The mitochondrial UPR induced by ATF5 attenuates intervertebral disc degeneration via cooperating with mitophagy.

Intervertebral disc degeneration (IVDD) is an aging disease that results in a low quality of life and heavy socioeconomic burden. The mitochondrial unfolded protein response (UPRmt) take part in various aging-related diseases. Our research intents to explore the role and underlying mechanism of UPRmt in IVDD. Nucleus pulposus (NP) cells were exposed to IL-1ß and nicotinamide riboside (NR) served as UPRmt inducer to treat NP cells. Detection of ATP, NAD + and NADH were used to determine the function of mitochondria. MRI, Safranin O-fast green and Immunohistochemical examination were used to determine the degree of IVDD in vivo. In this study, we discovered that UPRmt was increased markedly in the NP cells of human IVDD tissues than in healthy controls. In vitro, UPRmt and mitophagy levels were promoted in NP cells treated with IL-1ß. Upregulation of UPRmt by NR and Atf5 overexpression inhibited NP cell apoptosis and further improved mitophagy. Silencing of Pink1 reversed the protective effects of NR and inhibited mitophagy induced by the UPRmt. In vivo, NR might attenuate the degree of IDD by activating the UPRmt in rats. In summary, the UPRmt was involved in IVDD by regulating Pink1-induced mitophagy. Mitophagy induced by the UPRmt might be a latent treated target for IVDD.

Optimizing percutaneous vertebroplasty: extra-facet puncture for osteoporotic vertebral compression fractures.

PURPOSE: To assess the safety and efficacy of the extra-facet puncture technique applied in unilateral percutaneous vertebroplasty (PVP) for treating osteoporotic vertebral compression fractures. METHODS: Demographics (age, gender, body mass index and underlying diseases) were recorded for analyzing. Visual analog scale (VAS) and Oswestry Disability Index (ODI) scores as well as their corresponding minimal clinically important difference (MCID) were used to evaluate clinical outcomes. The segmental kyphotic angle, the vertebral compression ratio and bone cement distribution pattern were evaluated by the plain radiographs. The facet joint violation (FJV) was defined by the postoperative computed tomography scan. Binary logistic regression analysis was performed to investigate relationships between multiple risk factors and residual back pain. RESULTS: VAS and ODI scores in both traditional puncture group and extra-facet puncture group were significantly decreased after PVP surgery (p < 0.05). However, no significant difference was observed between the two groups according to VAS and ODI scores. The proportion of patients achieving MCID of VAS and ODI scores was higher in extra-facet puncture group as compared to traditional puncture group within a month (p < 0.05). Finally, multivariate logistic regression analysis showed that FJV (odds ratio 16.38, p < 0.001) and unilateral bone cement distribution (OR 5.576, p = 0.020) were significant predictors of residual back pain after PVP surgery. CONCLUSIONS: Extra-facet puncture percutaneous vertebroplasty can decrease the risk of FJV and it also has the advantage of more satisfied bone cement distribution.

High Endplate Hounsfield Units Value Indicate Intervertebral Disc Degeneration Following Transforaminal Lumbar Interbody Fusion Surgery.

