Effect of genetic variants of OPTN in the pathophysiology of Paget's disease of bone

Silva, Iris; Conceição, Natércia; Gagnon, Édith; Caiado, Helena; Brown, Jacques P.; Gianfrancesco, Fernando; Michou, Laëtitia; Cancela, M. Leonor

doi:10.1016/j.bbadis.2017.10.008

Cited by 17 publications

(9 citation statements)

References 35 publications

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“…Altogether, the gathered evidence obtained from gene to protein analysis, from in vitro to patient samples, from genetic to morphological cellular features, show that OPTN appears to be important for NF-κB translocation into the nucleus, activation of its target genes and consequent increase in osteoclastogenesis, providing relevant information towards a better understanding on how genetic variants in OPTN can contribute to PDB by acting as modifiers and complementing previous data on the potential functional role of variants in OPTN and how they may contribute to affect the physiological regulatory mechanisms of this gene [ 45 ].…”

Section: Discussionmentioning

confidence: 81%

Molecular effect of an OPTN common variant associated to Paget's disease of bone

et al. 2018

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Paget’s disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains several candidate genes for metabolic bone diseases. We focused our analysis in the most significantly associated variant with PDB, within the Optineurin (OPTN) gene, i.e. the common variant rs1561570. Although it was previously shown to be strongly associated with PDB in several populations, its contribution to PDB pathogenesis remains unclear. In this study we have shown that rs1561570 may contribute to PDB since its T allele results in the loss of a methylation site in patients’ DNA, leading to higher levels of OPTN gene expression and a corresponding increase in protein levels in patients’ osteoclasts. This increase in OPTN expression leads to higher levels of NF-κB translocation into the nucleus and increasing expression of its target genes, which may contribute to the overactivity of osteoclasts observed in PDB. We also reported a tendency for a more severe clinical phenotype in the presence of a haplotype containing the rs1561570 T allele, which appear to be re-enforced with the presence of the SQSTM1/P392L mutation. In conclusion, our work provides novel insight towards understanding the functional effects of this variant, located in OPTN intron 7, and its implication in the contribution to PDB pathogenesis.

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Section: Discussionmentioning

confidence: 81%

Molecular effect of an OPTN common variant associated to Paget's disease of bone

et al. 2018

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“…Bone is a dynamic tissue, which is constantly remodeled by osteoclasts that resorb bone and by osteoblasts that form new bone. An uncontrolled osteoclast formation causes abnormal bone homeostasis, leading to diseases such as osteoporosis, periodontitis and Paget's disease of bone [1][2][3]19]. Thus, drug/compound that can effectively inhibit osteoclast differentiation and formation will provide a promising strategy for the prevention and treatment of bone resorbing diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Metabolic bone diseases such as osteoporosis, periodontitis and Paget's disease of bone are global public health concerns and are primarily caused by uncontrolled osteoclast formation and activation [1][2][3]. Osteoclasts (OC) are large and multinucleated cells that can resorb bones and differentiate from mononuclear progenitors of monocyte/macrophage lineage, which is strictly regulated by receptor activator of nuclear factor kappa-B ligand (RANKL).…”

Section: Introductionmentioning

confidence: 99%

CDDO-Me, Sulforaphane and tBHQ attenuate the RANKL-induced osteoclast differentiation via activating the NRF2-mediated antioxidant response

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et al. 2019

Biochemical and Biophysical Research Communications

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Metabolic bone diseases are global public health concerns and are primarily caused by uncontrolled osteoclast (OC) formation and activation. During OC differentiation, intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can serve as the signaling molecules to promote osteoclastic genes expression. Nuclear factor erythroid-2 related factor 2 (NRF2), a master mediator of cellular antioxidant response, also plays a critical role in OC differentiation through the regulation of redox homeostasis. In this study, we investigated the effects of three NRF2 inducers on osteoclastogenesis, including Bardoxolone methyl (CDDO-Me), Sulforaphane (SFN), and tert-butylhydroquinone (tBHQ). By treating RAW cells with three compounds, we found that NRF2 was activated and its downstream antioxidant genes were upregulated, and the RANKL-induced intracellular ROS production and osteoclastogenesis were impaired. Additionally, the expression of nuclear factor of activated T cells c1 (NFATC1), C-FOS and tumor necrosis factor alpha (TNFα) were inhibited after acute exposures (6 hours) to the three compounds. Furthermore, suppressed expression of osteoclast differentiation associated genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase-9 (MMP-9) and dendritic cell specific transmembrane protein (DC-STAMP) were observed after prolonged exposures (5 days) to the compounds. Taken together, these results suggest that CDDO-Me, SFN and tBHQ attenuate RANKL-induced osteoclastogenesis via activation of NRF2-mediated antioxidant response. Among these compounds, relatively low concentrations of CDDO-Me showed stronger active and inhibitory effects on antioxidant response and osteoclastogenesis, respectively.

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“…Genetic variants of OPTN have been identified in PDB in several populations and pathophysiological links have been proposed, although a direct causal relationship has not yet been established 104,105 . To date, there have not been reported cases of OPTN‐associated ALS co‐occurring with PDB 23 …”

Section: Optnmentioning

confidence: 99%

Multisystem proteinopathy: Where myopathy and motor neuron disease converge

2020

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Multisystem proteinopathy (MSP) is a pleiotropic group of inherited disorders that cause neurodegeneration, myopathy, and bone disease, and share common pathophysiology. Originally referred to as inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), attributed to mutations in the gene encoding valosin‐containing protein (VCP), it has more recently been discovered that there are several other genes responsible for similar clinical and pathological phenotypes with muscle, brain, nerve, and bone involvement, in various combinations. These include heterogeneous nuclear ribonucleoprotein A2B1 and A1 (hnRNPA2B1, hnRNPA1), sequestosome 1 (SQSTM1), matrin 3 (MATR3), T‐cell restricted intracellular antigen 1 (TIA1), and optineurin (OPTN), all of which share disruption of RNA stress granule function and autophagic degradation. This review will discuss each of the genes implicated in MSP, exploring the molecular pathogenesis, clinical features, current standards of care, and future directions for this diverse yet mechanistically linked spectrum of disorders.

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Effect of genetic variants of OPTN in the pathophysiology of Paget's disease of bone

Cited by 17 publications

References 35 publications

Molecular effect of an OPTN common variant associated to Paget's disease of bone

Molecular effect of an OPTN common variant associated to Paget's disease of bone

CDDO-Me, Sulforaphane and tBHQ attenuate the RANKL-induced osteoclast differentiation via activating the NRF2-mediated antioxidant response

Multisystem proteinopathy: Where myopathy and motor neuron disease converge

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