Expression of the Hutchinson-Gilford progeria mutation during osteoblast development results in loss of osteocytes, irregular mineralization, and poor biomechanical properties.
Hutchinson-Gilford progeria syndrome (HGPS) is a very rare genetic disorder that is characterized by multiple features of premature aging and largely affects tissues of mesenchymal origin. In this study, we describe the development of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C>T, p.G608G) in osteoblasts. Already at the age of 5 weeks, HGPS mutant mice show growth retardation, imbalanced gait and spontaneous fractures. Histopathological examination revealed an irregular bone structure, characterized by widespread loss of osteocytes, defects in mineralization, and a hypocellular red bone marrow. Computerized tomography analysis demonstrated impaired skeletal geometry and altered bone structure. The skeletal defects, which resemble the clinical features reported for bone disease in HGPS patients, was associated with an abnormal osteoblast differentiation. The osteoblast-specific expression of the HGPS mutation increased DNA damage and affected Wnt signaling. In the teeth, irregular dentin formation, as was previously demonstrated in human progeria cases, caused severe dental abnormalities affecting the incisors. The observed phenotype also shows similarities to reported bone abnormalities in aging mice and may therefore help to uncover general principles of the aging process.
Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet, Huddinge SE-14183, Sweden.
Eva
E
Schmidt
Ola
O
Nilsson
Antti
A
Koskela
Juha
J
Tuukkanen
Claes
C
Ohlsson
Björn
B
Rozell
Maria
M
Eriksson
D000375:Aging; D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D006801:Humans; D034904:Lamin Type A; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology; D011371:Progeria / Q000235:genetics* / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D051153:Wnt Proteins; C090764:prelamin A