Bone microstructural defects and osteopenia in hemizygous βIVSII-654 knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function.
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.
Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Exercise Science Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand; and.
Kanogwun
K
Thongchote
Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Thailand.
Saovaros
S
Svasti
Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
Jarinthorn
J
Teerapornpuntakit
Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand;
Panan
P
Suntornsaratoon
Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
Nateetip
N
Krishnamra
Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; naratt@narattsys.com.
Narattaphol
N
Charoenphandhu
D000375:Aging; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D055598:Chemical Phenomena; D003433:Crosses, Genetic; D005260:Female; D005452:Fluoresceins / Q000008:administration & dosage / Q000737:chemistry; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D055879:Gene Knock-In Techniques; D006132:Growth Plate / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D007279:Injections, Subcutaneous; D008297:Male; D055595:Mechanical Phenomena; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D010024:Osteoporosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012727:Sex Characteristics; D017086:beta-Thalassemia / Q000503:physiopathology*
D005452:Fluoresceins; D005456:Fluorescent Dyes; C007740:fluorexon
bone histomorphometry; bone mineral density; osteoporosis; β-thalassemia