Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission.

BACKGROUND: Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. MATERIALS AND METHODS: In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. RESULTS: We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. CONCLUSION: Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.

Role of Galectin-3 in intervertebral disc degeneration: an experimental study.

BACKGROUND: This study investigated the role of Galectin-3 in the degeneration of intervertebral disc cartilage. METHODS: The patients who underwent lumbar spine surgery due to degenerative disc disease were recruited and divided into Modic I, Modic II, and Modic III; groups. HE staining was used to detect the pathological changes in endplates. The changes of Galectin-3, MMP3, Aggrecan, CCL3, and Col II were detected by immunohistochemistry, RT-PCR, and Western blot. MTT and flow cytometry were used to detect cartilage endplate cell proliferation, cell cycle, and apoptosis. RESULTS: With the progression of degeneration (from Modic I to III), the chondrocytes and density of the cartilage endplate of the intervertebral disc decreased, and the collagen arrangement of the cartilage endplate of the intervertebral disc was broken and calcified. Meanwhile, the expressions of Aggrecan, Col II, Galectin-3, Aggrecan, and CCL3 gradually decreased. After treatment with Galectin-3 inhibitor GB1107, the proliferation of rat cartilage end plate cells was significantly reduced (P < 0.05). GB1107 (25 µmol/L) also significantly promoted the apoptosis of cartilage endplate cells (P < 0.05). Moreover, the percentage of cartilage endplate cells in the G1 phase was significantly higher, while that in the G2 and S phases was significantly lower (P < 0.05). Additionally, the mRNA and protein expression levels of MMP3, CCL3, and Aggrecan in rat cartilage end plate cells were lower than those in the control group. CONCLUSIONS: Galectin-3 decreases with the progression of the cartilage endplate degeneration of the intervertebral disc. Galectin-3 may affect intervertebral disc degeneration by regulating the degradation of the extracellular matrix.

Sesamin-mediated high expression of BECN2 ameliorates cartilage endplate degeneration by reducing autophagy and inflammation.

Lumbar disc degeneration (LDD) is a prevalent clinical spinal disease characterized by the calcification and degeneration of the cartilage endplate (CEP), which significantly reduces nutrient supply to the intervertebral disc. Traditional Chinese medicine offers a conservative and effective approach for treating LDD. We aimed to investigate the molecular mechanisms underlying the therapeutic effects of Sesamin in LDD treatment. Transcriptome sequencing was used to analyze the effect of Sesamin on LPS-induced ATDC5. We explored the role of BECN2, a target gene of Sesamin, in attenuating LPS-induced degeneration of ATDC5 cells. Our results revealed the identification of 117 differentially expressed genes (DEGs), with 54 up-regulated and 63 down-regulated genes. Notably, Sesamin significantly increased the expression of BECN2 in LPS-induced ATDC5 cell degeneration. Overexpressed BECN2 enhanced cell viability and inhibited cell apoptosis in LPS-induced ATDC5 cells, while BECN2 knockdown reduced cell viability and increased apoptosis. Furthermore, BECN2 played a crucial role in attenuating chondrocyte degeneration by modulating autophagy and inflammation. Specifically, BECN2 suppressed autophagy by reducing the expression of ATG14, VPS34, and GASP1, and alleviated the inflammatory response by decreasing the expression of inflammasome proteins NLRP3, NLRC4, NLRP1, and AIM2. In vivo experiments further supported the beneficial effects of Sesamin in mitigating LDD. This study provides novel insights into the potential molecular mechanism of Sesamin in treating LDD, highlighting its ability to mediate autophagy and inflammation inhibition via targeting the BECN2. This study provides a new therapeutic strategy for the treatment of LDD, as well as a potential molecular target for LDD.

Abdominal aortic calcification is independently associated with lumbar endplate degeneration.

BACKGROUND: Abdominal aortic calcification (AAC) is associated with lower back pain, reduced bone mineral density of the spine. Vascular changes could also affect the already sparsely perfused intervertebral endplate and intervertebral disc. METHODS: Lumbar MRIs and lateral radiographs of patients with lower back pain were retrospectively analyzed. AAC was assessed on lateral lumbar radiographs according to the Kauppila score, with a maximum score of 24. Patients were grouped into no (AAC = 0), moderate (AAC 1 to ≤ 4), and severe AAC (AAC ≥ 5). Endplate and disc degeneration were classified according to the total endplate score (TEPS) and Pfirrmann classification. The associations between AAC and degenerative changes was analyzed with a generalized mixed model and was adjusted for age, sex, body mass index as well as diabetes mellitus, and smoking status. RESULTS: A total of 217 patients (47.9% female) were included in the analysis, totaling 1085 intervertebral levels. Of those, 45 (20.7%) patients had moderate, and 39 (18%) had severe AAC. The results of the generalized mixed model showed no significant association between AAC and disc degeneration (p > 0.05). In contrast, a significant positive association between AAC and the severity of TEPS (ß: 0.51, 95% CI: 1.92-2.12, p = 0.004) was observed in the multivariable analysis. CONCLUSIONS: This study demonstrates an independent association between AAC and endplate degeneration. These findings expand our knowledge about the degenerative cascade of the lumbar spine and suggest that AAC might be a modifiable risk factor for endplate changes.

Basivertebral nerve ablation for the treatment of chronic low back pain in a community practice setting: 6 Months follow-up.

Background: Strong innervation of the vertebral endplates by the basivertebral nerve makes it an ideal target for ablation in the treatment of vertebrogenic low back pain with Modic changes. This data represents the clinical outcomes for 16 consecutively treated patients in a community practice setting. Methods: Basivertebral nerve ablations were performed on 16 consecutive patients by a single surgeon (WS) utilizing the INTRACEPT® device (Relievant Medsystems, Inc.). Evaluations were performed at baseline, 1 month, 3 months, and 6 months. The Oswestry Disability Index (ODI), Visual Analog Scale (VAS), and SF-36 were recorded in Medrio electronic data capture software. All patients (n = 16) completed the baseline, 1 month, 3 months, and 6 months follow-up. Results: The ODI, VAS, and SF-36 Pain Component Summary showed statistically significant improvements above minimal clinically important differences at 1 month, 3 months, and 6 months (all p values <0.05). Change in ODI pain impact declined 13.1 points [95% CI: 0.01,27.2] at one month from baseline, 16.5 points [95% CI: 2.5,30.6] at three months from baseline, and 21.1 points [95% CI: 7.0,35.2] six-months from baseline. SF-36 Mental Component Summary also showed some improvements, but with significance only at 3 months (p = 0.0091). Conclusions: Basivertebral nerve ablation appears to be a durable, minimally invasive treatment for the relief of chronic low back pain that can be successfully implemented in a community practice setting. To our knowledge, this is the first independently funded US study on basivertebral nerve ablation.

Basivertebral Nerve Ablation for the Treatment of Chronic Low Back Pain: A Scoping Review of the Literature.

BACKGROUND: Chronic low back pain is a leading cause of disability worldwide and its pathophysiology remains poorly understood, a problem exacerbated by the heterogeneity of the patient population with chronic low back pain. Although the intervertebral discs are often implicated in chronic low back pain, studies have demonstrated strong innervation of the vertebral endplates by the basivertebral nerve, therefore making it a possible target for ablation in the treatment of vertebrogenic chronic low back pain. OBJECTIVES: This work reviews the current evidence for the efficacy and safety of basivertebral nerve ablation as a treatment modality for chronic low back pain, and discusses the possible study biases and gaps in the current knowledge to provide insight on future research. STUDY DESIGN: The authors registered with the Center for Open Sciences and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews  (PRISMA-ScR). SETTING: A private clinic. METHODS: This study was performed in accordance with the following 5-stage methodological framework for scoping reviews: (i) identifying the research question; (ii) identifying relevant studies; (iii) selecting studies; (iv) charting the data; and (v) collating, summarizing and reporting the results. Three databases (PubMed, Web of Science, Embase) were searched using the keywords "basivertebral", "nerve", and "ablation". RESULTS: From March 2002 to March 2022, a total of 47 articles were identified, of which 12 were included in this scoping review, based on the exclusion criteria described in Table 1. LIMITATIONS: The limitations found were: • A very specific chronic pain population is typically utilized for this intervention. The inclusion criteria leave many who experience chronic low back pain ineligible for the procedure. • Study demographics need to be more diversified to truly represent the chronic low back pain population.• There is a lack of true control groups due to high crossover rates in published studies.• Very few high-level or long-term studies have been published.• Funding for many of the studies published on the subject is industry-led (Table 6). With an already limited amount of published research, a need for out-of-industry funding is required to avoid any possibility of bias. CONCLUSIONS: Current research has shown that basivertebral nerve ablation might be a promising treatment for chronic low back pain in patients exhibiting Modic type 1 or 2 endplate changes, while additional research on the association between Modic changes and low back pain is still needed to gain widespread use and acceptance of this new treatment modality. The introduction of new devices and a larger number of independent studies would greatly enhance the confidence in the outcomes reported with this treatment modality in order to ultimately benefit patients, clinicians, and society.

