SLAT Negatively Regulates RANKL-Induced Osteoclast Differentiation

Youn, Bang Ung; Kim, Kabsun; Kim, Jung Ha; Lee, Jongwon; Moon, Jang Bae; Kim, In-Young; Park, Yong-Wook; Kim, Nacksung

doi:10.1007/s10059-013-0159-x

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…Its regulation mechanism is reported to act through its differential regulation of transforming growth factor (TGF)‐β and bone morphogenetic protein (BMP) bioavailability in bone, where both TGF‐β and BMP signaling pathways play a critical role in bone development. Differentially expressed in FDCP 6 homolog ( DEF6 ) at 6p21.31 modulates RANKL‐induced osteoclast differentiation in vitro and in vivo . DEF6 deficiency enables TNF‐alpha alone to induce osteoclastogenesis in the absence of RANKL, and it markedly enhances TNF‐α–induced osteoclastogenesis and bone resorption .…”

Section: Resultsmentioning

confidence: 99%

Joint Association Analysis Identified 18 New Loci for Bone Mineral Density

Pei

Liu

et al. 2019

Journal of Bone and Mineral Research

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Bone mineral density (BMD) at various skeletal sites have shared genetic determinants. In the present study, aiming to identify shared loci associated with BMD, we conducted a joint association study of a genomewide association study (GWAS) and a metaanalysis of BMD at different skeletal sites: (i) a single GWAS of heel BMD in 142,487 individuals from the UK Biobank, and (ii) a meta-analysis of 30 GWASs of total body (TB) BMD in 66,628 individuals from the Genetic Factors for Osteoporosis (GEFOS) Consortium. The genetic correlation coefficient of the two traits was estimated to be 0.57. We performed joint association analysis with a recently developed statistical method multi-trait analysis of GWAS (MTAG) to account for trait heterogeneity and sample overlap. The joint association analysis combining samples of up to 209,115 individuals identified 18 novel loci associated with BMD at the genomewide significance level (a ¼ 5.0 Â 10 -8 ), explaining an additional 0.43% and 0.60% of heel-BMD and TB-BMD heritability, respectively. The vast majority of the identified lead SNPs or their proxies exerted local expression quantitative trait loci (cis-eQTL) activity. Credible risk variants, defined as those SNPs located within 500 kilobases (kb) of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in transcription factor binding sites (p ¼ 3.58 Â 10 -4 ) and coding regions (p ¼ 5.71 Â 10 -4 ). Fifty-six candidate genes were prioritized at these novel loci using multiple sources of information, including several genes being previously reported to play a role in bone biology but not reported in previous GWASs (PPARG, FBN2, DEF6, TNFRSF19, and NFE2L1). One newly identified gene, SCMH1, was shown to upregulate the expression of several bone biomarkers, including alkaline phosphatase (ALP), collagen type 1 (COL-I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), in mouse osteoblastic MC3T3-E1 cells, highlighting its regulatory role in bone formation. Our results may provide useful candidate genes for future functional investigations.

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Section: Resultsmentioning

confidence: 99%

Joint Association Analysis Identified 18 New Loci for Bone Mineral Density

Pei

Liu

et al. 2019

Journal of Bone and Mineral Research

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“…Although the mechanisms that contribute to the bone resorption in these mice with complex autoimmunity have not been fully elucidated, these data suggest potential involvement of Def6 in pathologic bone resorption. Def6 was reported to modulate RANKL-induced osteoclast differentiation in vitro (41). However, the role of Def6 in vivo especially bone erosion in inflammatory conditions and the underlying molecular mechanisms have not been delineated.…”

Section: Introductionmentioning

confidence: 99%

Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

Binder

Miller

Yoshida

et al. 2017

The Journal of Immunology

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Inflammatory bone resorption mediated by osteoclasts is a major cause of morbidity and disability in many inflammatory disorders, including rheumatoid arthritis (RA). The mechanisms that regulate osteoclastogenesis and bone resorption in inflammatory settings are complex and have not been well elucidated. In this study, we identify the immunoregulator Def6 as a novel inhibitor of osteoclastogenesis in both physiological and inflammatory conditions. Def6 deficiency in Def6−/− mice enhanced the sensitivity of osteoclast precursors to the physiological osteoclastogenic inducer RANKL, and Def6−/− osteoclasts formed actin rings. Furthermore, Def6 deficiency markedly increased TNF-α-induced osteoclastogenesis both in vitro and in vivo and enhanced bone resorption in an inflammatory osteolysis mouse model. TNF-α serum levels negatively correlated with Def6 expression levels in osteoclast precursors obtained from RA patients and the osteoclastogenic capacity of the osteoclast precursors was significantly inversely correlated with their Def6 expression levels, indicating that Def6 functions as an inhibitor of excessive osteoclast formation and bone destruction in RA. Mechanistically, Def6 suppressed osteoclastogenesis and the expression of key osteoclastogenic factors NFATc1, Blimp1 and c-Fos by regulating an endogenous IFN-β mediated autocrine feedback loop. The Def6-dependent pathway may represent a novel therapeutic target to prevent pathological bone destruction.

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“…Murine osteoclasts were prepared from bone marrow cells as previously described ( Youn et al, 2013 ). Murine bone marrow cells were cultured in α-MEM (HyClone Laboratories) containing 10% FBS (HyClone Laboratories) with M-CSF (20 ng/ml) for 3 days.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-26a Regulates RANKL-Induced Osteoclast Formation

Kim

et al. 2015

Molecules and Cells

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Osteoclasts are unique cells responsible for the resorption of bone matrix. MicroRNAs (miRNAs) are involved in the regulation of a wide range of physiological processes. Here, we examined the role of miR-26a in RANKL-induced osteoclastogenesis. The expression of miR-26a was up-regulated by RANKL at the late stage of osteoclastogenesis. Ectopic expression of an miR-26a mimic in osteoclast precursor cells attenuated osteoclast formation, actin-ring formation, and bone resorption by suppressing the expression of connective tissue growth factor/CCN family 2 (CTGF/CCN2), which can promote osteoclast formation via up-regulation of dendritic cell-specific transmembrane protein (DC-STAMP). On the other hand, overexpression of miR-26a inhibitor enhanced RANKL-induced osteoclast formation and function as well as CTGF expression. In addition, the inhibitory effect of miR-26a on osteoclast formation and function was prevented by treatment with recombinant CTGF. Collectively, our results suggest that miR-26a modulates osteoclast formation and function through the regulation of CTGF.

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SLAT Negatively Regulates RANKL-Induced Osteoclast Differentiation

Cited by 7 publications

References 23 publications

Joint Association Analysis Identified 18 New Loci for Bone Mineral Density

Joint Association Analysis Identified 18 New Loci for Bone Mineral Density

Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

MicroRNA-26a Regulates RANKL-Induced Osteoclast Formation

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