Intervertebral Disc Degeneration Research Articles

Orthobiologic Management Options for Degenerative Disc Disease.

Degenerative disc disease (DDD) is a pervasive condition that limits quality of life and burdens economies worldwide. Conventional pharmacological treatments primarily aimed at slowing the progression of degeneration have demonstrated limited long-term efficacy and often do not address the underlying causes of the disease. On the other hand, orthobiologics are regenerative agents derived from the patient's own tissue and represent a promising emerging therapy for degenerative disc disease. This review comprehensively outlines the pathophysiology of DDD, highlighting the inadequacies of existing pharmacological therapies and detailing the potential of orthobiologic approaches. It explores advanced tools such as platelet-rich plasma and mesenchymal stem cells, providing a historical overview of their development within regenerative medicine, from foundational in vitro studies to preclinical animal models. Moreover, the manuscript delves into clinical trials that assess the effectiveness of these therapies in managing DDD. While the current clinical evidence is promising, it remains insufficient for routine clinical adoption due to limitations in study designs. The review emphasizes the need for further research to optimize these therapies for consistent and effective clinical outcomes, potentially revolutionizing the management of DDD and offering renewed hope for patients.

Buck technique supplemented by temporary intersegmental pedicle screw fixation to repair lumbar spondylolysis in youth

BackgroundLumbar spondylolysis is a bone defect in the pars interarticularis of the lumbar vertebral, which is a common cause of low back pain in youth. Although non-surgical treatment is a mainstream option, surgery is necessary for patients with persistent symptoms. Buck technique is widely used as a classical direct repair technique, but it cannot achieve reduction of low-grade spondylolisthesis and reconstruction of lumbosacral sagittal balance. We have described a novel surgical procedure based on Buck technique with temporary intersegmental pedicle screw fixation, and report a series of clinical outcomes in 5 patients to provide a reference for the clinical treatment of young lumbar spondylolysis.MethodsFive young patients with symptomatic lumbar spondylolysis with a mean age of 19.20 ± 5.41 years underwent surgical treatment after an average of 7.60 ± 1.52 months of failure to respond to conservative treatment, using a new surgical procedure based on Buck technique combined with temporary intersegmental pedicle screw fixation.ResultsFive patients were successfully operated without serious complications such as nerve and vascular injury. The average operation time was 109.00 ± 7.42 min, the interpretative average blood loss was 148.00 ± 31.14 ml, and the average fusion time was 11.20 ± 1.64 months. All patients were followed up for 2 years after surgery, and the visual analogue score (VAS) of low back pain and Oswestry disability index (ODI) scores were significantly improved compared with those before surgery, and the Henderson’s evaluation were rated excellent or good. After the removal of the internal fixation, it was observed that temporary intersegmental fixation could repair the isthmus, reduce lumbar spondylolisthesis, and reconstruct the sagittal balance of the lumbosacral vertebrae while preserving lumbar motion and preventing intervertebral disc degeneration. Postoperative MRI indicated the Pfirrmann classification of the affected discs: 1 case from grade III to grade II, 3 cases from grade II to grade I, and 1 case remained grade II.ConclusionsBuck technique supplemented by temporary intersegmental pedicle screw fixation is a highly applicable and effective method for the treatment of adolescent lumbar spondylolysis. The isthmic fusion is accurate, and temporary intersegmental fixation can effectively prevent disc degeneration and reconstruct the sagittal balance of lumbosacral vertebra.

Myricetin Restores Autophagy to Attenuate Lumbar Intervertebral Disk Degeneration Via Negative Regulation of the JAK2/STAT3 Pathway.

Autophagy is a critical player in lumbar intervertebral disk degeneration (IDD), and autophagy activation has been suggested to prevent the apoptosis of nucleus pulposus cells (NPCs). Myricetin has anti-cancer, anti-inflammatory, and antioxidant potentials and can activate autophagy. Thus, this study focused on the roles and mechanisms of myricetin in IDD. A puncture-induced rat IDD model was established and intraperitoneally injected with 20-mg/kg/day myricetin. Histopathological changes of intervertebral disks (IVDs) were assessed by hematoxylin and eosin staining and Safranin O/Fast Green staining. The isolated NPCs from IVDs of healthy rats were stimulated with IL-1β to mimic IDD-like conditions. The roles of myricetin in cell apoptosis, extracellular matrix (ECM) degradation, autophagy repression, and the JAK2/STAT3 pathway activation were examined by cell counting kit-8, flow cytometry, western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence staining. Myricetin treatment attenuated the apoptosis and ECM degradation, and enhanced autophagy in the IL-1β-treated NPCs, whereas the myricetin-mediated protection was limited by autophagy inhibition. Mechanistically, myricetin activated autophagy through blocking the JAK2/STAT3 signaling. In vivo experiments revealed that intraperitoneal injection of myricetin activated NPC autophagy to relieve puncture injury in rats. Myricetin prevents IDD by attenuating NPC apoptosis and ECM degradation through blocking the JAK2/STAT3 pathway to enhance autophagy.