YAP1 controls degeneration of human cartilage chondrocytes in response to mechanical tension.

Disc herniation is a kind of disease caused by degenerative discs, which is common in the elderly, bringing substantial financial burden to families and society. Mechanical tension has a vital effect on the maintenance of cartilage function, however, the molecular mechanism by which mechanical tension causes degenerative discs to remain unclear. This study was the first to reveal Yes-associated protein 1(YAP1) is a key regulator in mechanical tension-mediated degenerative discs. Activation of YAP1 may be a valuable strategy to delays the degeneration of human cartilage chondrocytes. We found that YAP1 expression was significantly decreased in degenerative human endplate cartilage and tissue with the strength and time of mechanical stimulation, but the cell cycle distribution was significantly changed under the 10% cyclic mechanical tension(CMT). Besides, the degeneration of endplate cartilage can be delayed by activating the expression level of YAP1 in vitro and it has also been verified in the cartilage endplate tissue in vitro. Furthermore, We found that YAP1 and TEAD1 overexpression increased the activity of the ACAN or COL2A1 promoter to enhance the transcriptional activity of human chondrocyte collagen. The CMT activates the classic Hippo signaling pathway of YAP1, and piezo1 may regulate YAP1 expression through the Hippo signaling pathway. In conclusion, these results suggest the novel mechanism of YAP contributes to delaying the degeneration of endplate cartilage and targeting YAP in combination with Piezo1 is a potential therapeutic approach for the treatment of endplate cartilage degeneration.

The Role and Mechanisms of Mechanical Stimulation in Degeneration of Vertebral Cartilage Endplates / 医用生物力学

The important function of the endplate is to transmit stress and supply nutrition. Endplate degeneration might induce or promote degeneration of the intervertebral disc, causing a series of spine diseases that seriously impair people’s health and life quality. Endplate chondrocytes can respond to mechanical stimulation, which is an important factor affecting endplate degeneration. Inappropriate mechanical stimulation will accelerate endplate degeneration. This review summarized the effects of mechanical stimulation on vertebral endplate chondrocyte apoptosis, synthesis inhibition, calcification, and extracellular matrix degradation. The endplate degeneration induced by mechanical stimulation is regulated by a complex network of signal pathways composed of various signal transduction factors. The signal pathways involved in this review included NF-κB, Wnt, Hedgehog, MAPK, RhoA/Rock-1, AKT/mTOR, TGF-β signaling pathway and miRNA related signals. The interconnection of these pathways was highlighted and summarized. Multiple signaling pathways work together to regulate endplate chondrocyte metabolism, which ultimately leads to the endplate degeneration. This review might shed light on early diagnosis and precise treatment of cartilage endplate degeneration.

Correlation between the HIF-1α/Notch signaling pathway and Modic changes in nucleus pulposus cells isolated from patients with low back pain.