OBJECTIVE: Lumbar disc degeneration (LDD) is a common cause of low back pain and disability, and its prevalence increases with age. The aim of this study is to investigate whether endplate Hounsfield unit (HU) values have an effect on lumbar disc degeneration (LDD) after transforaminal lumbar interbody fusion (TLIF) surgery in patients with degenerative lumbar stenosis. METHODS: This study was a retrospective analysis of patients who underwent TLIF surgery in January 2016 to October 2019. One hundred and fifty-seven patients who underwent TLIF surgery for degenerative lumbar stenosis were enrolled in this study. Demographic data was recorded. VAS and ODI values were compared to assess the surgical outcomes in patients with or without process of LDD after TLIF surgery. Correlation analysis was performed to investigate associations between LDD and endplate HU value. Binary logistic regression analysis was carried out to study relationships between the DDD and the multiple risk factors. RESULTS: There was a statistically significant correlation between LDD, body mass index (BMI), age, paraspinal muscle atrophy, and total endplate scores (TEPS). Also, a strong and independent association between endplate HU value and LDD was found at every lumbar disc level (p < 0.01). After conditioning on matching factors, multivariate logistic regression analysis showed that higher endplate HU (odds ratio [OR]: 1.003, p = 0.003), higher TEPS (OR: 1.264, p = 0.002), higher BMI (odds ratio [OR]: 1.202, p = 0.002), a smaller cross-sectional area (CSA) of the paraspinal muscle preoperatively (OR: 0.096, p < 0.001) were significant predictors of LDD development after TLIF surgery. CONCLUSIONS: There is a significant association between LDD and endplate HU value after TLIF surgery in patients with degenerative lumbar stenosis. Beyond that, results from this study provide a mechanism by which high endplate HU value predisposes to LDD after TLIF surgery.

Safety and Efficacy of Polyetheretherketone (PEEK) Cages and Cadaveric Allografts in Transforaminal Lumbar Interbody Fusion (TLIF) for Treating Lumbar Pyogenic Spondylodiscitis.

Purpose: There have been many studies in the operative management of pyogenic spondylodiscitis with foreign materials. However, it still remains an issue of debate on whether the allografts may be used in pyogenic spondylodiscitis. This study sought to evaluate the safety and effectiveness of PEEK cages and the cadaveric allograft in transforaminal lumbar interbody fusion (TLIF) for treating lumbar pyogenic spondylodiscitis. Methods: From January 2012 to December 2019, 56 patients underwent surgery for lumbar pyogenic spondylodiscitis. The posterior debridement of all patients and their fusion with allografts, local bone grafts, and bone chip cages were performed before posterior pedicle screw fusion. An assessment of the residual pain, the grade of neurological injury, and the resolution of infection was conducted on 39 patients. The clinical outcome was evaluated using a visual analog scale (VAS) and the Oswestry Disability Index (ODI), and neurological outcomes were appraised based on Frankel grades. The radiological outcomes were evaluated via focal lordosis, lumbar lordosis, and the state of the fusion. Results: Staphylococcus aureus and Staphylococcus epidermidis were the most common causative organisms. The mean preoperative focal lordosis was -1.2° (-11.4° to 5.7°), and the mean postoperative focal lordosis increased to 10.3° (4.3°-17.2°). At the final follow-up, there were five cases with subsidence of the cage, no case of recurrence, and no case with cage and screw loosening or migration. The mean preoperative VAS and ODI scores were 8.9 and 74.6%, respectively, and improvements in VAS and ODI were 6.6 ± 2.2 and 50.4 ± 21.3%, respectively. The Frankel grade D was found in 10 patients and grade C in 7. Following the final follow-up, only one patient improved from Frankel grade C to grade D while the others recovered completely. Conclusion: The PEEK cage and cadaveric allograft combined with local bone grafts is a safe and effective choice for intervertebral fusion and restoring sagittal alignment without increased incidence of relapse for treating lumbar pyogenic spondylodiscitis.

Sesn2 Serves as a Regulator between Mitochondrial Unfolded Protein Response and Mitophagy in Intervertebral Disc Degeneration.

