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Genetically engineered missense mutations in β‐propeller 1 of the low‐density‐lipoprotein receptor‐related protein 5 (LRP5) induce high bone mass and strength
Author(s) -
Niziolek Paul Joseph,
Cui Yajun,
Warman Matthew L.,
Robling Alexander G.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb16
Subject(s) - lrp5 , missense mutation , endocrinology , bone mineral , medicine , mutant , osteoporosis , ldl receptor , bone density , biology , wild type , wnt signaling pathway , mutation , lipoprotein , genetics , gene , cholesterol
The low‐density‐lipoprotein receptor‐related protein 5 (LRP5), a co‐receptor in the Wnt signaling pathway, has been implicated as an important modulator of bone mass. Among humans, a loss of function mutation in LRP5 results in a severe osteoporotic disease, while certain missense mutations in the gene result in a high bone mass (HBM) phenotype. To explore the role of the HBM mutation in skeletal development and function, we have inserted (knocked‐in) two missense LRP5 mutations, A214V and G171V, into mice. We measured areal bone mineral density (aBMD) in vivo from 4.5 weeks to 16.5 weeks of age, and found that HBM mice had a 13‐26% greater aBMD at 4.5 weeks of age when compared to age‐matched wild‐type relatives. These gains were further increased to 28‐47% greater aBMD, compared to wild‐type, at 16.5 weeks of age. We also compared 16 wk old male HBM mice to their wild‐type relatives for bone structural differences. We found significant increases in skull thickness and vertebral trabecular bone parameters. We also found significantly increased femoral bone strength as determined by three‐point bending tests. In summary, we have created two strains of Lrp5 missense mutant mice that model the human high bone mass phenotypes. Supported by NIH AR‐53237 and Indiana CTSI.