LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders.
The LDL receptor-related protein 5 (LRP5) is a member of the LDL receptor family, which also includes the VLDL receptor and the apolipoprotein E receptor 2. The LRP5 is a co-receptor of Wnt located on the osteoblast membrane between two other receptors, Frizzled and Kremen. Frizzled and LRP5 bind to Wnt, thereby stabilizing beta-catenin and activating bone formation. When the dickkopf protein (Dkk) binds to Kremen and LRP5, this last undergoes internalization and therefore becomes unable to bind Wnt; this leads to degradation of beta-catenin and to inhibition of bone formation. In humans, loss of LRP5 function causes osteoporosis-pseudoglioma syndrome, which is characterized by congenital blindness and extremely severe childhood-onset osteoporosis (lumbar spine Z-score often < -4) with fractures. The G171V mutation prevents Dkk from binding to LRP5, thereby increasing LRP5 function; the result is high bone mass due to uncoupling of bone formation and resorption. The Z-scores in this condition can exceed +6 at the hip and spine. The LRP5 and Wnt/beta-catenin reflect the level of bone formation and play a central role in bone mass accrual and normal distribution. Furthermore, LRP5 may contribute to mediate mechanical loads within bone tissue. Identification of the Wnt/beta-catenin pathway is a breakthrough in the elucidation of pathophysiological mechanisms affecting bone tissue and suggests new treatment targets for patients with osteoporosis or specific malignant conditions such as myeloma and sclerotic bone metastases.
Levasseur
Régis
R
Rheumatology Department, Angers Teaching Hospital, 49933 Angers cedex 9, France. ReLevasseur@chu-angers.fr
Lacombe
Didier
D
de Vernejoul
Marie Christine
MC
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism*; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005128:Eye Diseases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D015398:Signal Transduction; D013577:Syndrome; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin