Background: A major complication of lateral lumbar interbody fusion (LLIF) is cage subsidence, which may lead to clinical problems, including loss of disc height correction, altered spinal alignment, recurrent pain, and vertebral body fracture. A thorough review of the current knowledge about the risk factors for the two types of cage subsidence after LLIF—intraoperative endplate injury and late-onset cage subsidence—could bring attention to well-established risk factors for clinical consideration while identifying any incompletely characterized factors that require further research to clarify. Questions/purposes: We performed a systematic review to answer the following questions: (1) Are bone quality and surrogates for bone quality, such as patient age and sex, associated with an increased likelihood of cage subsidence? (2) Are implant-related factors associated with an increased likelihood of cage subsidence? Methods: Two independent reviewers comprehensively searched Medline, Embase, Cochrane Library, PubMed, and Web of Science from 1997 to 2020 to identify all potential risk factors for cage subsidence after LLIF. Discrepancies were settled through discussion during full-text screening. Search terms included “lateral” AND “interbody fusion” AND “subsidence” OR “settling” OR “endplate injury” OR “endplate violation” WITHOUT “cervical” OR “transforaminal” OR “biomechanical.” Eligible studies were retrospective or prospective comparative studies, randomized controlled trials, and case series with sample sizes of 10 patients or more reporting risk factors for cage subsidence or endplate injury after LLIF. Studies that involved cervical interbody fusions and biomechanical and cadaveric experiments were excluded. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the studies’ quality of evidence. The initial database review found 400 articles. Thirty-four articles with moderate- to very-low-quality evidence met the inclusion criteria for analysis. A total of 3233 patients (58% [1860] of whom were female) were included in this review. Two types of cage subsidence were reviewed: late-onset cage subsidence, which occurs gradually postoperatively, and intraoperative endplate injury, which is derived from iatrogenic endplate violation during endplate preparation or cage insertion. Among 20 studies with moderate quality of evidence according to the GRADE criteria, eight studies reported risk factors for cage subsidence related to bone mineral density and its surrogates and 12 studies focused on risk factors regarding implant factors, including cage dimension, cage material, construct length, and supplementary instrumentation. Results: Patients with a dual x-ray absorptiometry T-score of -1.0 or less, age older than 65 years, and female sex were considered to have a high risk of both types of cage subsidence. Regarding cage size, cage width ≥ 22 mm helped to avoid late-onset cage subsidence, and cage height ≤ 11 mm was recommended by some studies to avoid intraoperative endplate injuries. Studies recommended that multilevel LLIF should be conducted with extra caution because of a high risk of losing the effect of indirect decompression. Studies found that standalone LLIF might be sufficient for patients without osteoporosis or obesity, and supplementary instrumentation should be considered to maintain the postoperative disc height and prevent subsidence progression in patients with multiple risk factors. The effect of the bone graft, cage material, endplate condition, and supplementary instrumentation on cage subsidence remained vague or controversial. Conclusion: Patients with poor bone density, patients who are older than 65 years, and female patients should be counseled about their high risk of developing cage subsidence. Surgeons should avoid narrow cages when performing LLIF to minimize the risk of late-onset cage subsidence, while being cautious of an aggressive attempt to restore disc height with a tall cage as it may lead to intraoperative endplate injury. For multilevel constructs, direct decompression approaches, such as posterior and transforaminal LIF, should be considered before LLIF, since the effect of indirect decompression may be difficult to maintain in multilevel LLIF because of high risks of cage subsidence. The effect of the cage material and supplementary instrumentation require stronger evidence from prospectively designed studies with larger sample size that randomly assign patients to polyetheretherketone (PEEK) or titanium cages and different fixation types. Future research on intraoperative endplate injuries should focus on the specific timing of when endplate violation occurs with the help of intraoperative imaging so that attempts can be made to minimize its occurrence. Level of Evidence: Level IV, therapeutic study.

