Brief research report: Effects of Pinch deficiency on cartilage homeostasis in adult mice

Wu, Xiaohao; Lin, Sixiong; Liao, Rongdong; Yao, Qing; Li, Lin; Zou, Xuenong; Xiao, Guozhi

doi:10.3389/fcell.2023.1116128

Cited by 3 publications

(1 citation statement)

References 29 publications

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“…The generation of floxed Pinch1 (Pinch1 fl/fl ) and Pinch2 global knockout (Pinch2 -/-) mice was previously described [29][30][31][32][33]. The genotyping primer information is listed in Supplementary Table 2.…”

Section: Animal Studiesmentioning

confidence: 99%

Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice

Wu¹,

Chen²,

Lin³

et al. 2023

Aging and disease

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Degenerative disc disease (DDD) is one of the most common skeletal disorders affecting aged populations. DDD is the leading cause of low back/neck pain, resulting in disability and huge socioeconomic burdens. However, the molecular mechanisms underlying DDD initiation and progression remain poorly understood. Pinch1 and Pinch2 are LIM-domain-containing proteins with crucial functions in mediating multiple fundamental biological processes, such as focal adhesion, cytoskeletal organization, cell proliferation, migration, and survival. In this study, we found that Pinch1 and Pinch2 were both highly expressed in healthy intervertebral discs (IVDs) and dramatically downregulated in degenerative IVDs in mice. Deleting Pinch1 in aggrecanexpressing cells and Pinch2 globally (Aggrecan CreERT2 ; Pinch1 fl/fl ; Pinch2 -/-) caused striking spontaneous DDD-like lesions in lumbar IVDs in mice. Pinch loss inhibited cell proliferation and promotes extracellular matrix (ECM) degradation and apoptosis in lumbar IVDs. Pinch loss markedly enhanced the production of pro-inflammatory cytokines, especially TNFα, in lumbar IVDs and exacerbated instability-induced DDD defects in mice. Pharmacological inhibition of TNFα signaling mitigated the DDD-like lesions caused by Pinch loss. In human degenerative NP samples, reduced expression of Pinch proteins was correlated with severe DDD progression and a markedly upregulated expression of TNFα. Collectively, we demonstrate the crucial role of Pinch proteins in maintaining IVD homeostasis and define a potential therapeutic target for DDD.

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Section: Animal Studiesmentioning

confidence: 99%

Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice

Wu¹,

Chen²,

Lin³

et al. 2023

Aging and disease

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Inactivation of Tnf‐α/Tnfr signaling attenuates progression of intervertebral disc degeneration in mice

Tao,

Lin,

Shi

et al. 2024

JOR Spine

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BackgroundIntervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), worsened by chronic inflammatory processes associated with aging. Tumor necrosis factor alpha (Tnf‐α) and its receptors, Tnf receptor type 1 (Tnfr1) and Tnf receptor type 2 (Tnfr2), are upregulated in IVDD. However, its pathologic mechanisms remain poorly defined.MethodsTo investigate the role of Tnfr in IVDD, we generated global Tnfr1/2 double knockout (KO) mice and age‐matched control C57BL/6 male mice, and analyzed intervertebral disc (IVD)‐related phenotypes of both genotypes under physiological conditions, aging, and lumbar spine instability (LSI) model through histological and immunofluorescence analyses and μCT imaging. Expression levels of key extracellular matrix (ECM) proteins in aged and LSI mice, especially markers of cell proliferation and apoptosis, were evaluated in aged (21‐month‐old) mice.ResultsAt 4 months, KO and control mice showed no marked differences of IVDD‐related parameters. However, at 21 months of age, the loss of Tnfr expression significantly alleviated IVDD‐like phenotypes, including a significant increase in height of the nucleus pulposus (NPs) and reductions of endplates (EPs) porosity and histopathological scores, when compared to controls. Tnfr deficiency promoted anabolic metabolism of the ECM proteins and suppressed ECM catabolism. Tnfr loss largely inhibited hypertrophic differentiation, and, in the meantime, suppressed cell apoptosis and cellular senescence in the annulus fibrosis, NP, and EP tissues without affecting cell proliferation. Similar results were observed in the LSI model, where Tnfr deficiency significantly alleviated IVDD and enhanced ECM anabolic metabolism while suppressing catabolism.ConclusionThe deletion of Tnfr mitigates age‐related and LSI‐induced IVDD, as evidenced by preserved IVD structure, and improved ECM integrity. These findings suggest a crucial role of Tnf‐α/Tnfr signaling in IVDD pathogenesis in mice. Targeting this pathway may be a novel strategy for IVDD prevention and treatment.

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A review of tamoxifen administration regimen optimization for Cre/loxp system in mouse bone study

Chen

Zhao

Chu

et al. 2023

Biomedicine & Pharmacotherapy

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Brief research report: Effects of Pinch deficiency on cartilage homeostasis in adult mice

Cited by 3 publications

References 29 publications

Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice

Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice

Inactivation of Tnf‐α/Tnfr signaling attenuates progression of intervertebral disc degeneration in mice

A review of tamoxifen administration regimen optimization for Cre/loxp system in mouse bone study

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