Introduction. Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder caused by a loss-of-function mutation in the low-density lipoprotein related protein 5 (LRP5) gene. OPPG is characterized with early onset of osteoporosis, low bone mineral density, and eye abnormalities leading to blindness (pseudoglioma). LRP5 is a cell-surface receptor that activates the canonical Wnt/B-catenin pathway, regulating osteoblastic bone formation. WNT signaling through LRP5 and LRP6 is inhibited by the protein sclerostin (encoded by SOST). Studies have found that anti-sclerostin antibody therapy can improve bone mass, strength, and density, regardless of the functionality of LRP5. These findings could suggest a potential therapy for patients with OPPG. Methods. To determine if loss of sclerostin in OPPG stimulates bone synthesis, bone phenotypes were measured in mice model of OPPG (Lrp5-/-), mice lacking sclerostin (Sost-/-), and in mice with double knockouts representing OPPG with loss of sclerostin (Lrp5-/-;Sost-/-). Next, 17-week old Lrp5-/- mice were treated with anti-sclerostin antibodies for 3 weeks to determine whether anabolic effects of sclerostin depletion in Lrp5-/- mice is retained in adult mice. To determine whether bone formation in Lrp5-/-;Sost-/- depends on Lrp6, mice were treated with Lrp6 function blocking antibodies. Results. Mice lacking Lrp5 and Sost have higher bone mass than those lacking Lrp5 alone. Double knockout (Lrp5-/-;Sost-/-) mice had whole-body bone mass density (BMD) and total bone mineral content (BMC) values greater than those measured in Lrp5-/- mice and were intermediate between those of wild type (WT) and Sost-/-. MicroCT showed greater bone volume fraction in the double knockout mice then Lrp5-/- alone and were intermediate between WT and Sost-/-mice. Femurs from double knockout mice were stronger than those from Lrp5-/- and even WT mice. In the 17-week-old mice the midshaft cortical bone area increased in anti-sclerostin antibody treated Lrp5-/- mice and WT mice. Blocking of Lrp6 reduced bone mass and density in WT mice and reversed the bone gain in Sost-/- and double knockout mice back to WT levels. Conclusions. These findings indicate that inhibiting sclerostin can improve bone mass regardless of Lrp5 mutation. In the absence of Lrp5-/- (OPPG) the anabolic effects of Sost depletion occur via Lrp6[2,3]. These results suggest that humans with OPPG may potentially benefit from anti-sclerostin antibody therapy.
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