Research ArticleBONE DISEASE

Sclerostin Inhibition Reverses Skeletal Fragility in an Lrp5-Deficient Mouse Model of OPPG Syndrome

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Science Translational Medicine  13 Nov 2013:
Vol. 5, Issue 211, pp. 211ra158
DOI: 10.1126/scitranslmed.3006627

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Building Stronger Bones

Osteoporosis pseudoglioma syndrome (OPPG) is a rare genetic condition caused by an autosomal recessive mutation in LRP5, which contributes to regulation of bone mineral density. This mutation results in severely thinner, brittle bones—osteoporosis. Most therapies for osteoporosis aim at inhibiting bone loss; however, in OPPG patients, bone resorption is normal but bone formation is markedly reduced, which suggests that anabolic therapies that promote bone formation may be more beneficial. Now, Kedlaya et al. examine the effects of the anabolic therapy sclerostin neutralization in an OPPG animal model.

Sclerostin inhibits bone formation by binding to LRP5/6. Thus, although neutralizing sclerostin seemed a promising anabolic track for general osteoporosis patients, it was predicted to be less effective for OPPG patients with mutated LRP5. The authors tested this hypothesis in an LRP5-deficient mouse model. They found through both genetic and therapeutic experiments that sclerostin neutralization can improve bone mineral density even in the absence of functional LRP5. These data support the advent of clinical trials for sclerostin neutralization in OPPG patients.

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