VPS35: Two Ways to Recycle the Parathyroid Hormone Receptor (PTH1R) in Osteoblasts

The recombinant parathyroid hormone (PTH) Teriparatide is the only therapy for postmenopausal osteoporosis that increases bone mass (i.e., is anabolic). Its therapeutic action depends on a short “burst” of PTH in the circulation followed by a rapid return to normal levels; if PTH levels remain high, bone loss occurs (i.e., the effect is catabolic) (Frolik et al., 2003). This occurs because PTH not only stimulates the bone forming activity of osteoblasts, but also stimulates their ability to support osteoclast formation by producing RANKL. If PTH-induced RANKL production persists for longer than usual, anabolic intermittent PTH treatment can be switched to a catabolic effect (Walker et al., 2012). This may explain why PTH therapy is not effective in all patients, andwhy PTH anabolic effect is not sustainedwith long-term treatment. Identifying mechanisms that control how PTH signalling is terminated within the cell may provide new ways to design PTH-based therapies to overcome this problem. Three recent papers including work in EBiomedicine by Xiong et al. (Xiong et al., 2016; Chan et al., 2016; McGarvey et al., 2016) indicate that PTH receptor signalling duration is controlled by VPS35 and SNX27, two components of the retromer complex. PTH signals through PTH receptor (PTH1R). This G protein-coupled receptor is shared with PTHrP (PTH-related protein), a paracrine factor produced by osteoblasts essential for normal physiological bone