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

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

doi:10.1371/journal.pone.0197543

Cited by 10 publications

(5 citation statements)

References 46 publications

(51 reference statements)

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“…Optn can also mediate the removal of protein aggregation through UB‐independent mechanisms. Moreover, it appears to be part of the TNF‐α pathway involved in the NF‐κB regulatory process(Pierrefite‐Carle et al, 2015; Silva et al, 2018). Subsequent studies need to explore further the role of autophagy alterations and aggregate defect clearance in PBD.…”

Section: Bone Diseases and Autophagymentioning

confidence: 99%

The role of autophagy in bone homeostasis

Guo

Yang

et al. 2021

Journal Cellular Physiology

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Autophagy is an evolutionarily conserved intracellular process and is considered one of the main catabolism pathways. In the process of autophagy, cells are digested nonselectively or selectively to recover nutrients and energy, so it is regarded as an antiaging process. In addition to the essential role of autophagy in cellular homeostasis, autophagy is a stress response mechanism for cell survival. Here, we review recent literature describing the pathway of autophagy and its role in different bone cell types, including osteoblasts, osteoclasts, and osteocytes. Also discussed is the mechanism of autophagy in bone diseases associated with bone homeostasis, including osteoporosis and Paget's disease. Finally, we discuss the application of autophagy regulators in bone diseases. This review aims to introduce autophagy, summarize the understanding of its relevance in bone physiology, and discuss its role and therapeutic potential in the pathogenesis of bone diseases such as osteoporosis.

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Section: Bone Diseases and Autophagymentioning

confidence: 99%

The role of autophagy in bone homeostasis

Guo

Yang

et al. 2021

Journal Cellular Physiology

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“…Autophagy participates in bone homeostasis, and inhibition of autophagy reduces osteogenic differentiation of BMSCs 53–55 . Several studies demonstrated that optn mutation is closely related to Paget disease of bone (PDB), which is featured by focal increased bone turnover 56–58 . Recently, Mizuno et al reported that optn controls osteoblast differentiation, depletion of which impairs bone formation 59 .…”

Section: Discussionmentioning

confidence: 99%

Alkbh1‐mediated DNA N6‐methyladenine modification regulates bone marrow mesenchymal stem cell fate during skeletal aging

et al. 2022

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Objectives DNA N6‐methyladenine (N6‐mA) demethylase Alkbh1 participates in regulating osteogenic differentiation of mesenchymal stem cell (MSCs) and vascular calcification. However, the role of Alkbh1 in bone metabolism remains unclear. Materials and Methods Bone marrow mesenchymal stem cells (BMSCs)‐specific Alkbh1 knockout mice were used to investigate the role of Alkbh1 in bone metabolism. Western blot, qRT‐PCR, and immunofluorescent staining were used to evaluate the expression of Alkbh1 or optineurin (optn). Micro‐CT, histomorphometric analysis, and calcein double‐labeling assay were used to evaluate bone phenotypes. Cell staining and qRT‐PCR were used to evaluate the osteogenic or adipogenic differentiation of BMSCs. Dot blotting was used to detect the level of N6‐mA in genomic DNA. Chromatin immunoprecipitation (Chip) assays were used to identify critical targets of Alkbh1. Alkbh1 adeno‐associated virus was used to overexpress Alkbh1 in aged mice. Results Alkbh1 expression in BMSCs declined during aging. Knockout of Alkbh1 promoted adipogenic differentiation of BMSCs while inhibited osteogenic differentiation. BMSC‐specific Alkbh1 knockout mice exhibited reduced bone mass and increased marrow adiposity. Mechanistically, we identified optn as the downstream target through which Alkbh1‐mediated DNA m6A modification regulated BMSCs fate. Overexpression of Alkbh1 attenuated bone loss and marrow fat accumulation in aged mice. Conclusions Our findings demonstrated that Alkbh1 regulated BMSCs fate and bone‐fat balance during skeletal aging and provided a potential target for the treatment of osteoporosis.

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“…Frontiers in Genetics frontiersin.org many physiological activities, including NFB signaling, autophagy, and innate immunity (Zhu et al, 2007;Wild et al, 2011). Previous investigations have found a negative regulatory function for OPTN in osteoclast formation by altering in vitro and in vivo NF-kB and interferon signaling in mouse models (Obaid et al, 2015) (Silva et al, 2018a;Silva et al, 2018b).…”

Section: Frontiers In Geneticsmentioning

confidence: 99%

Paget’s disease: a review of the epidemiology, etiology, genetics, and treatment

et al. 2023

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Paget’s disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%–8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget’s disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research.

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

Cited by 10 publications

References 46 publications

The role of autophagy in bone homeostasis

The role of autophagy in bone homeostasis

Alkbh1‐mediated DNA N6‐methyladenine modification regulates bone marrow mesenchymal stem cell fate during skeletal aging

Paget’s disease: a review of the epidemiology, etiology, genetics, and treatment

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