A FKBP5 mutation is associated with Paget’s disease of bone and enhances osteoclastogenesis

Lu, Bingru; Jiao, Yang; Yinchang, Wang; Dong, Jing; Wei, Muyun; Cui, Bin; Sun, Yafang; Wang, Laicheng; Zhang, Bingchang; Chen, Zi‐Jiang; Zhao, Yong

doi:10.1038/emm.2017.64

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…52 More recently, the c.163G>C mutation in FKBP5 was related to enhanced osteoclast differentiation and activity in Paget’s disease of bone. 52,53 Additional functional studies of FKBP5 are necessary to understand its role in the development of OP.…”

Section: Discussionmentioning

confidence: 99%

Identification of miR-708-5p in peripheral blood monocytes: Potential marker for postmenopausal osteoporosis in Mexican-Mestizo population

Cruz-Montoya

Ramírez‐Salazar

Martínez-Aguilar

et al. 2018

Exp Biol Med (Maywood)

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Osteoporosis is the most frequent disorder of bone metabolism, owing to an alteration between osteoclast and osteoblast activity, which results from the interaction of genetic, environmental, and epigenetic factors. microRNAs, small non-coding RNAs of around 22 nucleotides with important regulatory roles in gene regulation, that target mRNAs for post-transcriptional destabilization have been suggested as biomarkers in several disorders. In this work, we used small RNA sequencing to identify microRNAs from peripheral blood monocytes that were differentially expressed between non-osteoporotic and osteoporotic Mexican postmenopausal women, to elucidate the potential role of microRNAs as non-invasive marker candidates in osteoporosis. We identified six candidate microRNAs: four were up-regulated (miR-708-5p, miR-34b-5p, miR-3161, miR-328-5p), while two were down-regulated (miR-4422 and miR-939-3p) in osteoporotic women. Differential expression was validated by quantitative RT-PCR and only the upregulation of miR-708-5p was found to be statistically significant. Bioinformatic analysis of target genes for miR-708-5p showed 15 signaling pathways related to bone metabolism. Since monocytes are osteoclast precursors, 10 potential target genes present in these pathways and related to osteoclastogenesis were identified ( AKT1, AKT2, CCND1, PARP1, SMAD3, CXCL5, FKBP5, MAP2K3, MMP2, and IKBKG). Five of them were found to be down-regulated according to microarray expression data. This is the first time that miR-708-5p has been identified in peripheral blood monocytes and associated with postmenopausal osteoporosis. Our results suggest that miR-708-5p reduces the expression of AKT1, AKT2, PARP1 FKBP5, and MP2K3 in peripheral blood monocytes contributing to an osteoporotic phenotype and could be a candidate marker for postmenopausal osteoporosis in Mexican population. Impact statement This is the first study in which hsa-miR-708-5p has been identified in peripheral blood monocytes (osteoclast precursors) and associated with postmenopausal osteoporosis through small RNA-Sequencing, in an Admixed Mexican Mestizo population. By conducting in silico and bioinformatic analyzes, we identified target genes and important signaling pathways involved in bone metabolism pointing hsa-miR-708-5p as a candidate marker for osteoporosis in Mexican population. These approaches provide a landscape of the post-transcriptional regulation, which can be useful for the management of postmenopausal osteoporosis along with the potential use of microRNAs as markers for its early detection.

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Section: Discussionmentioning

confidence: 99%

Identification of miR-708-5p in peripheral blood monocytes: Potential marker for postmenopausal osteoporosis in Mexican-Mestizo population

Cruz-Montoya

Ramírez‐Salazar

Martínez-Aguilar

et al. 2018

Exp Biol Med (Maywood)

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“…Mutation of FKBP51 tyrosine 54 (but not Y243 or Y409) to phenylalanine abrogated SRMS-mediated FKBP51 tyrosine phosphorylation (Fig 3H). Tyrosine 54 of FKBP51 is well conserved in birds and mammals but is not present in the closely related protein FKBP52 encoded by the FKBP4 gene (S3G Fig) . FKBP51 Y54 is directly adjacent to the V55L variant that has been identified in humans and linked to Paget's disease of bone [21].…”

Section: Srms Phosphorylates Fkbp51 On Tyrosine 54mentioning

confidence: 99%

The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51

et al. 2021

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Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

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“…Given that the protein coding regions of the genome have been predicted to harbour 85% of human disease causing variants, whole exome sequencing is likely to be a more efficient way of elucidating the remaining genetic variation in human disease ( Lacey et al, 2014 ). A number of studies have utilised whole exome sequencing in the context of PDB, however these have benefited from either conducting the study in a region where the disease is exceptionally rare ( Lu et al, 2017 ; Qi et al, 2017 ), or from a large kindred ( Divisato et al, 2016 ). Targeted sequencing of genes close to or within a number of the loci identified in the GWAS has been performed, including TNFRSF11A ( Gianfrancesco et al, 2012 ), OPTN ( Obaid et al, 2015 ), RIN3 ( Vallet et al, 2015 ), and DCSTAMP ( Beauregard et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing of DCSTAMP in familial Paget's disease of bone

et al. 2019

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Paget's disease of bone (PDB) has a strong genetic component. Variants in SQSTM1 are found in up to 40% of patients with a family history of the disease, where a pattern of autosomal dominance with incomplete penetrance is apparent. By contrast, SQSTM1 variants are only found in up to 10% of patients with sporadic disease. It has been hypothesised that the remaining genetic susceptibility to PDB, particularly in familial cases, could be explained by rare genetic variants in loci previously identified by Genome Wide Association Studies. It is likely that polygenic factors are involved in many individuals. In this study we utilised whole exome sequencing to investigate predisposing genetic factors in an unsolved PDB kindred and identified a c.1189C > T p.L397F variant in DC-STAMP , also known as TM7SF4 , that co-segregated with disease. DCSTAMP was identified as a gene of interest in PDB following Genome Wide Association Studies and has been previously shown to play critical roles in osteoclast fusion. The variant we identified has also been reported in association with PDB in a French-Canadian cohort however the significance of this variant was inconclusive. Targeted screening of DCSTAMP in our familial cohort of PDB patients revealed an additional 8 variants; however we did not find a significant association between any of these, including p.L397F, with PDB. Osteoclastogenesis assays from the affected proband and his unaffected brother demonstrated an increase in osteoclast number and nucleation, consistent with the pagetic phenotype. In converse to other established Paget's associated genetic variations such as SQSTM1 , TNFRSF11A and OPTN , expression of the mutant DC-STAMP protein attenuated the activation of transcription factors NFκB and AP-1 when exogenously expressed. We found that the p.L397F variant did not influence the subcellular localization of the protein. Based on these findings we conclude that genetic variation in DCSTAMP is not a significant predisposing factor in our specific cohort of PDB patients and the p.L397F variant is unlikely to be a contributing factor in PDB pathogenesis.

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A FKBP5 mutation is associated with Paget’s disease of bone and enhances osteoclastogenesis

Cited by 25 publications

References 41 publications

Identification of miR-708-5p in peripheral blood monocytes: Potential marker for postmenopausal osteoporosis in Mexican-Mestizo population

Identification of miR-708-5p in peripheral blood monocytes: Potential marker for postmenopausal osteoporosis in Mexican-Mestizo population

The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51

Targeted sequencing of DCSTAMP in familial Paget's disease of bone

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