BACKGROUND: The HIF-1α/Notch signaling pathway regulates cell proliferation, apoptosis, and metabolism in the intervertebral discs (IVDs) and is implicated in disc degeneration. The nucleus pulposus (NP) is an important structure adjacent to the IVDs. However, the role of the HIF-1α/Notch signaling pathway in NP cells obtained from patients with different Modic changes (MCs) remains unclear. The purpose of the present study was to investigate the role of HIF-1α and components of the Notch pathway in the NP obtained from patients with various MCs. METHODS: A total of 85 NP tissue samples were collected from patients undergoing diskectomy for the treatment of low back pain. The NP tissues were divided into four groups based on the adjacent endplate degeneration, namely, MC I, II, III, and negative MC groups. The expression of HIF-1α and Notch-related components was measured and compared. RESULTS: The expression of HIF-1α, Notch1, and Notch2 was gradually increased in the MC I and MC II groups compared with that in the negative MC group. HIF-1α and Notch-related components were rarely detected in the MC III group. CONCLUSIONS: The expression of HIF-1α/Notch increased in the NP cells of patients with MC I and MC II. HIF-1α and Notch-related components are potential biomarkers and the HIF-1α/Notch signaling pathway may serve as a promising therapeutic target for disc degeneration in patients with MCs.

Propionibacterium acnes induces cartilaginous endplate degeneration by promoting MIF expression via the NF-κB pathway.

BACKGROUND: Propionibacterium acnes (P. acnes) is a novel pathogenic factor that contributes to cartilaginous endplate (CEP) degeneration. However, the underlying mechanism of P. acnes-induced CEP degeneration remains unclear. The objective of this study is to investigate the underlying mechanism of P. acnes-induced CEP degeneration. METHODS: We first examined MIF expression in degenerated human CEP samples by immunohistochemistry. We developed a P. acnes-induced rat model and detected MIF expression using immunohistochemistry. Additionally, we investigated the mechanism of P. acnes-induced CEP degeneration in CEP cells using western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: We found that compared with the normal human CEP, the expression of MIF was increased in the degenerated human CEP. In a rat model, P. acnes induced CEP degeneration and upregulated MIF expression significantly. More importantly, we revealed the underlying mechanism of P. acnes-induced CEP degeneration in the rat CEP cells. Firstly, P. acnes induced the expression of MIF in a concentration-dependent manner. Then, MIF upregulated the expression of MMP-13 and promoted the secretion of IL-6 and IL-1ß. Finally, P. acnes may promote MIF expression via NF-κB pathway rather than ERK1/2 pathway. CONCLUSION: P. acnes-induced MIF expression via NF-κB pathway may be the underlying mechanism of CEP degeneration.

Back to the beginning: Identifying lesions of diffuse idiopathic skeletal hyperostosis prior to vertebral ankylosis.

OBJECTIVE: To better understand the pathogenesis of DISH, identifying early or pre-DISH lesions in the spine and investigating the relationship between spinal and extra-spinal manifestations of DISH. MATERIAL: 44 skeletonized individuals with DISH from the WM Bass Donated Skeletal Collection. METHODS: For each vertebra, location, extension, point of origin and appearance of vertebral outgrowths were recorded. The size of the enthesophytes at the olecranon process, patella and calcaneal tuberosity was measured with digital callipers. RESULTS: At either end of the DISH-ankylosed segment, isolated vertical outgrowths arising from the central third of the anterior aspect of the vertebral body can usually be observed. These bone outgrowths show a well-organized external cortical layer, an internal structure of trabecular bone and usually are unaccompanied by or show minimal associated endplate degeneration. Analysis of the relationship between spinal and extra-spinal manifestations (ESM) suggests great inter-individual variability. No correlation between any ESM and the stage of spinal DISH was found. CONCLUSIONS: Small isolated outgrowths represent the earliest stages of the spinal manifestations of DISH. The use of ESM as an indicator of DISH should be undertaken with great caution until the relationship between these two features is understood. SIGNIFICANCE: Improved accuracy of paleopathological diagnostic criteria of DISH. LIMITATIONS: Small sample comprised of only individuals with DISH. FUTURE RESEARCH: micro-CT analysis to investigate the internal structure of the spinal lesions. Analysis of extra-spinal enthesophytes in individuals with and without DISH to understand their pathogenesis and association with the spinal lesions in individuals with DISH.

A prospective, randomized, multicenter study of intraosseous basivertebral nerve ablation for the treatment of chronic low back pain.