Andrographolide influences IDD cell autophagy and oxidative stress under mechanical pressure via miR-9/FoxO3/PINK1/Parkin molecular axis.

Intervertebral disc degeneration (IDD) is characterized by the decreased function and number of nucleus pulposus cells (NPCs) caused by excessive intervertebral disc (IVD) pressure. This research aims to provide novel insights into IDD prevention and treatment by clarifying the effect of andrographolide (ANDR) on IDD cell autophagy and oxidative stress under mechanical stress. Human primary NPCs were extracted from the nucleus pulposus tissue of non-IDD trauma patients. An IDD cell model was established by posing mechanical traction on NPCs. Through the construction of an IDD rat model, the influence of ANDR on IDD pathological changes was explored in vivo. The proliferation and autophagy of NPCs were decreased while the apoptosis rate and oxidative stress reaction were increased by mechanical traction. ANDR intervention obviously alleviated this situation. MiR-9 showed upregulated expression in IDD cell model, while FoxO3 and PINK1/Parkin were downregulated. Decreased proliferation and autophagy as well as enhanced apoptosis and oxidative stress response of NPCs were observed following miR-9 mimics and H89 intervention, while the opposite trend was observed after FoxO3 overexpression. FoxO3 is a direct target downstream miR-9. The in vivo experiments revealed that after ANDR intervention, the number of apoptotic cells in rat IVD tissue decreased and the autophagy increased. In conclusion, ANDR improves NPC proliferation, and autophagy, inhibits apoptosis and oxidative stress, and alleviates the pathological changes of IDD via the miR-9/FoxO3/PINK1/Parkin axis, which may be a new and effective treatment for IDD in the future.

Pip5k1γ promotes anabolism of nucleus pulposus cells and intervertebral disc homeostasis by activating CaMKII-Ampk pathway in aged mice.

Degenerative disc disease (DDD) represents a significant global health challenge, yet its underlying molecular mechanisms remain elusive. This study aimed to investigate the role of type 1 phosphatidylinositol 4-phosphate 5-kinase (Pip5k1) in intervertebral disc (IVD) homeostasis and disease. All three Pip5k1 isoforms, namely Pip5k1α, Pip5k1β, and Pip5k1γ, were detectable in mouse and human IVD tissues, with Pip5k1γ displaying a highest expression in nucleus pulposus (NP) cells. The expression of Pip5k1γ was significantly down-regulated in the NP cells of aged mice and patients with severe DDD. To determine whether Pip5k1γ expression is required for disc homeostasis, we generated a Pip5k1γfl/fl; AggrecanCreERT2 mouse model for the conditional knockout of the Pip5k1γ gene in aggrecan-expressing IVD cells. Our findings revealed that the conditional deletion of Pip5k1γ did not affect the disc structure or cellular composition in 5-month-old adult mice. However, in aged (15-month-old) mice, this deletion led to several severe degenerative disc defects, including decreased NP cellularity, spontaneous fibrosis and cleft formation, and a loss of the boundary between NP and annulus fibrosus. At the molecular level, the absence of Pip5k1γ reduced the anabolism of NP cells without markedly affecting their catabolic or anti-catabolic activities. Moreover, the loss of Pip5k1γ significantly dampened the activation of the protective Ampk pathway in NP cells, thereby accelerating NP cell senescence. Notably, Pip5k1γ deficiency blunted the effectiveness of metformin, a potent Ampk activator, in activating the Ampk pathway and mitigating lumbar spine instability (LSI)-induced disc lesions in mice. Overall, our study unveils a novel role for Pip5k1γ in promoting anabolism and maintaining disc homeostasis, suggesting it as a potential therapeutic target for DDD.