Mitochondrial unfold protein response (UPRmt) can induce mitophagy to protect cell from unfold protein. However, how UPRmt induces mitophagy to protect cell is not yet clear. Herein, Sesn2 was considered to be a key molecule that communicated UPRmt and mitophagy in the intervertebral disc. Silencing of Sesn2 was able to reverse the protective effects of Nicotinamide riboside (NR) on nucleus pulposus (NP) cells and inhibit mitophagy induced by UPRmt. UPRmt upregulated Sesn2 through Eif2ak4/eIF2α/Atf4, and further induced mitophagy. Sesn2 promoted the translocation of cytosolic Parkin and Sqstm1 to the defective mitochondria respectively, thereby enhancing mitophagy. The translocation of cytosolic Sqstm1 to the defective mitochondria was dependent on Parkin. The two functional domains of Sesn2 were necessary for the interaction of Sesn2 with Parkin and Sqstm1. The cytosolic interaction of Sesn2 between Parkin and Sqstm1 was independent on Pink1 (named as PINK1 in human) but the mitochondrial translocation was dependent on Pink1. Sesn2-/- mice showed a more severe degeneration and NR did not completely alleviate the intervertebral disc degeneration (IVDD) of Sesn2-/- mice. In conclusion, UPRmt could attenuate IVDD by upregulation of Sesn2-induced mitophagy. This study will help to further reveal the mechanism of Sesn2 regulating mitophagy, and open up new ideas for the prevention and treatment of IVDD.

Mitochondrial Dysfunction in Oxidative Stress-Mediated Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is the most common contributor to low back pain (LBP). Recent studies have found that oxidative stress and reactive oxygen species (ROS) play an important role in IVDD. As a by-product of aerobic respiration, ROS is mainly produced in the mitochondria by the electron transport chain and other mitochondrial located proteins. With the excessive accumulation of ROS, mitochondria are also the primary target of ROS attack in disc cells. A disrupted balance between intracellular ROS production and antioxidant capacity will lead to oxidative stress, which is the key contributor to cell apoptosis, cell senescence, excessive autophagy, and mitochondrial dysfunction. As the pivotal ingredient of oxidative stress, mitochondrial dysfunction manifests as imbalanced mitochondrial dynamics and dysregulated mitophagy. Mitochondria can alter their own dynamics through the process of fusion and fission, so that disabled mitochondria can be separated from the mitochondrial pool. Moreover, mitophagy participates by clearing these dysfunctional mitochondria. Abnormality in any of these processes either increases the production or decreases the clearance of ROS, leading to a vicious cycle that results in the death of intervertebral disc cells in large quantities, combined with degradation of the extracellular matrix and overproduction of matrix metalloproteinase. In this review, we explain the changes in mitochondrial morphology and function during oxidative stress-mediated IVDD and highlight the important role of mitochondria in this process. Eventually, we summarize the IVDD therapeutic strategies targeting mitochondrial dysfunction based on current understanding of the role of oxidative stress in IVDD.

Increased Expression of Prolyl Endopeptidase Induced by Oxidative Stress in Nucleus Pulposus Cells Aggravates Intervertebral Disc Degeneration.

A healthy microenvironment of the intervertebral disc tissue is characterized by hypoxia owing to its sparse vascular distribution. Oxidative stress plays a pivotal role in the pathological development of intervertebral disc degeneration (IVDD). We found that the expression of prolyl endopeptidase (PREP) increased in degenerative nucleus pulposus (NP) tissues. The purpose of this study was to determine whether PREP is involved in oxidative-stress-induced IVDD. Tertbutyl hydroperoxide can inhibit the expression of PREP by activating the PI3K/AKT signaling pathway at low concentrations in NP cells. Knockdown of PREP protected NP cells from apoptosis induced by oxidative stress, whereas overexpression of PREP exacerbated the apoptosis of NP cells. We also investigated the connection between the PI3K/AKT signaling pathway and PREP and found that the activation of the PI3K/AKT signaling pathway downregulated the expression of PREP by inhibiting p53. As a crucial transcription factor, p53 binds to the PREP promoter region and promotes its transcription. Overexpression of PREP also impairs protein secretion in the extracellular matrix of NP cells. Furthermore, the in vivo knockout of PREP could attenuate puncture-induced IVDD. These findings suggested that the downregulation of PREP might maintain the viability of NP cells and attenuate IVDD under oxidative stress.

Anterior cervical discectomy and fusion to treat cervical instability with vertigo and dizziness: A single center, retrospective, observational study.