BACKGROUND CONTEXT: Current literature suggests that degenerated or damaged vertebral endplates are a significant cause of chronic low back pain (LBP) that is not adequately addressed by standard care. Prior 2-year data from the treatment arm of a sham-controlled randomized controlled trial (RCT) showed maintenance of clinical improvements at 2 years following radiofrequency (RF) ablation of the basivertebral nerve (BVN). PURPOSE: The purpose of this RCT was to compare the effectiveness of intraosseous RF ablation of the BVN to standard care for the treatment of chronic LBP in a specific subgroup of patients suspected to have vertebrogenic related symptomatology. STUDY DESIGN/SETTING: A prospective, parallel, open label RCT was conducted at 20 U.S. sites. PATIENT SAMPLE: A total of 140 patients with chronic LBP of at least 6 months duration, with Modic Type 1 or 2 vertebral endplate changes between L3 and S1, were randomized 1:1 to undergo either RF ablation of the BVN or continue standard care. OUTCOME MEASURES: Oswestry Disability Index (ODI) was collected at baseline, 3, 6, 9, and 12-months postprocedure. Secondary outcome measures included a 10-point Visual Analog Scale (VAS) for LBP, ODI and VAS responder rates, SF-36, and EQ-5D-5L. The primary endpoint was a between-arm comparison of the mean change in ODI from baseline to 3 months post-treatment. METHODS: Patients were randomized 1:1 to receive RF ablation or to continue standard care. Self-reported patient outcomes were collected using validated questionnaires at each study visit. An interim analysis to assess for superiority was prespecified and overseen by an independent data management committee when a minimum of 60% of patients had completed their 3-month primary endpoint visit. RESULTS: The interim analysis showed clear statistical superiority (p<.001) for all primary and secondary patient-reported outcome measures in the RF ablation arm compared with the standard care arm. This resulted in a data management committee recommendation to halt enrollment in the study and offer early cross-over to the control arm. These results are comprised of the outcomes of the 104 patients included in the intent-to-treat analysis of the 3-month primary endpoint, which included 51 patients in the RF ablation arm and 53 patients in the standard care arm. Baseline ODI was 46.1, VAS was 6.67, and mean age was 50 years. The percentage of patients with LBP symptoms ≥5 years was 67.3%. Comparing the RF ablation arm to the standard care arm, the mean changes in ODI at 3 months were -25.3 points versus -4.4 points, respectively, resulting in an adjusted difference of 20.9 points (p<.001). Mean changes in VAS were -3.46 versus -1.02, respectively, an adjusted difference of 2.44 cm (p<.001). In the RF ablation arm, 74.5% of patients achieved a ≥10-point improvement in ODI, compared with 32.7% in the standard care arm (p<0.001). CONCLUSIONS: Minimally invasive RF ablation of the BVN led to significant improvement of pain and function at 3-months in patients with chronic vertebrogenic related LBP.

A prospective, open-label, single-arm, multi-center study of intraosseous basivertebral nerve ablation for the treatment of chronic low back pain.

PURPOSE: A prospective, single-arm, open-label study to evaluate the effectiveness of intraosseous radio frequency (RF) ablation of the basivertebral nerve (BVN) for the treatment of vertebrogenic-related chronic low back pain (CLBP) in typical spine practice settings using permissive criteria for study inclusion. METHODS: Consecutive patients with CLBP of at least 6 months duration and with Modic Type 1 or 2 vertebral endplate changes between L3 and S1 were treated with RF ablation of the BVN in up to four vertebral bodies. The primary endpoint was patient-reported change in Oswestry Disability Index (ODI) from baseline to 3 months post-procedure. Secondary outcome measures included change in visual analog scale (VAS), SF-36, EQ-5D-5L, and responder rates. RESULTS: Median age was 45 years; baseline ODI was 48.5; VAS was 6.36. Seventy-five percent (75%) of the study patients reported LBP symptoms for ≥ 5 years; 25% were actively using opioids; and 61% were previously treated with injections. Mean change in ODI at 3 months posttreatment was - 30.07 +14.52 points (p < 0.0001); mean change in VAS was - 3.50 + 2.33 (p < 0.0001). Ninety-three percent (93%) of patients achieved a ≥ 10-point improvement in ODI, and 75% reported ≥ 20-point improvement. CONCLUSIONS: Minimally invasive RF ablation of the BVN demonstrated a significant improvement in pain and function in this population of real-world patients with chronic vertebrogenic-related LBP. These slides can be retrieved under Electronic Supplementary Material.