ARRB1 inhibits extracellular matrix degradation and apoptosis of nucleus pulposus cells by promoting autophagy and attenuates intervertebral disc degeneration

ObjectiveIntervertebral disc degeneration (IVDD) is the leading cause of lower back pain (LBP). β-arrestin 1 (ARRB1) is a multifunctional protein that regulates numerous pathological processes. The aim of this study was to investigate the role of ARRB1 in IVDD. MethodsThe expression of ARRB1 in nucleus pulposus (NP) of rats with IVDD was assayed. Next, rat nucleus pulposus cells (NPCs) were infected with lentiviruses containing shArrb1 (LV-shArrb1) and overexpressing Arrb1 (LV-oeArrb1). The roles of Arrb1 in serum-deprived NPCs were investigated by measuring apoptosis, extracellular matrix degradation, and autophagic flux. For experiments in vivo, LV-oeArrb1 lentivirus was injected into the NP tissues of IVDD rats to evaluate the effects of Arrb1 overexpression on NP. ResultsIn the NP tissues of IVDD rats, ARRB1 and cleaved caspase-3 expression increased, and the ratio of LC3II/LC3I protein expression was upregulated. Arrb1 knockdown aggravated extracellular matrix degradation, cellular apoptosis, and impairment of autophagic flux in rat NPCs under serum-deprived conditions, whereas Arrb1 overexpression significantly reversed these effects. ARRB1 interacted with Beclin 1, and Arrb1 knockdown suppressed the formation of the Beclin1-PIK3C3 core complex. The autophagy inhibitor 3-methyladenine (3-MA) offset the protective effects of Arrb1 overexpression in serum-deprived NPCs. Furthermore, Arrb1 overexpression inhibited apoptosis and extracellular matrix degradation, promoted autophagy in NP, and delayed the development of IVDD in rats. ConclusionARRB1 prevents extracellular matrix degradation and apoptosis of NPCs by upregulating autophagy and ameliorating IVDD progression, presenting an innovative strategy for the treatment of IVDD.

Genopyc: a Python library for investigating the functional effects of genomic variants associated to complex diseases.

Integrative Biomedicl Informatics, Research Program on Biomedical Informatics (IBI - GRIB), Hospital Del Mar Medical Research Institute (IMIM), Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF) C/ del Dr. Aiguader 88 Barcelona 08003 Spain.Understanding the genetic basis of complex diseases is one of the main challenges in modern genomics. However, current tools often lack the versatility to efficiently analyze the intricate relationships between genetic variations and disease outcomes. To address this, we introduce Genopyc, a novel Python library designed for comprehensive investigation of how the variants associated to complex diseases affects downstream pathways. Genopyc offers an extensive suite of functions for heterogeneous data mining and visualization, enabling researchers to delve into and integrate biological information from large-scale genomic datasets. In this work, we present the Genopyc library through application to real-world genome wide association studies variants. Using Genopyc to investigate the functional consequences of variants associated to intervertebral disc degeneration enabled a deeper understanding of the potential dysregulated pathways involved in the disease, which can be explored and visualized by exploiting the functionalities featured in the package. Genopyc emerges as a powerful asset for researchers, facilitating the investigation of complex diseases paving the way for more targeted therapeutic interventions. Genopyc is available on pip https://pypi.org/project/genopyc/.The source code of Genopyc is available at https://github.com/freh-g/genopyc. A tutorial notebook is available at https://github.com/freh-g/genopyc/blob/main/tutorials/Genopyc_tutorial_notebook.ipynb. Finally, a detailed documentation is available at: https://genopyc.readthedocs.io/en/latest/.

Comparison of the efficacy of ROI-C cage with Zero-P device in anterior cervical discectomy and fusion of cervical degenerative disc disease: a two-year follow-up study.

