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

Nan Yang; Aaron Schindeler; Michelle M. McDonald; Jane T. Seto; Peter J. Houweling; Monkol Lek; Marshall Hogarth; Alyson R. Morse; Joanna M. Raftery; Dominic Balasuriya; Daniel G. MacArthur; Yemima Berman; Kate G. R. Quinlan; John A. Eisman; Tuan V. Nguyen; Jacqueline R. Center; Richard L. Prince; Scott G. Wilson; Kathy Zhu; David G. Little; Kathryn N. North

doi:10.1016/j.bone.2011.07.009

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

Nan Yang^*, Aaron Schindeler, Michelle M. McDonald, Jane T. Seto, Peter J. Houweling, Monkol Lek, Marshall Hogarth, Alyson R. Morse, Joanna M. Raftery, Dominic Balasuriya, Daniel G. MacArthur, Yemima Berman, Kate G. R. Quinlan, John A. Eisman, Tuan V. Nguyen, Jacqueline R. Center, Richard L. Prince, Scott G. Wilson, Kathy Zhu, David G. LittleKathryn N. North

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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. ?-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 ?-actinin-3 protein in approximately 20% of Eurasians. Absence of ?-actinin-3 does not cause any disease phenotypes in muscle because of compensation by ?-actinin-2. However, ?-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for ?-actinin-3 in bone. ?-Actinin-3 but not ?-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.

Original language	English
Pages (from-to)	790-798
Journal	Bone
Volume	49
Issue number	4
DOIs	https://doi.org/10.1016/j.bone.2011.07.009
Publication status	Published - Oct 2011

Keywords

ACTN3
R577X
Bone mass
BMD

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10.1016/j.bone.2011.07.009

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Yang, N., Schindeler, A., McDonald, M. M., Seto, J. T., Houweling, P. J., Lek, M., Hogarth, M., Morse, A. R., Raftery, J. M., Balasuriya, D., MacArthur, D. G., Berman, Y., Quinlan, K. G. R., Eisman, J. A., Nguyen, T. V., Center, J. R., Prince, R. L., Wilson, S. G., Zhu, K., ... North, K. N. (2011). alpha-Actinin-3 deficiency is associated with reduced bone mass in human and mouse. Bone, 49(4), 790-798. https://doi.org/10.1016/j.bone.2011.07.009

@article{616d513a9d0b4506a76df392ef0a2b1b,

title = "alpha-Actinin-3 deficiency is associated with reduced bone mass in human and mouse",

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. ?-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 ?-actinin-3 protein in approximately 20% of Eurasians. Absence of ?-actinin-3 does not cause any disease phenotypes in muscle because of compensation by ?-actinin-2. However, ?-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for ?-actinin-3 in bone. ?-Actinin-3 but not ?-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.",

keywords = "ACTN3, R577X, Bone mass, BMD",

author = "Nan Yang and Aaron Schindeler and McDonald, {Michelle M.} and Seto, {Jane T.} and Houweling, {Peter J.} and Monkol Lek and Marshall Hogarth and Morse, {Alyson R.} and Raftery, {Joanna M.} and Dominic Balasuriya and MacArthur, {Daniel G.} and Yemima Berman and Quinlan, {Kate G. R.} and Eisman, {John A.} and Nguyen, {Tuan V.} and Center, {Jacqueline R.} and Prince, {Richard L.} and Wilson, {Scott G.} and Kathy Zhu and Little, {David G.} and North, {Kathryn N.}",

year = "2011",

month = oct,

doi = "10.1016/j.bone.2011.07.009",

language = "English",

volume = "49",

pages = "790--798",

journal = "Bone",

issn = "8756-3282",

publisher = "Elsevier Inc.",

number = "4",

}

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 2011, 'alpha-Actinin-3 deficiency is associated with reduced bone mass in human and mouse', Bone, vol. 49, no. 4, pp. 790-798. https://doi.org/10.1016/j.bone.2011.07.009

TY - JOUR

T1 - alpha-Actinin-3 deficiency is associated with reduced bone mass in human and mouse

AU - Yang, Nan

AU - Schindeler, Aaron

AU - McDonald, Michelle M.

AU - Seto, Jane T.

AU - Houweling, Peter J.

AU - Lek, Monkol

AU - Hogarth, Marshall

AU - Morse, Alyson R.

AU - Raftery, Joanna M.

AU - Balasuriya, Dominic

AU - MacArthur, Daniel G.

AU - Berman, Yemima

AU - Quinlan, Kate G. R.

AU - Eisman, John A.

AU - Nguyen, Tuan V.

AU - Center, Jacqueline R.

AU - Prince, Richard L.

AU - Wilson, Scott G.

AU - Zhu, Kathy

AU - Little, David G.

AU - North, Kathryn N.

PY - 2011/10

Y1 - 2011/10

N2 - 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. ?-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 ?-actinin-3 protein in approximately 20% of Eurasians. Absence of ?-actinin-3 does not cause any disease phenotypes in muscle because of compensation by ?-actinin-2. However, ?-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for ?-actinin-3 in bone. ?-Actinin-3 but not ?-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.

AB - 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. ?-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 ?-actinin-3 protein in approximately 20% of Eurasians. Absence of ?-actinin-3 does not cause any disease phenotypes in muscle because of compensation by ?-actinin-2. However, ?-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for ?-actinin-3 in bone. ?-Actinin-3 but not ?-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.

KW - ACTN3

KW - R577X

KW - Bone mass

KW - BMD

U2 - 10.1016/j.bone.2011.07.009

DO - 10.1016/j.bone.2011.07.009

M3 - Article

C2 - 21784188

SN - 8756-3282

VL - 49

SP - 790

EP - 798

JO - Bone

JF - Bone

IS - 4

ER -

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

Abstract

Keywords

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