α-Actinin-3 deficiency is associated with reduced bone mass in human and mouse

Yang, N; Schindeler, A; McDonald, MM; Seto, JT; Houweling, PJ; Lek, M; Hogarth, M; Morse, AR; Raftery, JM; Balasuriya, D; MacArthur, DG; Berman, Y; Quinlan, KGR; Eisman, JA; Nguyen, TV; Center, JR; Prince, RL; Wilson, SG; Zhu, K; Little, DG; North, KN

α-Actinin-3 deficiency is associated with reduced bone mass in human and mouse

Yang, N Schindeler, A McDonald, MM Seto, JT Houweling, PJ Lek, M Hogarth, M Morse, AR Raftery, JM Balasuriya, D MacArthur, DG Berman, Y Quinlan, KGR Eisman, JA Nguyen, TV

Center, JR Prince, RL Wilson, SG Zhu, K Little, DG North, KN

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Publication Type:: Journal Article
Citation:: Bone, 2011, 49 (4), pp. 790 - 798
Issue Date:: 2011-10-01

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Field	Value	Language
dc.contributor.author	Yang, N	en_US
dc.contributor.author	Schindeler, A	en_US
dc.contributor.author	McDonald, MM	en_US
dc.contributor.author	Seto, JT	en_US
dc.contributor.author	Houweling, PJ	en_US
dc.contributor.author	Lek, M	en_US
dc.contributor.author	Hogarth, M	en_US
dc.contributor.author	Morse, AR	en_US
dc.contributor.author	Raftery, JM	en_US
dc.contributor.author	Balasuriya, D	en_US
dc.contributor.author	MacArthur, DG	en_US
dc.contributor.author	Berman, Y	en_US
dc.contributor.author	Quinlan, KGR	en_US
dc.contributor.author	Eisman, JA	en_US
dc.contributor.author	Nguyen, TV https://orcid.org/0000-0002-3246-6281	en_US
dc.contributor.author	Center, JR	en_US
dc.contributor.author	Prince, RL	en_US
dc.contributor.author	Wilson, SG	en_US
dc.contributor.author	Zhu, K	en_US
dc.contributor.author	Little, DG	en_US
dc.contributor.author	North, KN	en_US
dc.date.available	2011-07-07	en_US
dc.date.issued	2011-10-01	en_US
dc.identifier.citation	Bone, 2011, 49 (4), pp. 790 - 798	en_US
dc.identifier.issn	8756-3282	en_US
dc.identifier.uri	http://hdl.handle.net/10453/28728
dc.description.abstract	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.	en_US
dc.relation.ispartof	Bone	en_US
dc.relation.isbasedon	10.1016/j.bone.2011.07.009	en_US
dc.subject.classification	Endocrinology & Metabolism	en_US
dc.subject.mesh	Bone and Bones	en_US
dc.subject.mesh	Bone Marrow Cells	en_US
dc.subject.mesh	Stromal Cells	en_US
dc.subject.mesh	Stem Cells	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Bone Resorption	en_US
dc.subject.mesh	Actinin	en_US
dc.subject.mesh	Tomography, X-Ray Computed	en_US
dc.subject.mesh	Absorptiometry, Photon	en_US
dc.subject.mesh	Organ Size	en_US
dc.subject.mesh	Analysis of Variance	en_US
dc.subject.mesh	Cohort Studies	en_US
dc.subject.mesh	Osteogenesis	en_US
dc.subject.mesh	Bone Density	en_US
dc.subject.mesh	Adolescent	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.title	α-Actinin-3 deficiency is associated with reduced bone mass in human and mouse	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	49	en_US
utslib.for	110306 Endocrinology	en_US
utslib.for	0903 Biomedical Engineering	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	09 Engineering	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	49	en_US

Abstract:

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.

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http://hdl.handle.net/10453/28728