This study aimed to compare the clinical outcomes of Zero-P and ROI-C devices applied to anterior cervical discectomy and fusion (ACDF) surgery of cervical degenerative disc disease (CDDD). From January 2020 and December 2020, 56 patients with CDDD who underwent ACDF using Zero-P or ROI-C were included in this retrospective study. The outcomes included visual analogue scale (VAS) score, Japanese Orthopedic Association (JOA) score, neck disability index (NDI) score, Cobb angle, dysphagia, and bone fusion rate. Dysphagia was assessed using the Bazaz grading system. The comparison of outcomes between the two groups was based on the 2-year follow-up time point, which was defined as the last follow-up visit. The Zero-P group included 16 males and 14 females, with a mean age of 56.2 (range, 35-65) years. The ROI-C group included 11 males and 15 females, with a mean age of 57.4 (range, 36-67) years. There was no significant difference in gender and mean age between the two groups. There were no significant differences in VAS score, JOA score, NDI score, Cobb angle, dysphagia, and bone fusion rate between two groups at the last follow up visit. In the Zero-P group, the duration of surgeries involving C3-4 or C6-7 segments was significantly longer than those including C4-5 or C5-6 segments (135.0 ± 19.0 vs. 105.6 ± 17.5 min, P < 0.05). In surgeries involving C3-4 or C6-7 segments, the operation time of ROI-C was significantly shorter than that of Zero-P (106.5 ± 19.5 vs.112.2 ± 20.5 min, P < 0.05). There were no significant differences in the dysphagia or cage subsidence rates between the Zero-P and ROI-C groups (P > 0.05). The Cobb angle in the last follow-up visit in the Zero-P group (24.4 ± 4.5°) was significantly higher than that in the ROI-C group (18.1 ± 2.3°) (P < 0.05). ACDF using ROI-C device showed an efficacy similar to the Zero-P device, as well as a shorter operation time for surgeries involving C3-4 or C6-7 segments. However, ROI-C could cause more loss of Cobb angle over time, which could lead to uncomfortable symptoms.

Comparative analysis of risk factors associated with degeneration of adjacent segments: zero-profile anchored spacer vs. anterior cervical plate and cage construct.

Anterior cervical discectomy and fusion (ACDF) is an established treatment for cervical degenerative disc disease, but cervical spine surgery may affect sagittal alignment parameters and induce adjacent segment degeneration (ASD). This study aimed to determine the risk factors for developing ASD following anterior cervical plate and cage (ACPC) compared with the use of zero-profile anchored spacer (ROI-C). A retrospective contrastive study included 105 patients who underwent ACPC or ROI-C between January 2014 and October 2019 at our treatment centre. There were 50 cases in the ROI-C group and 55 patients in the ACPC group. Clinical and radiological results and the incidence of ASD were assessed after surgery. All patients were further divided into the ASD and non-ASD groups for subgroup analysis. At each follow-up time, there was no statistically significant in radiographic parameters between the two groups. The overall ASD rate was higher in the ACPC group than in the ROI-C group (65.5% vs. 44.0%, p = 0.027). The low preoperative Cobb angle, low preoperative segment angle (SA), and loss of Cobb (ΔCobb) were significantly correlated with ASD. However, clinical outcomes were not associated with ASD at any postoperative follow-up visit. Equally good therapeutic effects were achieved with both the ROI-C and ACPC. The occurrence of ASD was considerably higher in the ACPC group than in the ROI-C group. The preoperative Cobb angle, preoperative SA, and ΔCobb were the most associated with an increase in the risk of ASD.

BMSC loaded photo-crosslinked hyaluronic acid/collagen hydrogel incorporating FG4592 for enhanced cell proliferation and nucleus pulposus differentiation

Intervertebral disc degeneration arises from damage or degeneration of the nucleus pulposus (NP). In this study, we developed a photo-crosslinkable hydrogel incorporating FG4592 to support the growth and differentiation of bone-marrow-derived mesenchymal stem cells (BMSC). Initially, hyaluronic acid was modified with tyramine and combined with collagen to introduce riboflavin as a photo-crosslinker. This hydrogel transitioned from liquid to gel upon exposure to blue light in 3 min. The results showed that the hydrogel was biodegradable and had mechanical properties comparable to those of human NP tissues. Scanning electron microscopy after BMSC seeding in the hydrogel revealed an even distribution, and cells adhered to the collagen fibers in the hydrogel with minimal cell mortality. The effect of FG4592 on BMSC proliferation and differentiation was examined, revealing the capability of FG4592 to promote BMSC proliferation and direct differentiation resembling human NP cells. After cultivating BMSCs in the photo-crosslinked hydrogel, there was an upregulation in the expression of glycosaminoglycans, aggrecan, type II collagen, and keratin 19 proteins. Cross-species analyses of rat and human BMSCs revealed consistent results. For potential clinical applications, BMSC loaded with photo-crosslinked hydrogels can be injected into damaged intervertebral disc to facilitate NP regeneration.

