FK506 Induces the TGF-β1/Smad 3 Pathway Independently of Calcineurin Inhibition to Prevent Intervertebral Disk Degeneration

Ge, Jun; Wang, Yingjie; Qi, Yan; Wu, Cenhao; Yu, Hao; Yang, Huilin; Zou, Jun

doi:10.3389/fcell.2020.608308

Cited by 6 publications

(4 citation statements)

References 54 publications

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“…Hyperosmotic culture has recently been shown to have similar effects on cell types from other skeletal tissues, such as the nucleus pulposus cells from the intervertebral disk (IVD) [12,13]. Indeed, a recent report suggested that FK506 induces the TGF-β1/SMAD3 pathway independently of Cn inhibition to prevent IVD degeneration [77]. This is largely in agreement with our results showing that FK506, but not CsA, induces Acan expression.…”

Section: Discussionsupporting

confidence: 92%

Physosmotic Induction of Chondrogenic Maturation Is TGF-β Dependent and Enhanced by Calcineurin Inhibitor FK506

Jahr

Windt

Timur

et al. 2022

IJMS

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Increasing extracellular osmolarity 100 mOsm/kg above plasma level to the physiological levels for cartilage induces chondrogenic marker expression and the differentiation of chondroprogenitor cells. The calcineurin inhibitor FK506 has been reported to modulate the hypertrophic differentiation of primary chondrocytes under such conditions, but the molecular mechanism has remained unclear. We aimed at clarifying its role. Chondrocyte cell lines and primary cells were cultured under plasma osmolarity and chondrocyte-specific in situ osmolarity (+100 mOsm, physosmolarity) was increased to compare the activation of nuclear factor of activated T-cells 5 (NFAT5). The effects of osmolarity and FK506 on calcineurin activity, cell proliferation, extracellular matrix quality, and BMP- and TGF-β signaling were analyzed using biochemical, gene, and protein expression, as well as reporter and bio-assays. NFAT5 translocation was similar in chondrocyte cell lines and primary cells. High supraphysiological osmolarity compromised cell proliferation, while physosmolarity or FK506 did not, but in combination increased proteoglycan and collagen expression in chondrocytes in vitro and in situ. The expression of the TGF-β-inducible protein TGFBI, as well as chondrogenic (SOX9, Col2) and terminal differentiation markers (e.g., Col10) were affected by osmolarity. Particularly, the expression of minor collagens (e.g., Col9, Col11) was affected. The inhibition of the FK506-binding protein suggests modulation at the TGF-β receptor level, rather than calcineurin-mediated signaling, as a cause. Physiological osmolarity promotes terminal chondrogenic differentiation of progenitor cells through the sensitization of the TGF-β superfamily signaling at the type I receptor. While hyperosmolarity alone facilitates TGF-β superfamily signaling, FK506 further enhances signaling by releasing the FKBP12 break from the type I receptor to improve collagenous marker expression. Our results help explain earlier findings and potentially benefit future cell-based cartilage repair strategies.

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Section: Discussionsupporting

confidence: 92%

Physosmotic Induction of Chondrogenic Maturation Is TGF-β Dependent and Enhanced by Calcineurin Inhibitor FK506

Jahr

Windt

Timur

et al. 2022

IJMS

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“…Although there are complex and multifactorial causes for the development of LBP, it is widely accepted that IVDD is the major contributor to LBP [ 19 ]. IVDD can be affected by both genetic and environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Novel Nomogram to Predict the Risk of Intervertebral Disc Degeneration

