Shivani Patel

The inverse relationship between osteoclasts (resorption of bone) and osteoblasts (formation of bone) is important to keep coupled so that formation and resorption match, and diseases such as osteoporosis can be avoided. Extracellular vesicles (EVs) that are shed by osteoclasts contain the protein RANK, which binds its receptor RANKL on osteoblasts, thus stimulating the formation of bone. The proteins of a trimeric complex called the retromer are also very abundant in EVs and this retromer is involved in the sorting of proteins in endosomal networks, from where EVs arise. Retromer proteins in the EVs may be present because the retromer is involved in sorting proteins like RANK into the extracellular vesicles. Furthermore, a transgenic mouse model that had reduced retromer activity was shown to be osteoporotic, which supports the idea that the retromer may play a key role in the coupling process. With these data, we aim to test our central hypothesis: Retromer activity regulates the amount of RANK released from osteoclasts in extracellular vesicles, and these RANK-containing EVs serve as coupling factors by stimulating osteoblasts to form bone. To test this, a membrane-permeable small molecule (R55), which stimulates hyperactivity of the retromer will be used to treat osteoclasts. We hypothesize that this treatment will promote shedding of more RANK-containing EVs, and the EVs from R55 treated osteoclasts will be better able to stimulate osteoblasts to mineralize than the osteoclasts treated with vehicle.