Identifying the protective effects of miR-874-3p/ATF3 axis in intervertebral disc degeneration by single-cell RNA sequencing and validation.

Intervertebral disc degeneration (IVDD) severely affects the work and the quality of life of people. We previously demonstrated that silencing activation transcription factor 3 (ATF3) blocked the IVDD pathological process by regulating nucleus pulposus cell (NPC) ferroptosis, apoptosis, inflammation, and extracellular matrix (ECM) metabolism. Nevertheless, whether miR-874-3p mediated the IVDD pathological process by targeting ATF3 remains unclear. We performed single-cell RNA sequencing (scRNA-seq) and bioinformatics analysis to identify ATF3 as a key ferroptosis gene in IVDD. Then, Western blotting, flow cytometry, ELISA, and animal experiments were performed to validate the roles and regulatory mechanisms of miR-874-3p/ATF3 signalling axis in IVDD. ATF3 was highly expressed in IVDD patients and multiple cell types of IVDD rat, as revealed by scRNA-seq and bioinformatics analysis. GO analysis unveiled the involvement of ATF3 in regulating cell apoptosis and ECM metabolism. Furthermore, we verified that miR-874-3p might protect against IVDD by inhibiting NPC ferroptosis, apoptosis, ECM degradation, and inflammatory response by targeting ATF3. Invivo experiments displayed the protective effect of miR-874-3p/ATF3 axis on IVDD. These findings propose the potential of miR-874-3p and ATF3 as biomarkers of IVDD and suggest that targeting the miR-874-3p/ATF3 axis may be a therapeutic target for IVDD.

Attenuating intervertebral disc degeneration through spermidine-delivery nanoplatform based on polydopamine for persistent regulation of oxidative stress

As one of the most widespread musculoskeletal diseases worldwide, intervertebral disc degeneration (IVDD) remains an intractable clinical problem. Currently, oxidative stress has been widely considered as a significant risk factor in the IVDD pathological changes, and targeting oxidative stress injury to improve the harsh microenvironment may provide a novel and promising strategy for disc repair. It is evident that spermidine (SPD) has the ability to attenuate oxidative stress across several disease models. However, limited research exists regarding its impact on oxidative stress within the intervertebral disc. Moreover, enhancing the local utilization rate of SPD holds great significance in IVDD management. This study aimed to develop an intelligent biodegradable mesoporous polydopamine (PDA) nanoplatform for sustained release of SPD. The obtained PDA nanoparticles with spherical morphology and mesoporous structure released loaded-therapeutic molecules under low pH and H2O2. Combined treatment with SPD loaded into PDA nanoparticles (SPD/PDA) resulted in better therapeutic potential than those with SPD alone on oxidative stress injury. Furthermore, both SPD and SPD/PDA could induce anti-inflammatory M2 macrophage polarization. Upon injection into degenerative IVDs, the SPD/PDA group achieved a good repair efficacy with a long-term therapeutic effect. These findings indicated that the synergized use of SPD with responsive drug delivery nanocarriers may steadily scavenge reactive oxygen species and provide an effective approach toward the treatment of IVDD.

Promoting Regeneration in Degenerative Disc Disease.

The degenerative disc disease has a multifactorial etiology and mechanical stress is one of the most important etiological factor. The purpose of this study was to evaluate the intervertebral disc (IVD) after axial stress diminution from the point of view of its proteoglycan (PG) content, with preoteoglicans (PGs) being very important in the normal function but also in the degenerative or regenerative processes. This is a single-center, prospective, non-randomized study of 38 degenerated intervertebral discs treated with monosegmental or polisegmental posterior lumbar spinal fixation in 27 patients. During surgery, a posterior intervertebral distraction at operated levels was applied. Patients' mean age was 50.77 years and the mean follow-up 28.74 months. Both clinical (visual analog pain scale, Oswestry disability index) and radiological (lumbar spine lordosis, disc thickness) analyses were made before and after surgery. A new method of cartilage analysis, which was also validated for the IVD, delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) was used to determine the PG content before and after surgery for both the intervertebral degenerative disc and control level L1-L2 disc. The clinical features improved significantly. The thickness of the operated discs increased by an average of 1.71 mm postoperatively and remained unchanged in the control group. The lumbar lordosis did not change significantly. In dGEMRIC studies, the discs accumulated in average 410.08 units /cm2 of gadolinium before surgery and 272.45 units/cm2 after surgery, without significant changes in the control group. Our study shows an improvement of PG quantity in degenerated IVD due to a decrease in gadolinium binding seen in dGEMRIC study. Thus, we can ameliorate IVD homeostasis by eliminating mechanical stress, which could be a step towards the process of disc regeneration.