Purpose: The current study attempts to investigate the role of anterior cervical discectomy and fusion (ACDF) in alleviating symptoms in patients with cervical vertigo associated with cervical instability. Methods: The patients of cervical instability with vertigo and dizziness who underwent ACDF between January 2011 and December 2019 were followed-up for more than two years. Demographic data (age, sex, follow up period and levels of instable cervical segments) were assessed; Symptoms of vertigo and dizziness before and after surgery were assessed by the 15-item version of the Vertigo Symptom Scale (VSS) and the 25-item Dizziness Handicap Inventory (DHI). The severity and frequency of other symptoms like neck and occipital pain, gastrointestinal discomfort, nausea, vomiting, tinnitus, palpitations, headache, diplopia and blurring of vision before and after surgery were also assessed. Results: A total of 92 patients underwent ACDF for cervical instability with vertigo and dizziness between January 2011 and December 2019, of which 79 patients were included in the final analysis. The number of instable levels had no correlation with VSS and DHI scores before surgery (p > 0.05), while patients with C3/4 instability suffering a severer vertigo than other levels. Both DHI and VSS scores were significantly reduced after ACDF and this was sustained within two years after surgery (p < 0.001). Although there was no statistical difference in the ratio of patients with vertigo relief, patients with one-level cervical instability demonstrated a more rapid recovery than patients with multi-level cervical instability (p = 0.048). Also, there was improvement in other symptoms such as neck and occipital pain, gastrointestinal discomfort, nausea, vomiting, tinnitus, palpitations, headache and blurring of vision after surgery. Conclusions: Vertigo caused by C3/4 instability was severer than other levels such as C4/5 and C5/6. During 2 years' follow-up the significant relief of vertigo and dizziness was observed after anterior cervical surgery. Other accompanying symptoms except hypomnesia were also extenuated in follow-up period.

Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination.

Bone health requires adequate bone mass, which is maintained by a critical balance between bone resorption and formation. In our study, we identified beraprost as a pivotal regulator of bone formation and resorption. The administration of beraprost promoted differentiation of mouse bone mesenchymal stem cells (M-BMSCs) through the PI3K-AKT pathway. In co-culture, osteoblasts stimulated with beraprost inhibited osteoclastogenesis in a rankl-dependent manner. Bone mass of p53 knockout mice remained stable, regardless of the administration of beraprost, indicating that p53 plays a vital role in the bone mass regulation by beraprost. Mechanistic in vitro studies showed that p53 binds to the promoter region of neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) to promote its transcription. As a ubiquitinating enzyme, Nedd4 binds to runt-related transcription factor 2 (Runx2), which results in its ubiquitination and subsequent degradation. These data indicate that the p53-Nedd4-Runx2 axis is an effective regulator of bone formation and highlight the potential of beraprost as a therapeutic drug for postmenopausal osteoporosis.

Exosomes derived from vascular endothelial cells antagonize glucocorticoid-induced osteoporosis by inhibiting ferritinophagy with resultant limited ferroptosis of osteoblasts.

High dose and long-term steroid treatment can alter antioxidative ability and decrease the viability and function of osteoblasts, leading to osteoporosis and osteonecrosis. Ferroptosis, a new type of cell death characterized by excessive lipid peroxidation due to the downregulation of GPX4 and system Xc- , is involved in glucocorticoid-induced osteoporosis. Endothelial cell-secreted exosomes (EC-Exos) are important mediators of cell-to-cell communication and are involved in many physiological and pathological processes. However, the effect of EC-Exos on osteoblasts exposed to glucocorticoids has not been reported. Here, we explored the role of EC-Exos in glucocorticoid-induced osteoporosis. In vivo and in vitro experiments indicated that EC-Exos reversed the glucocorticoid-induced osteogenic inhibition of osteoblasts by inhibiting ferritinophagy-dependent ferroptosis.

Vascular endothelial cell-secreted exosomes facilitate osteoarthritis pathogenesis by promoting chondrocyte apoptosis.

