The Protease Group (ProTarg)
The ProTarg research group is studying enzymes that cleave proteins (proteolytic enzymes/proteases). Such cleavage is irreversible and the enzymes are potential drug target molecules. Therefore, the name "PROTeases as pharmacological TARGets"!
Our main focus is proteolytic enzymes and especially the class of cysteine proteases, which include legumain, cathepsins and caspases. When these enzymes cleave protein substrates, both activation and inactivation of the substrates can occur. Proteolytic enzymes are involved in inflammatory processes (inflammation) and diseases such as cancer and atherosclerosis. Inhibiting proteases with drugs is therefore an interesting strategy for therapeutic treatment. If we better understand which roles the proteases play in such diseases, treatment can become more rational.
ProTarg has a special focus on the protease legumain, which is involved in diseases such as osteoporosis, atherosclerosis and cancer, as well as in neurodegenerative disorders such as Alzheimer's disease.
In bone remodeling, legumain is shown to inhibit the differentiation of stem cells into osteoblasts (bone-building cells), thus inhibiting the formation of new bone substance in the skeleton. Low concentration or inhibition of legumain is therefore a prerequisite for repair of damage to the skeleton. If a high concentration of legumain is present, the stem cells will instead develop into fat cells.
The interplay between bone and skeletal muscle is of high interest, partly due to the close proximity of the organs, but also the fact that these organs are major regulators of body metabolism. Furthermore, studies have shown that dysregulation in one organ affects the other organ, for example muscle atrophy results in osteoporosis. Recent studies indicate an emerging role of biochemical communication and crosstalk between bone and skeletal muscle which has the potential of exploring new drug targets for therapies of sarcopenia and osteoporosis. Bone cells produce and secrete mediators (osteokines) which are able to impact differentiation and metabolic flexibility of skeletal muscle cells. We have shown that legumain is secreted from osteoblasts, but whether legumain is involved in this crosstalk is still unknown. In collaboration with the Muscle Research Group we are studying the impact of legumain in the interplay between human bone and skeletal muscle cells.
In atherosclerosis, increased levels of legumain are found in blood (plasma/serum) and deposits in the arterial wall (atherosclerotic plaques) in patients with cardiovascular disease.
In cancer, legumain is shown to be highly expressed in malignant (malignant) cancers that spread in the body (metastasize).