Relationship between facet joint osteoarthritis and lumbar paraspinal muscle atrophy: a cross-sectional study.

The paraspinal muscles play an essential role in the stabilization of the lumbar spine. Lumbar paraspinal muscle atrophy has been linked to chronic back pain and degenerative processes within the spinal motion segment. However, the relationship between the different paraspinal muscle groups and facet joint osteoarthritis (FJOA) has not been fully explored. In this cross-sectional study, the authors analyzed adult patients who underwent lumbar spinal surgery between December 2014 and March 2023 for degenerative spinal conditions and had preoperative MRI and CT scans. The fatty infiltration (FI) and functional cross-sectional area (fCSA) of the psoas, erector spinae, and multifidus muscles were assessed on axial T2-weighted MR images at the level of the upper endplate of L4 based on established studies and calculated using custom-made software. Intervertebral disc degeneration at each lumbar level was evaluated using the Pfirrmann grading system. The grades from each level were summed to report the cumulative lumbar Pfirrmann grade. Weishaupt classification (0-3) was used to assess FJOA at all lumbar levels (L1 to S1) on preoperative CT scans. The total lumbar FJOA score was determined by adding the Weishaupt grades of both sides at all 5 levels. Correlation and linear regression analyses were conducted to assess the relationship between FJOA and paraspinal muscle parameters. A total of 225 patients (49.7% female) with a median age of 61 (IQR 54-70) years and a median BMI of 28.3 (IQR 25.1-33.1) kg/m2 were included. After adjustment for age, sex, BMI, and the cumulative lumbar Pfirrmann grade, only multifidus muscle fCSA (estimate -4.69, 95% CI -6.91 to -2.46; p < 0.001) and FI (estimate 0.64, 95% CI 0.33-0.94; p < 0.001) were independently predicted by the total FJOA score. A similar relation was seen with individual Weishaupt grades of each lumbar level after controlling for age, sex, BMI, and the Pfirrmann grade of the corresponding level. Atrophy of the multifidus muscle is significantly associated with FJOA in the lumbar spine. The absence of such correlation for the erector spinae and psoas muscles highlights the unique link between multifidus muscle quality and the degeneration of the spinal motion segment. Further research is necessary to establish the causal link and the clinical implications of these findings.

New evidence on the controversy over the correlation between vertebral osteoporosis and intervertebral disc degeneration: a systematic review of relevant animal studies.

The effect of vertebral osteoporosis on disc degeneration remains controversial. The aim of this study was to conduct a systematic review and meta-analysis of relevant animal studies to shed more light on the effects and mechanisms of vertebral osteoporosis on disc degeneration and to promote the resolution of the controversy. The PubMed, Cochrane Library, and Embase databases were searched for studies that met the inclusion criteria. Basic information and data were extracted from the included studies and data were analyzed using STATA 15.1 software. This study was registered on INPLASY with the registration number INPLASY202370099 and https://doi.org/10.37766/inplasy2023.7.0099 . A total of 13 studies were included in our study. Both animals, rats and mice, were covered. Meta-analysis results showed in disc height index (DHI) (P < 0.001), histological score (P < 0.001), number of osteoblasts in the endplate (P = 0.043), number of osteoclasts in the endplate (P < 0.001), type I collagen (P < 0.001), type II collagen (P < 0.001), aggrecan (P < 0.001), recombinant a disintegrin and metalloproteinase with thrombospondin-4 (ADAMTS-4) (P < 0.001), matrix metalloproteinase-1 (MMP-1) (P < 0.001), MMP-3 (P < 0.001), MMP-13 (P < 0.001), the difference between the osteoporosis group and the control group was statistically significant. In terms of disc volume, the difference between the osteoporosis group and the control group was not statistically significant (P = 0.459). Our study shows that vertebral osteoporosis may exacerbate disc degeneration. Abnormal bone remodeling caused by vertebral osteoporosis disrupts the structural integrity of the endplate, leading to impaired nutrient supply to the disc, increased expression of catabolic factors, and decreased levels of type II collagen and aggrecan may be one of the potential mechanisms.

