhibitor rebastinib, a drug that is currently in phase I clinical trials for cancer, prevented TGF-beta from inducing cell migration as well as the formation of myofibroblasts in both chick lens cells and in rat lens explants. Work is in progress to find agents that inhibit both myofibroblast and lens fiber cell formation. Such agents may be included in artificial lenses to prevent the formation of secondary cataract, Musil said.