title: Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5.
abstract: CONCLUSIONS
  We compared circulating levels of Wnt inhibitors among patients with high bone mass mutations in LRP5, unaffected kindred, and unrelated normal controls. Inhibitors were unchanged in affected and unaffected kindred. We saw no meaningful differences between controls and affected individuals. LRP5 signaling may not influence circulating levels of these inhibitors.
  
  
  BACKGROUND
  It is thought that gain-of-function mutations in LRP5 result in high bone mass syndromes because these allelic variants confer resistance to the actions of endogenous inhibitors of Wnt signaling. We therefore attempted to determine if circulating levels of Wnt inhibitors are altered in patients with gain-of-function mutations in LRP5.
  
  
  METHODS
  This is a cross-sectional study in a university research center. Serum was collected from consented volunteers known to have either the G171V or N198S gain-of-function mutations in LRP5, kindred members affected with either mutation, unrelated kindred, and unrelated normal age-matched controls. BMD was provided or measured on site.
  
  
  RESULTS
  There were no significant differences found in the serum levels of sclerostin (SOST), Dickkopf-1 (Dkk-1), or secreted frizzled-related protein-4 (SFRP-4) in affected vs. unaffected individuals from different kindreds or when compared to age-matched unrelated normal individuals. Mean serum SOST values in affected and unaffected kindred members and unrelated normal controls were 52.7 ± 6.1, 36.5 ± 9.6, and 54.8 ± 5.4, respectively. For Dkk-1, the values were 25.9 ± 3.4, 25.7 ± 3.0, and 17.3 ± 2.3 and for SFRP-4, 38.1 ± 2.3, 39.8 ± 3.6, and 28.5 ± 1.7. Serum levels of RANKL and osteoprotegerin (OPG) were not different in the three groups.
  
  
  CONCLUSIONS
  Circulating levels of endogenous Wnt inhibitors do not change in patients with gain-of-function mutations in LRP5 including Dkk1, which is suppressed by Wnt signaling. It may be that circulating levels of Wnt inhibitors do not reflect changes in target tissues. It is also possible that other mechanisms besides or in addition to resistance in Wnt inhibitors explains the skeletal effects of these mutations.
authors.affiliation: Department of Medicine, Section of Endocrinology, Yale School of Medicine, 330 Cedar Street, P.O.Box 208020, New Haven, CT, 06520-8020, USA, christine.simpson@yale.edu.
authors.forename: C A
authors.initials: CA
authors.lastname: Simpson
authors.forename: D
authors.initials: D
authors.lastname: Foer
authors.forename: G S
authors.initials: GS
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Bihuniak
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.forename: R
authors.initials: R
authors.lastname: Sullivan
authors.forename: J
authors.initials: J
authors.lastname: Belsky
authors.forename: K L
authors.initials: KL
authors.lastname: Insogna
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D015519:Bone Density / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053244:Osteoprotegerin / Q000097:blood; D011518:Proto-Oncogene Proteins / Q000097:blood; D053245:RANK Ligand / Q000097:blood; D012727:Sex Characteristics; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D053244:Osteoprotegerin; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; C501126:DKK1 protein, human; C555482:LRP5 protein, human; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C422903:SOST protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human