Intervertebral disc degeneration and regenerative medicine

AbstractIntervertebral disc (IVD) degeneration is a common phenomenon that affects patients with increasing prevalence with increasing age. Both conservative treatments, such as the use of pain medication or physical therapy, and surgical treatments, such as fusion or disc replacement therapies, are offered to patients. Both non‐invasive and invasive treatments have been shown to improve pain and quality of life for patients. This review explores the role of regenerative medicine techniques as a promising therapeutic intervention that can be used before or in combination with conservative therapy and surgery to enhance the treatment process in patients with IVD degeneration or disc pathology. Currently, there are four major modules of regenerative medicine: genetic therapy, platelet‐rich plasma therapy, stem cell transplantation and tissue engineering. Several research studies have shown promising outcomes of stem cell transplantation and tissue engineering when combined with either surgical or conservative treatment, resulting in improved pain outcomes. The additional benefit of regenerative medicine techniques, specifically stem cell transplantation, is the potential for treating the root pathology of degeneration. Regenerative medicine techniques also have the potential to either halt or reverse degeneration as opposed to current standards of care for managing symptoms. There is a plethora of current research highlighting the benefits of regenerative medicine techniques; however, there remains clinical concerns and ethical concerns regarding the use of regenerative therapy techniques such as stem cell transplantation in the context of IVD degeneration.

Allogeneic Disc Progenitor Cells Safely Increase Disc Volume and Improve Pain, Disability, and Quality of Life in Patients With Lumbar Disc Degeneration-Results of an FDA-Approved Biologic Therapy Randomized Clinical Trial.

Progenitor cells derived from intervertebral disc tissue demonstrated immunomodulatory and regenerative properties in preclinical studies. We report the safety and efficacy results of a US Food and Drug Administration-approved clinical trial of these cells for the treatment of symptomatic degenerative disc disease. Sixty patients with symptomatic single-level lumbar degenerative disc disease (mean age 37.9 years, 60% men) were enrolled in a randomized, double-blinded, placebo-controlled Phase I/Phase II study at 13 clinical sites. They were randomized to receive single intradiscal injections of either low-dose cells (N = 20), high-dose cells (N = 20), vehicle alone (N = 10), or placebo (N = 10). The primary endpoint was mean visual analog scale (VAS) pain improvement >30% at 52 weeks. Disc volume was radiologically assessed. Adverse events (AEs), regardless of whether they were related to treatment, were reported. Patients were assessed at baseline and at 4, 12, 26, 52, 78, and 104 weeks posttreatment. At week 52, the high-dose group had a mean VAS percentage decrease from baseline (-62.8%, P = 0.0005), achieving the endpoint of back pain improvement >30%; the mean change was also significantly greater than the minimal clinically important difference of a 20-point decrease (-42.8, P = 0.001). This clinical improvement was maintained at week 104. The vehicle group had a smaller significant decrease in VAS (-52.8%, P = 0.044), while the low-dose and placebo groups showed nonsignificant improvements. Only the high-dose group had a significant change in disc volume, with mean increases of 249.0 mm3 (P = 0.028) at 52 weeks and 402.1 mm3 (P = 0.028) at 104 weeks. A minority of patients (18.3%) reported AEs that were severe. Overall, 6.7% of patients experienced serious AEs, all in the vehicle (n = 1) or placebo (n = 3) groups, none treatment related. High-dose allogeneic disc progenitor cells produced statistically significant, clinically meaningful improvements in back pain and disc volume at 1 year following a single intradiscal injection and were safe and well tolerated. These improvements were maintained at 2 years post-injection. NCT03347708-Study to Evaluate the Safety and Preliminary Efficacy of Injectable Disc Cell Therapy, a Treatment for Symptomatic Lumbar Intervertebral Disc Degeneration.

