title: α-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. 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.
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney 2145, NSW, Australia. nan.yang@persongen.com
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
authors.forename: Michelle M
authors.initials: MM
authors.lastname: McDonald
authors.forename: Jane T
authors.initials: JT
authors.lastname: Seto
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houweling
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.forename: Marshall
authors.initials: M
authors.lastname: Hogarth
authors.forename: Alyson R
authors.initials: AR
authors.lastname: Morse
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Raftery
authors.forename: Dominic
authors.initials: D
authors.lastname: Balasuriya
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Yemima
authors.initials: Y
authors.lastname: Berman
authors.forename: Kate G R
authors.initials: KG
authors.lastname: Quinlan
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.forename: Tuan V
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Center
authors.forename: Richard L
authors.initials: RL
authors.lastname: Prince
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Kathy
authors.initials: K
authors.lastname: Zhu
authors.forename: David G
authors.initials: DG
authors.lastname: Little
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D015502:Absorptiometry, Photon; D000185:Actinin / Q000172:deficiency* / Q000378:metabolism; D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D015519:Bone Density; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009929:Organ Size; D010012:Osteogenesis; D013234:Stem Cells / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: C118456:ACTN3 protein, human; C525925:Actn3 protein, mouse; D000185:Actinin