Zhaomin Zheng

Intervertebral disc degeneration (IDD) is associated with low back pain, a leading cause of disability worldwide. Fibrosis of nucleus pulposus (NP) is a principal component of IDD, featuring an accumulation of myofibroblast-like cells. Previous study indicates that matrix metalloproteinase 12 (MMP12) expression is upregulated in IDD, but its role remains largely unexplored. We here showed that TGF-β1 could promote myofibroblast-like differentiation of human NP cells along with an induction of MMP12 expression. Intriguingly, MMP12 knockdown not only ameliorated the myofibroblastic phenotype but also increased chondrogenic marker expression. Transcriptome analysis revealed that the MMP12-mediated acquisition of myofibroblast phenotype was coupled to processes related to fibroblast activation and osteogenesis and to pathways mediated by MAPK and Wnt signaling. Injury induced mouse IDD showed NP fibrosis with marked increase of collagen deposition and αSMA-expressing cells. In contrast, MMP12-KO mice exhibited largely reduced collagen I and III but increased collagen II and aggrecan deposition, indicating an inhibition of NP fibrosis along with an enhanced cartilaginous matrix remodeling. Consistently, an increase of SOX9 ⁺ and CNMD ⁺ but decrease of αSMA ⁺ NP cells was found in the KO. