TGF-β regulates nerve growth factor expression in a mouse intervertebral disc injury model

Yokozeki, Yuji; Uchida, Katsuhisa; Kawakubo, Ayumu; Nakawaki, Mitsufumi; Okubo, Tadashi; Miyagi, Masayuki; Inoue, Gen; Itakura, Makoto; Sekiguchi, Hiroyuki; Takaso, Masashi

doi:10.1186/s12891-021-04509-w

Cited by 13 publications

(10 citation statements)

References 32 publications

(50 reference statements)

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“…We previously reported that TGF-β is dominantly expressed in disc cells compared to macrophages in degenerative IVDs in mice. 38 In our present study, chondrocytic cells in degenerative IVD were positive for TGF-β. Therefore, chondrocytic cell-derived TGF-β may modulate M2 polarization in degenerative IVDs.…”

Section: Discussionsupporting

confidence: 59%

Origin of M2 Mϕ and its macrophage polarization by TGF-β in a mice intervertebral injury model

Kawakubo

Miyagi

Yokozeki

et al. 2022

Int J Immunopathol Pharmacol

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Introduction Studies have identified the presence of M1 and M2 macrophages (Mϕ) in injured intervertebral discs (IVDs). However, the origin and polarization-regulatory factor of M2 Mϕ are not fully understood. TGF-β is a regulatory factor for M2 polarization in several tissues. Here, we investigated the source of M2 Mϕ and the role of TGF-β on M2 polarization using a mice disc-puncture injury model. Methods To investigate the origin of M2 macrophages, 30 GFP chimeric mice were created by bone marrow transplantation. IVDs were obtained from both groups on pre-puncture (control) and post-puncture days 1, 3, 7, and 14 and CD86 (M1 marker)- and CD206 (M2 marker)-positive cells evaluated by flow cytometry ( n = 5 at each time point). To investigate the role of TGF-β on M2 polarization, TGF-β inhibitor (SB431542) was also injected on post-puncture days (PPD) 5 and 6 and CD206 expression was evaluated on day 7 by flow cytometry ( n = 5) and real time PCR ( n = 10). Results The proportion of CD86+ Mϕ within the GFP+ population was significantly increased at PPD 1, 3, 7, and 14 compared to control. CD206-positive cells in GFP-populations were significantly increased on PPD 7 and 14. In addition, the percentage of CD206-positive cells was significantly higher in GFP-populations than in GFP+ populations. TGF-β inhibitor reduced CD206-positive cells and Cd206 expression at 7 days after puncture. Conclusion Our findings suggest that M2 Mϕ following IVD injury may originate from resident Mϕ. TGF-β is a key factor for M2 polarization of macrophages following IVD injury.

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Section: Discussionsupporting

confidence: 59%

Origin of M2 Mϕ and its macrophage polarization by TGF-β in a mice intervertebral injury model

Kawakubo

Miyagi

Yokozeki

et al. 2022

Int J Immunopathol Pharmacol

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“…TGF β (transforming growth factor-beta) belongs to a group of growth factors that are members of the TGF superfamily and are important in mediating various cellular functions [ 51 ]. It has been demonstrated to play a key regulatory role in the molecular biology of IDD [ 52 , 53 ]. However, the benefits and drawbacks of the TGF- β signaling pathway for IDD function remain controversial [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of SMIM1 and SEZ6L2 as Potential Biomarkers for Genes Associated with Intervertebral Disc Degeneration in Pyroptosis

