Replication of Caucasian Loci Associated with Osteoporosis-related Traits in East Asians

Kim, Beom-Jun; Ahn, Seong Hee; Kim, Hyeon-Mok; Ikegawa, Shiro; Yang, Tie‐Lin; Guo, Yan; Deng, Hong‐Wen; Koh, Jung‐Min; Lee, Seung Hun

doi:10.11005/jbm.2016.23.4.233

Cited by 10 publications

(11 citation statements)

References 21 publications

(37 reference statements)

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“…Bone regeneration is accelerated by activation of the Wnt/β-catenin signaling pathway 13 . Aberrant expression of CTNNB1, which is the gene that encodes β-catenin, is a frequent cause of altered Wnt signaling and has been reported to be strongly associated with a wide spectrum of cancers 14 as well as osteoporosis 15 , 16 . Bone anabolic therapy targeting the Wnt/β-catenin pathway, particularly CTNNB1, represents a novel antiresorptive strategy for osteoporosis treatment 17 .…”

Section: Introductionmentioning

confidence: 99%

LncRNA DANCR and miR-320a suppressed osteogenic differentiation in osteoporosis by directly inhibiting the Wnt/β-catenin signaling pathway

Wang

et al. 2020

Exp Mol Med

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Our study aimed to determine how lncRNA DANCR, miR-320a, and CTNNB1 interact with each other and regulate osteogenic differentiation in osteoporosis. qRT-PCR and western blotting were performed to determine the expression of DANCR, miR-320a, CTNNB1, and the osteoporosis- or Wnt/β-catenin pathway-related markers T-cell factor 1 (TCF-1), runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). Interactions between CTNNB1, DANCR, and miR-320a were predicted by bioinformatics approaches and validated using a luciferase assay. Osteoblastic phenotypes were evaluated by ALP staining, ALP activity assay and Alizarin Red staining. The bilateral ovariectomy method was used to establish an in vivo osteoporosis model. Bone morphological changes were examined using hematoxylin and eosin (H&E) and Alcian Blue staining. The expression levels of DANCR and miR-320a in BMSCs derived from osteoporosis patients were upregulated, whereas CTNNB1 expression was downregulated compared with that in healthy controls. Importantly, we demonstrated that miR-320a and DANCR acted independently from each other and both inhibited CTNNB1 expression, whereas the inhibitory effect was additive when miR-320a and DANCR were cooverexpressed. Moreover, we found that DANCR overexpression largely abrogated the effect of the miR-320a inhibitor on CTNNB1 expression and the Wnt/β-catenin signaling pathway in BMSCs during osteogenic differentiation. We further confirmed the results above in BMSCs derived from an osteoporosis animal model. Taken together, our findings revealed that DANCR and miR-320a regulated the Wnt/β-catenin signaling pathway during osteogenic differentiation in osteoporosis through CTNNB1 inhibition. Our results highlight the potential value of DANCR and miR-320a as promising therapeutic targets for osteoporosis treatment.

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Section: Introductionmentioning

confidence: 99%

LncRNA DANCR and miR-320a suppressed osteogenic differentiation in osteoporosis by directly inhibiting the Wnt/β-catenin signaling pathway

Wang

et al. 2020

Exp Mol Med

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“…Recently, a mutation in the forkhead gene ( FOXL1 ) was identified as the causative gene of autosomal dominant otosclerosis in a large Newfoundland family [ 35 ], and previous studies have associated this gene with osteoporosis [ 36 , 37 , 38 , 39 ]. In animal models, foxl1 is expressed in the paraxial mesoderm and NCCs of pharyngeal arches, and is a downstream target of both BMP and Hh signalling [ 40 , 41 ], yet few studies have examined foxl1’s role in bone development and remodelling of the craniofacial and axial skeleton.…”

Section: Introductionmentioning

confidence: 99%

Mutation of foxl1 Results in Reduced Cartilage Markers in a Zebrafish Model of Otosclerosis