Exosomes are major mediators of cell-to-cell communication, and are involved in many physiological and pathological processes. Recently, the roles of exosomes in osteoarthritis (OA) and their therapeutic potential have received increasing attention. Exosomes derived from vascular endothelial cells have been confirmed to participate in the occurrence and development of numerous diseases; however, their effects in OA have not been reported. Here, we demonstrated the roles of exosomes secreted by vascular endothelial cells in the development of OA. Through in vivo and in vitro experiments, we demonstrated that exosomes derived from vascular endothelial cells decreased the ability of chondrocytes to resist oxidative stress by inhibiting autophagy and p21 expression, thereby increasing the cellular ROS content and inducing apoptosis. These findings indicate that exosomes derived from vascular endothelial cells promote the progression of OA, thus, providing new ideas for the diagnosis and treatment of OA.

Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis.

Ferroptosis is a necrotic form of regulated cell death that was associated with lipid peroxidation and free iron-mediated Fenton reactions. It has been reported that iron deficiency had been implicated in the pathogenesis of intervertebral disc degeneration (IVDD) by activating apoptosis. However, the role of ferroptosis in the process of IVDD has not been illuminated. Here, we demonstrate the involvement of ferroptosis in IVDD pathogenesis. Our in vitro models show the changes in protein levels of ferroptosis marker and enhanced lipid peroxidation level during oxidative stress. Safranin O staining, hematoxylin-eosin staining, and immunohistochemical were used to assess the IVDD after 8 weeks of surgical procedure in vivo. Treatment with ferrostatin-1, deferoxamine, and RSL3 demonstrate the role of ferroptosis in tert-butyl hydroperoxide (TBHP)-treated annulus fibrosus cells (AFCs) and nucleus pulposus cells (NPCs). Ferritinophagy, nuclear receptor coactivator 4 (NCOA4)-mediated ferritin selective autophagy, is originated during the process of ferroptosis in response to TBHP treatment. Knockdown and overexpression NCOA4 further prove TBHP may induce ferroptosis of AFCs and NPCs in an autophagy-dependent way. These findings support a role for oxidative stress-induced ferroptosis in the pathogenesis of IVDD.

NDUFA4L2 Regulated by HIF-1α Promotes Metastasis and Epithelial-Mesenchymal Transition of Osteosarcoma Cells Through Inhibiting ROS Production.

Osteosarcoma (OS) accounts for a large proportion of the types of bone tumors that are newly diagnosed, and is a relatively common bone tumor. However, there are still no effective treatments for this affliction. One interesting avenue is related to the mitochondrial NDUFA4L2 protein, which is encoded by the nuclear gene and is known to be a critical mediator in the regulation of cell survival. Thus, in this study, we aimed to investigate the effect of NDUFA4L2 upon the metastasis and epithelial-mesenchymal transition of OS. We found that NDUFA4L2 protein expression was upregulated in hypoxic conditions. We also used 2-ME and DMOG, which are HIF-1α inhibitors and agonists, respectively, to assess the effects related to decreasing or increasing HIF-1α expression. 2-ME caused a significant decrease of NDUFA4L2 expression and DMOG had the opposite effect. It was obvious that down-regulation of NDUFA4L2 had a direct interaction with the apoptosis of OS cells. Western blotting, wound healing analyses, Transwell invasion assays, and colony formation assays all indicated and supported the conclusion that NDUFA4L2 promoted OS cell migration, invasion, proliferation, and the epithelial-mesenchymal transition. During experiments, we incidentally discovered that autophagy and the ROS inhibitor could be used to facilitate the rescuing of tumor cells whose NDUFA4L2 was knocked down. Our findings will help to further elucidate the dynamics underlying the mechanism of OS cells and have provided a novel therapeutic target for the treatment of OS.

Characterization of LncRNA SNHG22 as a protector of NKIRAS2 through miR-4492 binding in osteosarcoma.