Yes‐associated protein 1 (YAP1) is a transcriptional coactivator and negative regulator of the Hippo pathway. It regulates diverse cellular processes, such as cell proliferation, contact inhibition, and tissue size. However, the role of YAP1 in intervertebral disc degeneration (IDD) remains elusive. Here, we demonstrated that YAP1 was activated by Interleukin 6 (IL‐6) through tyrosine phosphorylation in nucleus pulposus cells (NP cells). Overexpression of YAP1 decreased Sox‐9, Col‐II, aggrecan expression, whereas increased matrix metalloproteinases 13 level. In contrast, knockdown of YAP1 by small interfering RNA (siRNA) showed opposite effects and rescued IL‐6 induced NP cells degeneration. In addition, western blot showed that IL‐6 treatment increased YAP1 and β‐catenin protein level; co‐immunoprecipitation (Co‐IP) and immunofluorescence analysis showed that IL‐6 enhanced YAP1 and β‐catenin interaction and nuclear accumulation. Knockdown of β‐catenin by siRNA blocked IL‐6 treatment or YAP1 overexpression induced degeneration. Moreover, we found that verteporfin, a specific inhibitor of YAP1, effectively alleviated IDD development in rat disks. Taken together, our findings indicated that YAP1 plays an important role in IDD, and β‐catenin is essential for IL‐6/YAP1 signaling.

Study Design. A retrospective survey on 85 consecutive patients with primary single-level lumbar disc herniation (LDH). Objective. To investigate associations between Modic changes (MCs) and the likelihood of resorption of herniated lumbar intervertebral discs. Summary of Background Data. Spontaneous resorption of LDH has been demonstrated, whereas the mechanisms are unclear. MCs are closely associated with disc degeneration, but research focusing on their association with spontaneous resorption of LDH has not been specifically investigated. Methods. Eighty-five consecutive patients with LDH (52 males, 33 females, aged 20–66 yr) were included. Patients' diagnosis was based on clinical presentation, magnetic resonance imaging, and computed tomography. Patients were divided into surgical and conservative groups and further divided into MC and non-MC subgroups. Spontaneous resorption and clinical success in the conservative group were assessed by reduction in the herniated volume and Oswestry Disability Index. Disc tissues collected from the surgical group were examined histologically, and immunohistochemistry was used to identify endothelial cells and macrophages. Results. In total, 35 of 85 patients showed MC, mostly type II. Herniated tissue in MC group contained relatively more hyaline cartilage endplate than that in non-MC group (on average, 50% vs. 8%, P < 0.05) but less nucleus pulposus (18% vs. 55%, P < 0.05). Conservative treatment reduced Oswestry Disability Index scores in non-MC group from 29.4 to 23.5 on average (P < 0.05), but reductions in MC group (30.1–29.0) were nonsignificant. Herniated volumes reduced after conservative treatment in non-MC group (0.44–0.21 cm³, P < 0.05) but not in MC group (0.52–0.45 cm³, P > 0.05). More neovascularization and macrophage infiltration was observed in herniated tissue from non-MC group than from MC group (P < 0.001). Conclusion. MCs in patients with LDH are associated with cartilaginous herniations that resorb poorly, so that patients respond less well to conservative treatments. Loss of cartilaginous endplate may explain the origins of MCs and their association with disc infection. Level of Evidence: 3

Obesity may promote intervertebral disc degeneration (IDD) by non-mechanical means, by influencing levels of free fatty acids which could impair cell metabolism. This study aims to establish metabolic factors in obesity-related IDD independent of mechanical loading. In clinical study, we retrospectively reviewed 128 volunteers (73 males, 55 females, aged 29–88 years) and compared their grades of disk degeneration with obesity-related factors such as body weight, BMI, and serum lipid levels. Clinically, the IDD group showed increased age, BMI and serum triglyceride. Triglyceride was a significant risk factor for IDD even after correction for BMI and age (P = 0.007). In obesity animal model, rats were fed a high-fat diet (HFD) in order to study its effects on disk metabolism and apoptosis. HFD rats had significantly higher serum levels of lipids, including triglyceride and non-esterified fatty acid, and showed significantly decreased markers of anabolism, increased catabolism and apoptosis in disk. Finally, rat nucleus pulposus (NP) cells were stimulated in vitro with a fatty acid (palmitic acid, PA) to gauge its effects on cell metabolism and apoptosis. Cell culture studies showed that NP cells exposed to PA showed increased apoptosis for activation of caspase 3, 7, 9, and PARP, which was primarily via the MAPK signal pathway, especially ERK pathway. In conclusion, hypertriglyceridemia can lead to IDD, independently of age and BMI. Hypertriglyceridemia appears to mediate disk cell apoptosis and matrix catabolism primarily via the ERK pathway.