Hawkey-Noble

Pater

Kollipara

et al. 2022

Genes

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Bone diseases such as otosclerosis (conductive hearing loss) and osteoporosis (low bone mineral density) can result from the abnormal expression of genes that regulate cartilage and bone development. The forkhead box transcription factor FOXL1 has been identified as the causative gene in a family with autosomal dominant otosclerosis and has been reported as a candidate gene in GWAS meta-analyses for osteoporosis. This potentially indicates a novel role for foxl1 in chondrogenesis, osteogenesis, and bone remodelling. We created a foxl1 mutant zebrafish strain as a model for otosclerosis and osteoporosis and examined jaw bones that are homologous to the mammalian middle ear bones, and mineralization of the axial skeleton. We demonstrate that foxl1 regulates the expression of collagen genes such as collagen type 1 alpha 1a and collagen type 11 alpha 2, and results in a delay in jawbone mineralization, while the axial skeleton remains unchanged. foxl1 may also act with other forkhead genes such as foxc1a, as loss of foxl1 in a foxc1a mutant background increases the severity of jaw calcification phenotypes when compared to each mutant alone. Our zebrafish model demonstrates atypical cartilage formation and mineralization in the zebrafish craniofacial skeleton in foxl1 mutants and demonstrates that aberrant collagen expression may underlie the development of otosclerosis.

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“…The variant c.3781C>A (rs1026364; RefSeq NM_001009899.2) located in 3′‐untranslated region (3′‐UTR) of upstream transcription factor family member 3 ( USF3 ), previously known as KIAA2018 , [MIM# 617568]) has been associated with femoral neck BMD ( p = 4.1 × 10 −10 ) in genome‐wide meta‐analysis (Styrkarsdottir et al, ) and replication studies (Kim et al, ; Paternoster et al, ; Warrington, Kemp, Tilling, Tobias, & Evans, ). However, the molecular mechanism by which the c.3781C>A variant influences BMD and osteoporosis risk is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…[MIM# 617568]) has been associated with femoral neck BMD (p = 4.1 × 10 −10 ) in genome-wide meta-analysis (Styrkarsdottir et al, 2008) and replication studies (Kim et al, 2016;Paternoster et al, 2013;Warrington, Kemp, Tilling, Tobias, & Evans, 2015). However, the molecular mechanism by which the c.3781C>A variant influences BMD and osteoporosis risk is unknown.…”

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confidence: 99%

Osteoporosis genome‐wide association study variant c.3781 C>A is regulated by a novel anti‐osteogenic factor miR‐345‐5p

Liu

et al. 2020

Human Mutation

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Upstream transcription factor family member 3 (USF3) c.3781C>A (rs1026364) in the 3′-untranslated region (3′-UTR) has been firmly associated with bone mineral density (BMD) in genome-wide association study (GWAS). However, the molecular mechanism by which it influences BMD and osteoporosis is unknown. Bioinformatics analyses suggested that the risk c.3781A allele creates a target site for hsa-miR-345-5pbinding. Luciferase assay validated that the c.3781A allele displayed significantly lower luciferase activities than the c.3781C allele in the human osteoblast cell line hFOB1.19, osteosarcoma cell lines U-2OS and Saos-2, and embryonic kidney cell line 293T. Furthermore, hsa-miR-345-5p regulated USF3 expression on both messenger RNA and protein levels in hFOB1.19 and U937 cells with heterozygous A/C genotype.Transfection of hsa-miR-345-5p antagomiR in heterozygous hFOB1.19 cells significantly increased the expression of osteogenic marker genes RUNX2, OSTERIX, COL1A1, ALP, OPN, OCN, and alkaline phosphatase activity and matrix mineralization level. Importantly, we found that hsa-miR-345-5p also inhibits osteoblast maturation in cell lines U-2OS with hsa-miR-345-5p nonbinding C/C genotype by targeting RUNX3 and SMAD1. Our findings uncovered a novel pathogenetic mechanism of osteoporosis by GWAS variant c.3781C>A-mediated disruption of hsa-miR-345-5p binding at the 3′-UTR of USF3 and the functional role of hsa-miR-345-5p in osteogenic differentiation. K E Y W O R D SGWAS SNP, miR-345-5p, osteoporosis, RUNX3, SMAD1, USF3

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Replication of Caucasian Loci Associated with Osteoporosis-related Traits in East Asians

Cited by 10 publications

References 21 publications

LncRNA DANCR and miR-320a suppressed osteogenic differentiation in osteoporosis by directly inhibiting the Wnt/β-catenin signaling pathway

LncRNA DANCR and miR-320a suppressed osteogenic differentiation in osteoporosis by directly inhibiting the Wnt/β-catenin signaling pathway

Mutation of foxl1 Results in Reduced Cartilage Markers in a Zebrafish Model of Otosclerosis

Osteoporosis genome‐wide association study variant c.3781 C>A is regulated by a novel anti‐osteogenic factor miR‐345‐5p

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