The Effects of Sclerostin Depletion in Osteoporosis-Pseudoglioma syndrome
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.
- Alonso N, Soares D, McCloskey E, Summers G, Ralston S, Gregson Atypical femoral fracture in osteoporosis pseudoglioma syndrome associated with two novel compound heterozygous mutations in LRP5. Journal of Bone and Mineral Research 2015;30(4):615-620.
- Chang M, Kramer I, Keller H, Gooi J, Collett C, Jenkins D, Ettenberg S, Cong F, Halleux C, kneissel Reversing LRP5-Dependent Osteoporosis and SOST Deficiency-Induced Sclerosing Bone Disorders by Altering WNT Signaling Activity. Journal of Bone and Mineral Research 2014;29(1):29-42.
- Kedlaya R, Veera S, Horan D, Moss R, Ayturk U, Jacobsen C, Bowen M, Paszty C, Warman M, Robling Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome. Science translational medicine 2013;5(211):211ra158-211ra158.
- Monroe D, McGee-Lawrence M, Oursler M, Westendorf Update on Wnt signaling in bone cell biology and bone disease. Gene 2012;492(1):1-18.