title: Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity.
abstract: The bone formation inhibitor sclerostin encoded by SOST binds in vitro to low-density lipoprotein receptor-related protein (LRP) 5/6 Wnt co-receptors, thereby inhibiting Wnt/β-catenin signaling, a central pathway of skeletal homeostasis. Lrp5/LRP5 deficiency results in osteoporosis-pseudoglioma (OPPG), whereas Sost/SOST deficiency induces lifelong bone gain in mice and humans. Here, we analyzed the bone phenotype of mice lacking Sost (Sost(-/-) ), Lrp5 (Lrp5(-/-) ), or both (Sost(-/-) ;Lrp5(-/-) ) to elucidate the mechanism of action of Sost in vivo. Sost deficiency-induced bone gain was significantly blunted in Sost(-/-) ;Lrp5(-/-) mice. Yet the Lrp5 OPPG phenotype was fully rescued in Sost(-/-) ;Lrp5(-/-) mice and most bone parameters were elevated relative to wild-type. To test whether the remaining bone increases in Sost(-/-) ;Lrp5(-/-) animals depend on Lrp6, we treated wild-type, Sost(-/-) , and Sost(-/-) ;Lrp5(-/-) mice with distinct Lrp6 function blocking antibodies. Selective blockage of Wnt1 class-mediated Lrp6 signaling reduced cancellous bone mass and density in wild-type mice. Surprisingly, it reversed the abnormal bone gain in Sost(-/-) and Sost(-/-) ;Lrp5(-/-) mice to wild-type levels irrespective of enhancement or blockage of Wnt3a class-mediated Lrp6 activity. Thus, whereas Sost deficiency-induced bone anabolism partially requires Lrp5, it fully depends on Wnt1 class-induced Lrp6 activity. These findings indicate: first, that OPPG syndrome patients suffering from LRP5 loss-of-function should benefit from principles antagonizing SOST/sclerostin action; and second, that therapeutic WNT signaling inhibitors may stop the debilitating bone overgrowth in sclerosing disorders related to SOST deficiency, such as sclerosteosis, van Buchem disease, and autosomal dominant craniodiaphyseal dysplasia, which are rare disorders without viable treatment options.
authors.affiliation: Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Ming-Kang
authors.initials: MK
authors.lastname: Chang
authors.forename: Ina
authors.initials: I
authors.lastname: Kramer
authors.forename: Hansjoerg
authors.initials: H
authors.lastname: Keller
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Gooi
authors.forename: Corinne
authors.initials: C
authors.lastname: Collett
authors.forename: David
authors.initials: D
authors.lastname: Jenkins
authors.forename: Seth A
authors.initials: SA
authors.lastname: Ettenberg
authors.forename: Feng
authors.initials: F
authors.lastname: Cong
authors.forename: Christine
authors.initials: C
authors.lastname: Halleux
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015519:Bone Density; D001846:Bone Development / Q000502:physiology; D006023:Glycoproteins / Q000172:deficiency*; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000172:deficiency*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000276:immunology / Q000502:physiology*; D051379:Mice; D010013:Osteogenesis Imperfecta / Q000188:drug therapy; D013977:Tibia / Q000737:chemistry; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; C486030:Sost protein, mouse
keywords: GENETIC ANIMAL MODELS; OPPG; OSTEOPOROSIS-PSEUDOGLIOMA; SCLEROSING BONE DISORDERS; SOST/SCLEROSTIN; WNT/LRP5/6