Inactivation of Lrp5 in osteocytes reduces Young's modulus and responsiveness to the mechanical loading

Liming Zhao, Joon W. Shim, Todd R. Dodge, Alexander Robling, Hiroki Yokota

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of-function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in the bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre;Lrp5f/f) would alter responses to ulna loading. Loading was applied to the right ulna for 3min (360cycles at 2Hz) at a peak force of 2.65N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young's modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young's modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young's modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass.

Original languageEnglish
Pages (from-to)35-43
Number of pages9
JournalBone
Volume54
Issue number1
DOIs
StatePublished - May 2013

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-5
Osteocytes
Elastic Modulus
Ulna
Bone Density
Bone and Bones
Mutation
Wnt Receptors
Maintenance
Bone Development
Osteogenesis
Femur
Minerals

Keywords

  • Lrp5
  • Mechanotransduction
  • Osteocytes
  • Osteoporosis
  • Young's modulus

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Inactivation of Lrp5 in osteocytes reduces Young's modulus and responsiveness to the mechanical loading. / Zhao, Liming; Shim, Joon W.; Dodge, Todd R.; Robling, Alexander; Yokota, Hiroki.

In: Bone, Vol. 54, No. 1, 05.2013, p. 35-43.

Research output: Contribution to journalArticle

Zhao, Liming ; Shim, Joon W. ; Dodge, Todd R. ; Robling, Alexander ; Yokota, Hiroki. / Inactivation of Lrp5 in osteocytes reduces Young's modulus and responsiveness to the mechanical loading. In: Bone. 2013 ; Vol. 54, No. 1. pp. 35-43.
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abstract = "Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of-function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in the bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre;Lrp5f/f) would alter responses to ulna loading. Loading was applied to the right ulna for 3min (360cycles at 2Hz) at a peak force of 2.65N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young's modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young's modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52{\%}, 85{\%}, and 69{\%}, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young's modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass.",
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