Sun

Wang

et al. 2022

Mediators of Inflammation

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Intervertebral disc degeneration (IVDD) has been a complex disorder resulted from genetic and environmental risk factors. The aim of this study was to identify the risk factors associated with IVDD in orthopaedic patients and develop a prediction model for predicting the risk of IVDD. A total of 309 patients were retrospectively included in the study and randomly divided into the training group and the validation group. The least absolute shrinkage and selection operator regression (LASSO) and the univariate logistic regression analysis were used to optimize factors selection for the IVDD risk model. Multivariable logistic regression analysis was used to establish a predicting nomogram model incorporating the factors. In addition, discrimination, calibration, and clinical usefulness of the nomogram model were evaluated via the C-index, receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA). Then, based on the results above, the relationship between IVDD and angiotensin II (AngII) level in peripheral blood was examined prospectively. The predictors of the nomogram include age, sex, hypertension, diabetes, gout, working posture, and exercising hours per week. The C -index values of the training and validation groups were 0.916 (95% CI, 0.876-0.956) and 0.949 (95% CI, 0.909-0.989), respectively, which indicated that the model displayed good discrimination. In addition, the area under the curve (AUC) values of the ROC curve of the training and the validation group were 0.815 (95% CI, 0.759-0.870) and 0.805 (95% CI, 0.718-0.892), respectively, revealing the satisfactory discrimination performance of the model. The prospective investigation showed that the average AngII level in the degenerated group ( 97.62 ± 44.02 pg/mL) was significantly higher than that in the nondegenerated group ( 52.91 ± 9.01 pg/mL) ( p < 0.001 ). This present study explored the risk factors for IVDD and established a prediction model, which would effectively predict the risk of IVDD. In addition, based on the prediction model, AngII was revealed to be a potentially auxiliary clinical diagnostic marker for IVDD.

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“…Furthermore, the degradation of the ECM is also an important factor driving the progression of IVDD ( 27 ). The ECM is a non-cellular 3D macromolecular network composed of collagen, proteoglycans/glycosaminoglycans, elastin, fibronectin, laminin and several other glycoproteins ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Hydroxysafflor yellow A attenuates oxidative stress injury‑induced apoptosis in the nucleus pulposus cell line and regulates extracellular matrix balance via CA XII

Yang

Liao

2021

Exp Ther Med

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Intervertebral disc degeneration (IVDD) is the main cause of lower back pain. Oxidative stress injury and degradation of the extracellular matrix (ECM) are important factors causing IVDD, while hydroxysafflor yellow A (HSYA) has significant anti-oxidative stress and anti-apoptotic effects. The present study aimed to investigate the protective role of HSYA in IVDD using nucleus pulposus (NP) cells. A Cell Counting Kit-8 assay was used to detect cell viability following HSYA and tert-Butyl hydroperoxide (TBHP) treatment. Cellular reactive oxygen species levels and the level of apoptosis were measured using flow cytometry. The concentration of superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and glutathione peroxidase GSH-Px were detected using ELISA. DAPI staining was performed for nuclear morphology analysis, while western blot analysis was used to detect apoptotic-and ECM-related protein expression levels. Bioinformatics analysis was used to predict the binding site between HSYA and carbonic anhydrase 12 (CA12; CA XII). NP cells were transfected withsmall interference RNA (siRNA) for CA XII downregulation. Following TBHP treatment, the level of ROS increased significantly, and the concentrations of SOD, CAT and GSH-Px were decreased. In addition, the apoptosis level of the NP cell line significantly increased following TBHP treatment. Furthermore, the expression levels of ECM-related proteins, collagen II and aggrecan were significantly decreased, and the protein expression level of MMP-13 was significantly increased. HSYA (10 µM) could effectively alleviate the effects of TBHP on NP cell apoptosis, oxidative stress damage and the expression level of ECM-related proteins. A binding site was found between HSYA and CA XII. In addition, CA XII-siRNA significantly reduced the increase in the expression level of collagen II and aggrecan proteins and decrease in the expression level of MMP-13 induced by HSYA in the NP cell line. In conclusion, HSYA could attenuate oxidative stress injury and apoptosis induced by TBHP in the NP cell line, and could improve the regulation of ECM balance.

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FK506 Induces the TGF-β1/Smad 3 Pathway Independently of Calcineurin Inhibition to Prevent Intervertebral Disk Degeneration

Cited by 6 publications

References 54 publications

Physosmotic Induction of Chondrogenic Maturation Is TGF-β Dependent and Enhanced by Calcineurin Inhibitor FK506

Physosmotic Induction of Chondrogenic Maturation Is TGF-β Dependent and Enhanced by Calcineurin Inhibitor FK506

Development and Validation of a Novel Nomogram to Predict the Risk of Intervertebral Disc Degeneration

Hydroxysafflor yellow A attenuates oxidative stress injury‑induced apoptosis in the nucleus pulposus cell line and regulates extracellular matrix balance via CA XII

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