Bone Diseases: Sclerostin Neutralization—A Viable Pathway For

RESEARCH HIGHLIGHTS Nature Reviews Rheumatology 10, 4 (2014); published online 3 December 2013; doi:10.1038/nrrheum.2013.189

BONE DISEASES Sclerostin neutralization—a viable pathway for OPPG? The anabolic effects of inhibiting lipoprotein receptor-related protein 5 the properties of bone through pathways sclerostin—a negative regulator of the (LRP5), a major sclerostin receptor. “We that do not require Lrp5. In addition, the Wnt bone forming pathway—can improve thought that inhibiting sclerostin would researchers tested antianabolic responses bone mass in the absence of low-density have a generally modest bone building by treating Lrp5-deficient mice with effect in Lrp5 knockout mice,” explains an anti-sclerostin antibody. Sclerostin Alexander Robling, lead author of the depletion resulted in increased bone article. He continues, “when the study mineral density and bone formation rates was complete we were surprised, but very in mice with and without Lrp5. “Our pleased, that the treatment had resulted results indicated that LRP6 likely has a in such a dramatic increase in bone significant role as a sclerostin receptor, formation and bone mineral density.” probably even more so when LRP5 is The research group previously reported absent,” says Robling. that the genetic basis for osteoporosis Sclerostin neutralization therapies pseudoglioma syndrome (OPPG)—a could, therefore, benefit patients with rare genetic disorder characterized by OPPG who have nonfunctional LPR5. “By reduced bone formation and an elevated using genetically engineered mice, such as incidence of fractures—is a loss-of- our Lrp5 knockout mice, we hope to gain function mutation in LRP5, which acts as a a better understanding of the respective co-receptor for the Wnt family of ligands, roles of LRP5 and LRP6 in this important and mediates osteoblast activity. pathway,” concludes Robling. Here, Kedlaya and colleagues measured Bryony Jones bone properties in various knockout mouse models. Mice lacking both Lrp5 and sclerostin had stronger bones than Original article Kedlaya, R. et al. Sclerostin inhibition mice lacking Lrp5 only, which suggests reverses skeletal fragility in an Lrp5-deficient mouse model Fluorochrome labelling to measure bone formation rate in of OPPG syndrome. Sci. Transl. Med. 5, 211ra158 (2013) mouse tibia. Courtesy of A. G. Robling. that a deficiency of sclerostin improves