Many studies have revealed the function of long noncoding RNA (LncRNA) in regulating tumorigenesis of osteosarcoma (OS). As a subgroup of LncRNA, small nucleolar RNA host genes (SNHGs) have emerged as potentially important in OS. According to our recent findings, small nucleolar RNA host gene 22 (SNHG22) plays an important role in inhibiting the growth and metastasis of OS. However, the underlying mechanism of SNHG22 in regulating OS progression remains unknown. In this study, we confirmed that SNHG22 was downregulated in OS, and the overexpression of SNHG22 significantly inhibited OS progression in vivo and in vitro. Meanwhile, overexpression of SNHG22 also inhibited the migration and proliferation of human umbilical vein endothelial cells (HUVECs) and prevented the epithelial-to-mesenchymal transition (EMT) in OS. Furthermore, the interaction between miR-4492 and SNHG22 we previously predicted was validated by RNA pull-down assays and RNA immunoprecipitation assays. Dual-luciferase reporter assays showed that SNHG22 could directly interact with miR-4492 and upregulate the expression of NK-κB inhibitor-interacting Ras-like 2 (NKIRAS2) by its competing endogenous RNA (ceRNA) activity on miR-4492. In conclusion, our study has clarified the function of SNHG22 in OS progression and suggests a novel therapeutic target for OS.

Mitochondrial NDUFA4L2 attenuates the apoptosis of nucleus pulposus cells induced by oxidative stress via the inhibition of mitophagy.

The main pathological mechanism of intervertebral disc degeneration (IVDD) is the programmed apoptosis of nucleus pulposus (NP) cells. Oxidative stress is a significant cause of IVDD. Whether mitophagy is induced by strong oxidative stress in IVDD remains to be determined. This study aimed to investigate the relationship between oxidative stress and mitophagy and to better understand the mechanism of IVDD in vivo and in vitro. To this end, we obtained primary NP cells from the human NP and subsequently exposed them to TBHP. We observed that oxidative stress induced mitophagy to cause apoptosis in NP cells, and we suppressed mitophagy and found that NP cells were protected against apoptosis. Interestingly, TBHP resulted in mitophagy through the inhibition of the HIF-1α/NDUFA4L2 pathway. Therefore, the upregulation of mitochondrial NDUFA4L2 restricted mitophagy induced by oxidative stress. Furthermore, the expression levels of HIF-1α and NDUFA4L2 were decreased in human IVDD. In conclusion, these results demonstrated that the upregulation of NDUFA4L2 ameliorated the apoptosis of NP cells by repressing excessive mitophagy, which ultimately alleviated IVDD. These findings show for the first time that NDUFA4L2 and mitophagy may be potential therapeutic targets for IVDD.

Chordin-Like 1 Improves Osteogenesis of Bone Marrow Mesenchymal Stem Cells Through Enhancing BMP4-SMAD Pathway.

Chordin-like 1 (CHRDL1) is a secreted glycoprotein with repeated cysteine-rich domains, which can bind to BMPs family ligands. Although it has been reported to play important roles in several systems, the exact roles of CHRDL1 on human bone mesenchymal stem cells (hBMSCs) osteogenesis remain to be explored. The present study aimed to investigate the roles of CHRDL1 on the osteogenic differentiation of hBMSCs and the underlying molecular mechanisms. We found that CHRDL1 was upregulated during hBMSCs osteogenesis, and rhBMP-4 administration could enhance CHRDL1 mRNA expression in a dose and time dependent manner. Knockdown of CHRDL1 did not affect hBMSCs proliferation, but inhibited the BMP-4-dependent osteogenic differentiation, showing decreased mRNA expression levels of osteogenic markers and reduced mineralization. On the contrary, overexpression of CHRDL1 enhanced BMP-4 induced osteogenic differentiation of hBMSCs. Moreover, in vivo experiments by transplanting CHRDL1 gene modified hBMSCs into nude mice defective femur models displayed higher new bone formation in CHRDL1 overexpression groups, but lower new bone formation in CHRDL1 knockdown groups, compared with control groups. In consistent with the bone formation rate, there were increased CHRDL1 protein expression in new bone formation regions of defective femur in CHRDL1 overexpression groups, while reduced CHRDL1 protein expression in CHRDL1 knockdown groups compared with control groups. These indicate that CHRDL1 can promote osteoblast differentiation in vivo. Furthermore, the mechanisms study showed that CHRDL1 improved BMP-4 induced phosphorylation of SMAD1/5/9 during osteogenic differentiation of hBMSCs. Besides, promotion of osteogenic differentiation and the activation of SMAD phosphorylation by CHRDL1 can be blocked by BMP receptor type I inhibitor LDN-193189. In conclusion, our results suggested that CHRDL1 can promote hBMSCs osteogenic differentiation through enhancing the activation of BMP-4-SMAD1/5/9 pathway.