A novel Mg-Zn-Nd-Zr alloy lumbar interbody fusion cage: An in vitro and in vivo study

Interbody fusion is recognized as the golden standard of surgical intervention for degenerative disc disease (DDD). Interbody fusion cage made of polyetheretherketone (PEEK) is commonly used in lumbar interbody fusion surgery in the treatment of DDD worldwide. However, there are some limitations of PEEK including their bio-inert nature and impediment to host bone integration. This study aimed to evaluate the degradation profile and osteoinductive potential of biodegradable Mg-Zn-Nd-Zr cages with/without micro-arc oxidation (MAO) coatings. The Mg-Zn-Nd-Zr alloy cages, whether coated with MAO or not, demonstrated commendable biocompatibility and biomechanical properties. Immersion and electrochemical tests show better corrosion resistance of MAO coatings in vitro. mRNA sequencing, RT-qPCR and Western blotting revealed that Mg-Zn-Nd-Zr and Mg-Zn-Nd-Zr/MAO had a better effectiveness on osteoinductivity. In vivo evaluations in ovine models over 12 weeks and 24 weeks post-implantation revealed radiological and histological evidence of enhanced bone formation adjacent to the Mg-Zn-Nd-Zr alloy cages compared to PEEK counterparts. Moreover, the MAO-coated cages exhibited a reduced propensity for gas formation. The Mg-Zn-Nd-Zr alloy is as a superior osteoinductive material compared with PEEK, with the MAO coating offering an advantage in mitigating gas production. Nonetheless, further research is warranted to refine the alloy's composition or surface treatments, particularly to address the challenges associated with rapid gas evolution during the early post-implantation period.

Predicting gene disease associations with knowledge graph embeddings for diseases with curtailed information.

Knowledge graph embeddings (KGE) are a powerful technique used in the biomedical domain to represent biological knowledge in a low dimensional space. However, a deep understanding of these methods is still missing, and, in particular, regarding their applications to prioritize genes associated with complex diseases with reduced genetic information. In this contribution, we built a knowledge graph (KG) by integrating heterogeneous biomedical data and generated KGE by implementing state-of-the-art methods, and two novel algorithms: Dlemb and BioKG2vec. Extensive testing of the embeddings with unsupervised clustering and supervised methods showed that KGE can be successfully implemented to predict genes associated with diseases and that our novel approaches outperform most existing algorithms in both scenarios. Our findings underscore the significance of data quality, preprocessing, and integration in achieving accurate predictions. Additionally, we applied KGE to predict genes linked to Intervertebral Disc Degeneration (IDD) and illustrated that functions pertinent to the disease are enriched within the prioritized gene set.

The association of lumbar intervertebral disc degeneration with low back pain is modified by underlying genetic propensity to pain

BACKGROUND CONTEXTAssociations between magnetic resonance imaging (MRI)-detected lumbar intervertebral disc degeneration (LDD) and LBP are often of modest magnitude. This association may be larger in specific patient subgroups. PURPOSETo examine whether the association between LDD and LBP is modified by underlying genetic predispositions to pain. STUDY DESIGNCross-sectional study in UK Biobank (UKB) and Twins UK. PATIENT SAMPLESA genome-wide association study (GWAS) of the number of anatomical chronic pain locations was conducted in 347,538 UKB participants. The GWAS was used to develop a genome-wide polygenic risk score (PRS) in a holdout sample of 30,000 UKB participants. The PRS model was then used in analyses of 645 TwinsUK participants with standardized LDD MRI assessments. OUTCOME MEASURESEver having had LBP associated with disability lasting ≥1 month (LBP1). METHODSUsing the PRS as a proxy for “genetically-predicted propensity to pain”, we stratified TwinsUK participants into PRS quartiles. A “basic” model examined the association between an LDD summary score (LSUM) and LBP1, adjusting for covariates. A “fully-adjusted” model also adjusted for PRS quartile and LSUM x PRS quartile interaction terms. RESULTSIn the basic model, the odds ratio (OR) of LBP1 was 1.8 per standard deviation of LSUM (95% confidence interval [CI] 1.4–2.3). In the fully-adjusted model, there was a statistically significant LSUM-LBP1 association in quartile 4, the highest PRS quartile (OR=2.5 [95% CI 1.7–3.7], p=2.6×10−6), and in quartile 3 (OR=2.0, [95% CI 1.3–3.0]; p=.002), with small-magnitude and/or nonsignificant associations in the lowest 2 PRS quartiles. PRS quartile was a significant effect modifier of the LSUM-LBP1 association (interaction p≤.05). CONCLUSIONSGenetically-predicted propensity to pain modifies the LDD-LBP association, with the strongest association present in people with the highest genetic propensity to pain. Lumbar MRI findings may have stronger connections to LBP in specific subgroups of people.