Bone microstructural defects and osteopenia in hemizygous βIVSII-654 knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function

Am J Physiol Endocrinol Metab. 2015 Dec 1;309(11):E936-48. doi: 10.1152/ajpendo.00329.2015. Epub 2015 Oct 20.

Abstract

β-Thalassemia, a hereditary anemic disorder, is often associated with skeletal complications that can be found in both males and females. The present study aimed to investigate the age- and sex-dependent changes in bone mineral density (BMD) and trabecular microstructure in β(IVSII-654) knockin thalassemic mice. Dual-energy X-ray absorptiometry and computer-assisted bone histomorphometry were employed to investigate temporal changes in BMD and histomorphometric parameters in male and female mice of a β(IVSII-654) knockin mouse model of human β-thalassemia, in which impaired splicing of β-globin transcript was caused by hemizygous C→T mutation at nucleotide 654 of intron 2. Young, growing β(IVSII-654) mice (1 mo old) manifested shorter bone length and lower BMD than their wild-type littermates, indicating possible growth retardation and osteopenia, the latter of which persisted until 8 mo of age (adult mice). Interestingly, two-way analysis of variance suggested an interaction between sex and β(IVSII-654) genotype, i.e., more severe osteopenia in adult female mice. Bone histomorphometry further suggested that low trabecular bone volume in male β(IVSII-654) mice, particularly during a growing period (1-2 mo), was primarily due to suppression of bone formation, whereas both a low bone formation rate and a marked increase in osteoclast surface were observed in female β(IVSII-654) mice. In conclusion, osteopenia and trabecular microstructural defects were present in both male and female β(IVSII-654) knockin thalassemic mice, but the severity, disease progression, and cellular mechanism differed between the sexes.

Keywords: bone histomorphometry; bone mineral density; osteoporosis; β-thalassemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Bone Density
  • Bone and Bones / chemistry
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Chemical Phenomena
  • Crosses, Genetic
  • Female
  • Fluoresceins / administration & dosage
  • Fluoresceins / chemistry
  • Fluorescent Dyes / administration & dosage
  • Fluorescent Dyes / chemistry
  • Gene Knock-In Techniques
  • Growth Plate / chemistry
  • Growth Plate / metabolism
  • Growth Plate / pathology
  • Injections, Subcutaneous
  • Male
  • Mechanical Phenomena
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Osteoclasts / metabolism
  • Osteoclasts / pathology*
  • Osteoporosis / etiology*
  • Osteoporosis / metabolism
  • Osteoporosis / pathology
  • Osteoporosis / physiopathology
  • Sex Characteristics
  • beta-Thalassemia / physiopathology*

Substances

  • Fluoresceins
  • Fluorescent Dyes
  • fluorexon