Expression of miR-625 and Fas in cervical vertebral cartilage endplate.

The aim of the present study was to assess miR-625 and Fas expression in normal and degenerative cervical cartilage endplate (CEP) tissues. Following biof-informatics analysis, the Fas gene was predicted to be one of the targets of miR-625. Quantitative PCR (qPCR) and western blotting were used to detect miR-625 and Fas expression in normal and degenerative CEP. A luciferase reporter assay was used to identify whether miR-625 could directly target the 3' untranslated region (3'-UTR) of Fas. Lentiviral overexpression and/or inhibition vectors of miR-625 (pre-miR-625)/antigomiR-625 were constructed to determine whether overexpression or inhibition of miR-625 could affect Fas and B-cell lymphoma 2 (Bcl-2) expression in cartilaginous endplate cells (CECs) and tissues. qPCR analysis demonstrated that miR-625 expression in degenerative CEP was significantly lower than in normal CEP tissue, while the production of Fas in degenerated CEP was significantly higher. Results from western blotting also showed a significant increase in Fas expression in degenerative CEP. miR-625 can bind directly to the 3'-UTR of the Fas gene. However, this inhibition was attenuated by a target mutation in the miR-625-binding site of the 3'-UTR of Fas mRNA. In addition, following transfection of CECs with pre-miR-625 and antigomiR-625, expression of Fas significantly decreased and increased, respectively, and Bcl-2 expression was upregulated and downregulated, respectively. Upregulation of miR-625 can inhibit Fas expression and further affect Bcl-2 expression in CEP degeneration, suggesting that miR-625-mediated inhibition of the Fas gene is important in cervical degeneration.

Nutrition deficiency promotes apoptosis of cartilage endplate stem cells in a caspase-independent manner partially through upregulating BNIP3.

Nutrition deficiency is reported to induce apoptosis of chondrocytes and degeneration of cartilage endplate (CEP) in rabbit. Cartilage endplate stem cells (CESCs) are important for the integrity of structure and function of CEP. Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) has been reported to regulate apoptosis, autophagy, and cytoprotection. In this study, we aimed to determine whether nutrition deficiency induces apoptosis of CESCs, and whether or not the BNIP3-related pathway is activated in CESCs during nutrition deficiency. CESCs isolated from degenerated human CEP were cultured under normal or nutrition-deficient condition. Then, apoptosis was analyzed by flow cytometry. The expression and intracellular localization of BNIP3 were detected by quantitative real-time polymerase chain reaction, western blot analysis, and immunofluorescence assay, respectively. Mitochondrial membrane potential (MMP) and caspase-3 activity were measured by JC-1 staining and caspase-3 activity assay. Our results showed that nutrition deficiency promotes apoptosis and BNIP3 expression in CESCs. Notably, knockdown of BNIP3 could partially decrease nutrition deficiency-induced apoptosis of CESCs. In addition, nutrition deficiency could also induce upregulation of BNIP3, resulting in mitochondrial translocation of BNIP3 and loss of MMP in CESCs in a time-dependent manner. However, nutrition deficiency showed no effects on caspase-3 activity in CESCs. In summary, nutrition deficiency may promote CESC apoptosis partially through upregulating BNIP3, which might lead to activation of the BNIP3-related pathway and apoptosis of CESCs in a caspase-independent manner.

Influence of alendronate and endplate degeneration to single level posterior lumbar spinal interbody fusion.

