MERTK Inhibition Increases Bone Density via Increased Osteoblast Activity
Bone density results from the balance of constant activity on the part of osteoblasts and osteoclasts, the former building bone, the latter breaking it down. With advancing age, the balance of activity shifts to favor osteoclasts, producing a gradual loss of bone density that leads to osteoporosis. Therapies have to date typically attempted to reduce osteoclast activity, but researchers here note an approach based on increased osteoblast activity.
Bones appear to be durable and solid. But appearances are deceptive: in fact, bone tissue is in a constant state of remodeling. Bone-degrading osteoclasts and bone-building osteoblasts ensure a fine balance in the healthy organism. But this balance is occasionally disturbed: in osteoporosis, bone resorption takes over, so that fractures and deformities can occur. Bone metastases, which occur in the course of many cancers, are also often caused by bone resorption processes. This is also true for multiple myeloma, which originates and spreads in the bone marrow.
So far, drugs are available that inhibit bone resorption by osteoclasts. However, researchers believe that agents that promote bone formation by osteoblasts are also medically necessary. To identify such substances, the researchers first had to find out which signaling pathways control osteoblast activity. The team identified in mouse osteoblasts the two enzymes MERTK and TYRO3, so-called receptor tyrosine kinases, which regulate bone production. The function of the two enzymes was studied in mice in whose osteoblasts either one or the other receptor tyrosine kinase was genetically switched off. The result: If MERTK was inactivated, the bone mass of the animals increased. Without TYRO3, on the other hand, it decreased.
The small-molecule agent R992 inhibits MERTK activity. When healthy mice were treated with R992, their osteoblast numbers increased and the animals' bone mass increased. Treatment with R992 also reduced bone loss and the number of bone metastases in mouse models with myeloma, lung cancer, and breast cancer cell lines. The agent R992 is not approved as a drug. To potentially study the effects of MERTK blockade in patients, the team is currently developing an antibody that specifically blocks the function of MERTK.