LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development

Gong, Yaoqin Slee, Roger B. Fukai, Naomi Rawadi, Georges Roman-Roman, Sergio Reginato, Anthony M. Wang, Hongwei Cundy, Tim Glorieux, Francis H. Lev, Dorit Zacharin, Margaret Oexle, Konrad Marcelino, Jose Suwairi, Wafaa Heeger, Shauna Sabatakos, George Apte, Suneel Adkins, William N. Allgrove, Jeremy Arslan-Kirchner, Mine Batch, Jennifer A. Beighton, Peter Black, Graeme C. Boles, Richard G. Boon, Laurence M. [UCL] Borrone, Carla Brunner, Han G. Carle, Georges F. Dallapiccola, Bruno De Paepe, Anne Floege, Barbara Halfhide, Melissa Lees Hall, Bryan Hennekam, Raoul C. Hirose, Tatsuo Jans, Ab Jüppner, Harald Kim, Chong Ae Keppler-Noreuil, Kim Kohlschuetter, Alfred LaCombe, Didier LAMBERT, Marie [UCL] Lemyre, Emmanuelle Letteboer, Tom Peltonen, Leena Ramesar, Rajkumar S. Romanengo, Marta Somer, Hannu Steichen-Gersdorf, Elisabeth Steinmann, Beat Sullivan, Beth Superti-Furga, Andrea Swoboda, Walter van den Boogaard, Marie-José Van Hul, Wim Vikkula, Miikka [UCL] Votruba, Marcela Zabel, Bernhard Garcia, Teresa Baron, Roland Olsen, Bjorn R. Warman, Matthew L. Osteoporosis-Pseudoglioma Syndrome Collaborative Group et al.[show all]

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.