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ATLANTA—Researchers from the Georgia Institute of Technology and Emory University have released data from a recent study uncovering unknown enzymatic interactions within the cathepsin family, a discovery that could have implications on a variety of diseases.
There are 11 cathepsins in the family group, and cathepsins are implicated in a variety of disease processes—cancer metastasis, arthritis, cardiovascular disease, osteoporosis and atherosclerosis among them. Cathepsins also have detrimental effects on proteins like collagen and elastin, a protein that enables tissue flexibility and is essential in arteries and the cardiovascular system. The new study shows that cathepsins might be prone to cannibalizing each other rather than their usual targets, and details from the study appeared in the Journal of Biological Chemistry on Aug. 10.
Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and student Zachary Barry discovered the interaction between cathepsin K and cathepsin S.
Cathepsin K is one of the most powerful proteases, and is known to degrade collagen and elastin, while cathepsin S degrades elastin but does not vigorously attack collagen. Cathepsin K, Platt notes, plays a role in bone resorption as osteoclasts produce cathepsin K to break down bone and release calcium to maintain calcium homeostasis. Cathepsin S, he says, plays a role in some immune processing. The cathepsin family as a whole plays a role in the breakdown and turnover of proteins and recycling amino acids.
When the two enzymes were combined and exposed to samples of elastin in the experiment, it was expected to result in heightened damage to the elastin, but instead resulted in little more damage than could be expected from cathepsin K by itself.
"These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue—or fight against each other," said Platt in a press release. "There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases."
As the results were so unexpected, Platt called for a repeat of the experiment, and Barry's results seemed to indicate that when the two cathepsins were combined, cathepsin S set about degrading cathepsin K rather than attacking the elastin samples.
Additional experiments showed that increasing the amount of cathepsin S led to a correlating decrease in the degradation of collagen, to the point that when the amount of cathepsin S was increased tenfold over the amount originally used, its cannibalization of cathepsin K completely blocked cathepsin K's activity and damage to collagen.
The discovery has the potential to lead to an even greater understanding about the enzyme family and its interactions, in addition to potentially benefiting the development of cathepsin inhibitors, which have been in development over the years for indications such as osteoporosis, metastatic bone cancer and arthritis. To date, these compounds have generally failed in the clinic.
"A lot of these cathepsin inhibitors have failed clinical trials around Phase II due to severe side effects," says Platt. "Where the cannibalism comes into play, if you have a higher dose of this drug and you even have less of the target enzyme that you were looking for because it's being cannibalized by other family members, then you still have now a greater chance of non-specific targeting, non-specific inhibiting. And again, blocking these other enzymes that have important bodily functions can then lead to some of these diseases or side effects that maybe have ended some of these studies."
Platt says that moving forward, they will be looking at two other cathepsins next, cathepsins V and L. Cathepsin V, he notes, is stronger than even cathepsin K, and cathepsin L is implicated in "lots of different tissue-destructive diseases as well." The researchers will look at the four cathepsins and how they degrade elastin, collagen one and collagen four.
"What we're also doing is we're developing kinetic models of these enzymes working together … this paper was using just the enzymes in vitro, but when you start to put cells in the mix, everything changes because cells start producing different quantities, they can produce different factors that can activate or hinder them. So now we're trying to move this into what one type of cell is doing and if we can match the degradation of a tissue, based on how many of these enzymes they're producing, by understanding how they're interacting with each other and their environment, we can then kind of say 'well, this would need to be targeted in this disease and these cells have turned on in connection with these enzymes.' Everything changes with cells."