alpha-Actinin-3 deficiency is associated with reduced bone mass in human and mouse
| Autor: | Richard L. Prince, Yemima Berman, Scott Wilson, Nan Yang, Monkol Lek, David G. Little, Michelle M. McDonald, Kate G. R. Quinlan, Joanna M. Raftery, Jane T. Seto, Tuan V. Nguyen, Alyson Morse, Peter J. Houweling, Kathy Zhu, Marshall W. Hogarth, Aaron Schindeler, Daniel G. MacArthur, Kathryn N. North, John A. Eisman, Dominic Balasuriya |
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| Přispěvatelé: | Family Medicine, RS: CAPHRI School for Public Health and Primary Care |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Histology Bone density Adolescent Physiology Endocrinology Diabetes and Metabolism Population R577X Bone Marrow Cells Biology Bone and Bones Bone remodeling ACTN3 Cohort Studies Endocrinology & Metabolism Mice Absorptiometry Photon Osteoclast Osteogenesis Bone Density BMD Internal medicine Genetic model medicine Animals Humans Actinin Bone Resorption education Aged Bone mineral Aged 80 and over education.field_of_study Analysis of Variance Stem Cells Osteoblast Organ Size Middle Aged Mice Inbred C57BL Bone mass medicine.anatomical_structure Endocrinology Cortical bone Female Stromal Cells Tomography X-Ray Computed |
| Zdroj: | Bone, 49(4), 790-798. Elsevier Science |
| ISSN: | 8756-3282 |
| Popis: | Bone mineral density (BMD) is a complex trait that is the single best predictor of the risk of osteoporotic fractures. Candidate gene and genome-wide association studies have identified genetic variations in approximately 30 genetic loci associated with BMD variation in humans. α-Actinin-3 (ACTN3) is highly expressed in fast skeletal muscle fibres. There is a common null-polymorphism R577X in human ACTN3 that results in complete deficiency of the α-actinin-3 protein in approximately 20% of Eurasians. Absence of α-actinin-3 does not cause any disease phenotypes in muscle because of compensation by α-actinin-2. However, α-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for α-actinin-3 in bone. α-Actinin-3 but not α-actinin-2 is expressed in osteoblasts. The Actn3 -/- mouse displays significantly reduced bone mass, with reduced cortical bone volume (-14%) and trabecular number (-61%) seen by microCT. Dynamic histomorphometry indicated this was due to a reduction in bone formation. In a cohort of postmenopausal Australian women, ACTN3 577XX genotype was associated with lower BMD in an additive genetic model, with the R577X genotype contributing 1.1% of the variance in BMD. Microarray analysis of cultured osteoprogenitors from Actn3 -/- mice showed alterations in expression of several genes regulating bone mass and osteoblast/osteoclast activity, including Enpp1, Opg and Wnt7b. Our studies suggest that ACTN3 likely contributes to the regulation of bone mass through alterations in bone turnover. Given the high frequency of R577X in the general population, the potential role of ACTN3 R577X as a factor influencing variations in BMD in elderly humans warrants further study. © 2011 Elsevier Inc. |
| Databáze: | OpenAIRE |
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