Cornering cathepsins

New research discovers cannibalism amidst enzymes associated with protein breakdown and disease processes

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ATLANTA—Researchers from the Georgia Institute of Technologyand Emory University have released data from a recent study uncovering unknownenzymatic interactions within the cathepsin family, a discovery that could haveimplications on a variety of diseases.
There are 11 cathepsins in the family group, and cathepsinsare implicated in a variety of disease processes—cancer metastasis,arthritis, cardiovascular disease, osteoporosis and atherosclerosis among them. Cathepsinsalso have detrimental effects on proteins like collagen and elastin, a proteinthat enables tissue flexibility and is essential in arteries and thecardiovascular system. The new study shows that cathepsins might be prone tocannibalizing each other rather than their usual targets, and details from thestudy appeared in the Journal ofBiological Chemistry on Aug. 10.
Manu Platt, an assistant professor in the Wallace H. CoulterDepartment of Biomedical Engineering at Georgia Tech and Emory University, andstudent Zachary Barry discovered the interaction between cathepsin K andcathepsin S.
Cathepsin K is one of the most powerful proteases, and is knownto degrade collagen and elastin, while cathepsin S degrades elastin but doesnot vigorously attack collagen. Cathepsin K, Platt notes, plays a role in boneresorption as osteoclasts produce cathepsin K to break down bone and releasecalcium to maintain calcium homeostasis. Cathepsin S, he says, plays a role insome immune processing. The cathepsin family as a whole plays a role in thebreakdown and turnover of proteins and recycling amino acids.
When the two enzymes were combined and exposed to samples ofelastin in the experiment, it was expected to result in heightened damage tothe elastin, but instead resulted in little more damage than could be expectedfrom cathepsin K by itself.
"These findings provide a new way of thinking about howthese proteases are working with and against each other to remodel tissue—orfight against each other," said Platt in a press release. "There has been anassumption that these cathepsins have been inert in relationship to oneanother, when in actuality they have been attacking one another. We think thismay have broader implications for other classes of proteases."
As the results were so unexpected, Platt called for a repeatof the experiment, and Barry's results seemed to indicate that when the twocathepsins were combined, cathepsin S set about degrading cathepsin K ratherthan attacking the elastin samples.
Additional experiments showed that increasing the amount ofcathepsin S led to a correlating decrease in the degradation of collagen, tothe point that when the amount of cathepsin S was increased tenfold over theamount originally used, its cannibalization of cathepsin K completely blockedcathepsin K's activity and damage to collagen.
The discovery has the potential to lead to an even greaterunderstanding about the enzyme family and its interactions, in addition topotentially benefiting the development of cathepsin inhibitors, which have beenin development over the years for indications such as osteoporosis, metastaticbone cancer and arthritis. To date, these compounds have generally failed inthe clinic.
"A lot of these cathepsin inhibitors have failed clinicaltrials around Phase II due to severe side effects," says Platt. "Where thecannibalism comes into play, if you have a higher dose of this drug and youeven have less of the target enzyme that you were looking for because it'sbeing cannibalized by other family members, then you still have now a greaterchance of non-specific targeting, non-specific inhibiting. And again, blockingthese other enzymes that have important bodily functions can then lead to someof these diseases or side effects that maybe have ended some of these studies." 
Platt says that moving forward, they will be looking at twoother cathepsins next, cathepsins V and L. Cathepsin V, he notes, is strongerthan even cathepsin K, and cathepsin L is implicated in "lots of differenttissue-destructive diseases as well." The researchers will look at the fourcathepsins and how they degrade elastin, collagen one and collagen four.
"What we're also doing is we're developing kinetic models ofthese enzymes working together … this paper was using just the enzymes in vitro, but when you start to putcells in the mix, everything changes because cells start producing differentquantities, they can produce different factors that can activate or hinderthem. So now we're trying to move this into what one type of cell is doing andif we can match the degradation of a tissue, based on how many of these enzymesthey're producing, by understanding how they're interacting with each other andtheir environment, we can then kind of say 'well, this would need to betargeted in this disease and these cells have turned on in connection withthese enzymes.' Everything changes with cells."
Support for this research came from the National Institutesof Health, the National Science Foundation and the Georgia Cancer Coalition.

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