Comparative proteomic analysis identifies differentially expressed proteins and reveals potential mechanisms of traumatic heterotopic ossification progression

Wei, Zheng; Guo, Shang; Wang, Hongwei; Yang, Zhao; Yan, Jiren; Zhang, Chi; Zhong, Biao

doi:10.1016/j.jot.2022.04.003

Cited by 8 publications

(6 citation statements)

References 62 publications

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“…EIF3E (eukaryotic translation initiation factor 3 subunit E) encodes a protein that is a component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which functions in and is essential for several steps in the initiation of protein synthesis ( Lee et al, 2015 ; Masutani et al, 2007 ). A proteomics study in a rat model of heterotopic ossification reported that Eif3e was upregulated in ossified tissues and may be involved in tissue ossification by regulating hypoxia-inducible factor (HIF) signaling, which has an important role in osteogenesis ( Wei et al, 2022 ). EMC2 (endoplasmic reticulum membrane protein complex subunit 2) encodes a part of the endoplasmic reticulum membrane protein complex (EMC) that functions in the energy-independent insertion of newly synthesized membrane proteins into the endoplasmic reticulum membrane, an essential cellular process ( Chitwood et al, 2018 ; O’Donnell et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Genetic insights into ossification of the posterior longitudinal ligament of the spine

Koike

Takahata

Nakajima

et al. 2023

eLife

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Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.

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Section: Resultsmentioning

confidence: 99%

Genetic insights into ossification of the posterior longitudinal ligament of the spine

Koike

Takahata

Nakajima

et al. 2023

eLife

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“…All animal experiments were performed according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the Experimental Animal Welfare Ethics Committee of Zhongnan Hospital of Wuhan University under animal protocol number ZN2022266. After being anesthetized by intraperitoneal pentobarbital sodium (1%, 5 mL/kg; Sigma-Aldrich, USA), a hundred male wild-type C57BL/6 mice received the Achilles tendon transection on the left hind limb, as previously described [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

NIR-triggered photodynamic therapy of traumatic heterotopic ossification with a type II collagen-targeted photosensitizer

Wang,

Sun,

et al. 2023

Materials Today Bio

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Section: Introductionmentioning

confidence: 99%

“… 17 Additionally, a recent Biosign report revealed 3547 differentially expressed proteins during HO formation, which were primarily enriched in oxidative phosphorylation and regulation of mitochondrial function. 18 This implies that mitochondria may play an overwhelming regulatory role in HO formation. Furthermore, recent studies have found that PPARγ inhibition impairs mitochondrial function, indicating a close relationship between PPARγ and mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

KLF2/PPARγ axis contributes to trauma‐induced heterotopic ossification by regulating mitochondrial dysfunction

Sun

Liu

et al. 2023

Cell Proliferation

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Trauma‐induced heterotopic ossification (HO) is a complex disorder after musculoskeletal injury and characterized by aberrant extraskeletal bone formation. Recent studies shed light on critical role of dysregulated osteogenic differentiation in aberrant bone formation. Krupel‐like factor 2 (KLF2) and peroxisome proliferator‐activated receptor gamma (PPARγ) are master adapter proteins that link cellular responses to osteogenesis; however, their roles and relationships in HO remain elusive. Using a murine burn/tenotomy model in vivo, we identified elevated KLF2 and reduced PPARγ levels in tendon stem/progenitor cells (TSPCs) during trauma‐induced HO formation. Both KLF2 inhibition and PPARγ promotion reduced mature HO, whereas the effects of PPARγ promotion were abolished by KLF2 overexpression. Additionally, mitochondrial dysfunction and reactive oxygen species (ROS) production also increased after burn/tenotomy, and improvements in mitochondrial function (ROS scavenger) could alleviate HO formation, but were abolished by KLF2 activation and PPARγ suppression by affecting redox balance. Furthermore, in vitro, we found increased KLF2 and decreased PPARγ levels in osteogenically induced TSPCs. Both KLF2 inhibition and PPARγ promotion relieved osteogenesis by improving mitochondrial function and maintaining redox balance, and effects of PPARγ promotion were abolished by KLF2 overexpression. Our findings suggest that KLF2/PPARγ axis exerts regulatory effects on trauma‐induced HO through modulation of mitochondrial dysfunction and ROS production in TSPCs by affecting redox balance. Targeting KLF2/PPARγ axis and mitochondrial dysfunction can represent attractive approaches to therapeutic intervention in trauma‐induced HO.

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Comparative proteomic analysis identifies differentially expressed proteins and reveals potential mechanisms of traumatic heterotopic ossification progression

Cited by 8 publications

References 62 publications

Genetic insights into ossification of the posterior longitudinal ligament of the spine

Genetic insights into ossification of the posterior longitudinal ligament of the spine

NIR-triggered photodynamic therapy of traumatic heterotopic ossification with a type II collagen-targeted photosensitizer

KLF2/PPARγ axis contributes to trauma‐induced heterotopic ossification by regulating mitochondrial dysfunction

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