Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates

As some people age, their bones may become weak, brittle, and break easily. This condition is called osteoporosis. To treat osteoporosis, doctors often prescribe drugs called nitrogen-containing bisphosphonates (NBPs). These drugs destroy cells called osteoclasts, which break down bone. This helps restore bone mass. To kill osteoclasts, the drugs must enter these cells. First, they must pass through an oily protective layer called a membrane. It is not completely clear how NBPs, which prefer to stay in water-like environments, can cross this oily membrane and enter osteoclasts. Understanding how NBPs cross the membrane is important to ensure the drugs work effectively. If NBPs do not efficiently cross the membrane, they will not work properly and may cause harmful side effects. Many patients who take NBPs suffer from side effects such as abnormal fractures. Now, Yu et al. show that two proteins help NBPs cross the membrane. In the experiments, proteins were removed from human cancer cells one at a time using a technique called CRISPRi. CRISPRi enabled the researchers to systematically turn off the genes for each protein and track what affect this had on the NBPs’ ability to cross the membrane. When one of the two genes called SLC37A3 and ATRAID was turned off, NBPs could not get into cells. The protein produced by the SLC37A3 gene opens a gate in the cell membrane allowing NBPs to enter osteoclasts. The protein made by the ATRAID gene helps this gate protein, and without it, the SLC37A3 proteins are unstable and NBPs cannot enter. Some people have variations of the SLC37A3 and ATRAID genes. Testing whether these genetic variations may alter NBPs’ ability to cross the membrane of osteoclasts in mice, might one day help physicians predict which patients with have side effects.