et al. 2022

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Background. Inflammatory reactions and pyroptosis play an important role in the pathology of intervertebral disc degeneration (IDD). The aim of the present study was to investigate pyroptosis in the nucleus pulposus cells (NPCs) of inflammatory induced IDD by bioinformatic methods and to search for possible diagnostic biomarkers. Methods. Gene expression profiles related to IDD were downloaded from the GEO database to identify differentially expressed genes (DEGs) between inflammation-induced IDD and non-inflammatory intervention samples. Pyroptosis genes were then searched for, and their expression in IDD was analyzed. Weighted gene co-expression network analysis (WGCNA) was then used to search for modules of IDD genes associated with pyroptosis and intersected with DEGs to discover candidate genes that would be diagnostically valuable. A LASSO model was developed to screen for genes that met the requirements, and ROC curves were created to clarify the diagnostic value of the genetic markers. Ultimately, the screened genes were further validated, and their diagnostic value assessed by selecting gene sets from the GEO database. RT-PCR was used to assess the mRNA expression of diagnostic markers in the nucleus pulposus (NP). Pan-cancer analysis was applied to demonstrate the expression and prognostic value of the screened genes in various tumors. Results. A total of 733 DEGs were identified in GSE41883 and GSE27494, which were mainly enriched in transmembrane receptor protein serine/threonine, kinase signaling pathway, response to lipopolysaccharide, and other biological processes, and they were mainly related to TGF beta signaling pathway, toll-like receptor signaling pathway, and TNF signaling pathway. A total of 81 genes related to pyroptosis were identified in the literature, and eight genes related to IDD were identified in the Veen diagram, namely, IL1A, IL1B, NOD2, GBP1, IL6, AK1, EEF2K, and PYCARD. Eleven candidate genes were obtained after locating the intersection of pyroptosis-related module genes and DEGs according to WGCNA analysis. A total of six valid genes were obtained after constructing a machine learning model, and five key genes were finally identified after correlation analysis. GSE23132 and GSE56081 validated the candidate genes, and the final IDD-related diagnostic markers were obtained as SMIM1 and SEZ6L2. RT-PCR results indicated that the mRNA expression of both was significantly elevated in IDD. The pan-cancer analysis demonstrated that SMIM1 and SEZ6L2 have important roles in the expression and prognosis of various tumors. Conclusion. In conclusion, this research identifies SMIM1 and SEZ6L2 as important biomarkers of IDD associated with pyroptosis, which will help to unravel the development and pathogenesis of IDD and determine potential therapeutic targets.

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“…From this point of view, finding a suitable animal model appears difficult. Most studies [37][38][39] on disc degeneration have therefore used surgically created animal models to cause similar changes. However, IVD degeneration also reveals that age-related changes in IVD structure might be more directly reflected in quadrupeds.…”

Section: Discussionmentioning

confidence: 99%

Manual therapy regulates oxidative stress in aging rat lumbar intervertebral discs through the SIRT1/FOXO1 pathway

Yao

Guo

Huang

et al. 2022

Aging

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With the increasing burden of a globally aging population, low back pain has become one of the most common musculoskeletal disorders, caused mainly by intervertebral disc (IVD) degeneration. There are currently several clinical methods to alleviate back pain, but there is scarce attention paid as to whether they can improve agerelated IVD degeneration. It is therefore difficult to conduct an in-depth evaluation of these methods. A large number of clinical studies have shown that manual therapy (MT), a widely used comprehensive alternative method, has effects on pain, the mechanisms of which require further study. In this study, MT was performed on aging rats for 6 months, and their behaviors were compared with those of a non-intervention group of aging and young rats. After the intervention, all rats were examined by X-ray to observe lumbar spine degeneration, and the IVD tissues were dissected for detection, including pathological staining, immunofluorescence, Western bolt, etc. This study demonstrated the possibility that MT intervention delay the lumbar IVD degeneration in aging rats, specifically improving the motor function and regulating senescence-associated β-galactosidase, p53, p21, p16, and telomerase activity to retard the senescence of cells in IVDs. Moreover, MT intervention can modify oxidative stress, increase the expression of SIRT1 and FOXO1 in IVDs and decrease ac-FOXO1 expression, suggesting that MT can reduce oxidative stress through the SIRT1/FOXO1 pathway, thereby playing a role in delaying the aging of IVDs. This study shows that drug-free, non-invasive mechanical interventions could be of major significance in improving the physical function of the elderly.

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TGF-β regulates nerve growth factor expression in a mouse intervertebral disc injury model

Cited by 13 publications

References 32 publications

Origin of M2 Mϕ and its macrophage polarization by TGF-β in a mice intervertebral injury model

Origin of M2 Mϕ and its macrophage polarization by TGF-β in a mice intervertebral injury model

Identification of SMIM1 and SEZ6L2 as Potential Biomarkers for Genes Associated with Intervertebral Disc Degeneration in Pyroptosis

Manual therapy regulates oxidative stress in aging rat lumbar intervertebral discs through the SIRT1/FOXO1 pathway

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