Pathogenic mutations and polymorphisms in the lipoprotein receptor-related protein 5 reveal a new biological pathway for the control of bone mass.
OBJECTIVE
This review summarizes recent findings concerning the genomic variations of the lipoprotein receptor-related protein 5 (LPR5) in relation to bone biology.


RESULTS
Mutations in the LRP5 gene causing high bone mass (HBM) and osteoporosis-pseudoglioma (OPPG) underscored the role of the Wnt-LRP5 canonical signaling on bone formation. Additional LRP5 activating mutations have been identified in a variety of sclerosing bone dysplasias, improving the diagnostic classification of these disorders. Association of polymorphisms in LRP5 with bone mineral density indicate that LRP5 genetic variation contribute to the risk of osteoporosis. Transgenic mice carrying the LRP5 HBM mutation have improved bone biomechanical properties, and the molecular mechanisms by which this mutation exerts its effects have been clarified. A number of KO mice have shown the complex effects of the Wnt-LRP5 pathway on bone mass and skeletal morphology. In vitro studies indicate that osteoblasts produce a variety of Wnts, the LRP5 co-receptor frizzled (Fzd), as well as LRP5 and Wnt inhibitors, i.e. dickkopf (Dkk1) and frizzled-related proteins (Sfrps), respectively, and delineate the role of these molecules in regulating the commitment of mesenchymal stem cells along the osteoblastic lineage.


CONCLUSIONS
Identification of pathogenic mutations and allelic variations in LRP5 has improved our understanding of the physiology of bone mass acquisition and the pathophysiology of several bone diseases, including osteoporosis. Understanding how complex interactions between agonistic and inhibitory factors in the Wnt-LRP5 canonical pathway influence osteoblast functions has the potential of providing new anabolic treatments for osteoporosis.
Ferrari
Serge L
SL
Division of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospital, Geneva, Switzerland. serge.ferrari@medicine.unige.ch
Deutsch
Samuel
S
Antonarakis
Stylianos E
SE
D000483:Alleles; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D051379:Mice; D009154:Mutation; D011110:Polymorphism, Genetic; D051153:Wnt Proteins
D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D051153:Wnt Proteins