OBJECTIVE: Using alendronate after spinal fusion is a controversial issue due to the inhibition of osteoclast mediated bone resorption. In addition, there are an increasing number of reports that the endplate degeneration influences the lumbar spinal fusion. The object of this retrospective controlled study was to evaluate how the endplate degeneration and the bisphosphonate medication influence the spinal fusion through radiographic evaluation. METHODS: In this study, 44 patients who underwent single-level posterior lumbar interbody fusion (PLIF) using cage were examined from April 2007 to March 2009. All patients had been diagnosed as osteoporosis and would be recommended for alendronate medication. Endplate degeneration is categorized by the Modic changes. The solid fusion is defined if there was bridging bone between the vertebral bodies, either within or external to the cage on the plain X-ray and if there is less than 5° of angular difference in dynamic X-ray. RESULTS: In alendronate group, fusion was achieved in 66.7% compared to 73.9% in control group (no medication). Alendronate did not influence the fusion rate of PLIF. However, there was the statistical difference of fusion rate between the endplate degeneration group and the group without endplate degeneration. A total of 52.4% of fusion rate was seen in the endplate degeneration group compared to 91.3% in the group without endplate degeneration. The endplate degeneration suppresses the fusion process of PLIF. CONCLUSION: Alendronate does not influence the fusion process in osteoporotic patients. The endplate degeneration decreases the fusion rate.

Influence of Alendronate and Endplate Degeneration to Single Level Posterior Lumbar Spinal Interbody Fusion

OBJECTIVE: Using alendronate after spinal fusion is a controversial issue due to the inhibition of osteoclast mediated bone resorption. In addition, there are an increasing number of reports that the endplate degeneration influences the lumbar spinal fusion. The object of this retrospective controlled study was to evaluate how the endplate degeneration and the bisphosphonate medication influence the spinal fusion through radiographic evaluation. METHODS: In this study, 44 patients who underwent single-level posterior lumbar interbody fusion (PLIF) using cage were examined from April 2007 to March 2009. All patients had been diagnosed as osteoporosis and would be recommended for alendronate medication. Endplate degeneration is categorized by the Modic changes. The solid fusion is defined if there was bridging bone between the vertebral bodies, either within or external to the cage on the plain X-ray and if there is less than 5degrees of angular difference in dynamic X-ray. RESULTS: In alendronate group, fusion was achieved in 66.7% compared to 73.9% in control group (no medication). Alendronate did not influence the fusion rate of PLIF. However, there was the statistical difference of fusion rate between the endplate degeneration group and the group without endplate degeneration. A total of 52.4% of fusion rate was seen in the endplate degeneration group compared to 91.3% in the group without endplate degeneration. The endplate degeneration suppresses the fusion process of PLIF. CONCLUSION: Alendronate does not influence the fusion process in osteoporotic patients. The endplate degeneration decreases the fusion rate.

The correlation between the lumbar endplate Modic degeneration and degeneration of lumbar intervertebral disc or pain provocation observed on CT discography / 中华骨科杂志

Objective To determine the correlation between the Modic degeneration of lumbar endplate on MRI and the pain provocation or degeneration of lumbar intervertebral discs observed on CT discography. Methods One hundred and twenty lumbar intervertebral discs (40 L3-4, 40 L4-5, 40 L5S1 intervertebral discs) of 40 patients among 45 patients were examined. 120 intervertebral discs underwent discography guided by CT scan, according to Dallas Discography Description system, degeneration of lumbar intervertebral disc were divided into 0-3 grade, and pain provocation were graded into negative, indifferent and positive. On the basis of Modic classification system of the lumbar endplate changes and Pearce classification system of the degeneration of lumbar intervertebral disc, the lumbar endplate changes were divided into 0-3 grade, the degeneration of lumbar intervertebral disc were graded into Ⅰ-Ⅴ. All the results were analysed by Chi-Square test for the correlations. Results There was positive correlation between pain provocation test and the lumbar endplate Modic degeneration; There was a positive correlation between the Modic degeneration of lumbar endplate and the degeneration of lumbar intervertebral disc and so is the relation between the CT discography and MRI on discs. Conclusion There is positive correlation between pain provocation test and the Modic degeneration of lumbar endplate, it suggest the endplate might be one of the sources of low back pain. There is a positive correlation between the Modic degeneration of lumbar endplate and the degeneration of lumbar intervertebral disc.