High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes

Paul J. Niziolek, Takeisha L. Farmer, Yajun Cui, Charles H. Turner, Matthew L. Warman, Alexander Robling

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Mutations among genes that participate in the canonical Wnt signaling pathway can lead to drastically different skeletal phenotypes, ranging from severe osteoporosis to severe osteosclerosis. Many high-bone-mass (HBM) causing mutations that occur in the LRP5 gene appear to impart the HBM phenotype, in part, by increasing resistance to soluble Wnt signaling inhibitors, including sclerostin. Sost loss-of-function mutant mice (Sost knock-out) and Lrp5 gain-of-function mutant mice (Lrp5 HBM knock-in) have high bone mass. These mutants potentially would be predicted to be phenocopies of one another, because in both cases, the sclerostin-Lrp5 interaction is disrupted. We measured bone mass, size, geometry, architecture, and strength in bones from three different genetic mouse models (Sost knock-out, Lrp5 A214V knock-in, and Lrp5 G171V knock-in) of HBM. We found that all three mouse lines had significantly elevated bone mass in the appendicular skeleton and in the cranium. Sost mutants and Lrp5 A214V mutants were statistically indistinguishable from one another in most endpoints, whereas both were largely different from the Lrp5 G171V mutants. Lrp5 G171V mutants preferentially added bone endocortically, whereas Lrp5 A214V and Sost mutants preferentially added bone periosteally. Cranial thickness and cranial nerve openings were similarly altered in all three HBM models. We also assessed serum serotonin levels as a possible mechanism accounting for the observed changes in bone mass, but no differences in serum serotonin were found in any of the three HBM mouse lines. The skeletal dissimilarities of the Lrp5 G171V mutant to the other mutants suggest that other, non-sclerostin-associated mechanisms might account for the changes in bone mass resulting from this mutation.

Original languageEnglish
Pages (from-to)1010-1019
Number of pages10
JournalBone
Volume49
Issue number5
DOIs
StatePublished - Nov 2011

Fingerprint

Wnt Signaling Pathway
Phenotype
Bone and Bones
Mutation
Serotonin
Osteosclerosis
Cranial Nerves
Genetic Models
Serum
Skull
Skeleton
Knockout Mice
Genes
Osteoporosis

Keywords

  • High bone mass
  • Lrp5
  • Sclerostin
  • Sost
  • Wnt

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes. / Niziolek, Paul J.; Farmer, Takeisha L.; Cui, Yajun; Turner, Charles H.; Warman, Matthew L.; Robling, Alexander.

In: Bone, Vol. 49, No. 5, 11.2011, p. 1010-1019.

Research output: Contribution to journalArticle

Niziolek, Paul J. ; Farmer, Takeisha L. ; Cui, Yajun ; Turner, Charles H. ; Warman, Matthew L. ; Robling, Alexander. / High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes. In: Bone. 2011 ; Vol. 49, No. 5. pp. 1010-1019.
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