PGC-1α acts as an mediator of Sirtuin2 to protect annulus fibrosus from apoptosis induced by oxidative stress through restraining mitophagy.

Apoptosis of annulus fibrosus (AF) is observed widely in intervertebral disc degeneration (IVDD) which causes weaken of tension in the annulus of intervertebral disc. Previous studies reported that apoptosis of AF is induced mainly by oxidative stress. SIRT2 is a major regulator of mitochondria to mediate ROS production. However, the mechanism of SIRT2 in IVDD remains unclear. Here, the expression of SIRT2 was detected in AF cells exposed to tert-Butyl hydroperoxide (TBHP) by western blotting. Autophagic flux and apoptosis were assessed by western blotting, flow cytometry and immunofluorescence respectively. Safranin O staining, HE, and immunohistochemical were used to assess the IVDD after 3, 6 and 9 months of surgical procedure in vivo. The expression of SIRT2 was decreased in AF cells treated with TBHP. Repression of mitophagy alleviated the apoptosis of AF cells caused by TBHP. Overexpression of PGC-1α prevented AF cells from apoptosis and mitophagy after applying Lenti-PGC-1α to transfect AF cells. These protections of PGC-1α were reduced by FCCP. Furthermore, the expression of PGC-1α was reduced and the level of mitophagy was increased in IVDD models. In conclusion, this study indicates that the regulation of PGC-1α expression provide a new theoretical basis for the mechanism of IVDD.

HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway.

Long-term and high dose glucocorticoid treatment can cause decreased viability and function of osteoblasts, which leads to osteoporosis and osteonecrosis. In this study, we investigated the role and mechanism of action of HIF-1α in glucocorticoid-induced osteogenic inhibition in MC3T3-E1 cells. Our results showed that HIF-1α protein expression was reduced when MC3T3-E1 cells were exposed to dexamethasone (Dex) at varying concentrations ranging from 10-9 to 10-6 M. PDK1 expression was also decreased in MC3T3-E1 cells after dexamethasone treatment. MC3T3-E1 cells when treated with the glucocorticoid receptor antagonist RU486 along with dexamethasone showed enhanced HIF-1α expression. In addition, upregulated expression of HIF-1α was capable of promoting the osteogenic ability of MC3T3-E1 cells and PDK1 expression. However, the HIF-1α antagonist 2-methoxyestradiol (2-ME) had a reverse effect in MC3T3-E1 cells exposed to dexamethasone. Furthermore, the PDK1 antagonist dichloroacetate could repress the osteogenic ability of MC3T3-E1 cells, although HIF-1α was upregulated when transduced with adenovirus-HIF-1α construct. The PDK1 agonist PS48 was able to promote the osteogenic ability of MC3T3-E1 cells treated with dexamethasone. Importantly, the protein levels of p-AKT and p-mTOR were increased in MC3T3-E1 cells treated with dexamethasone after PS48 treatment. in vivo, the PDK1 agonist PS48 could maintain the bone mass of mice treated with dexamethasone. This study provides a new understanding of the mechanism of glucocorticoid-induced osteoporosis.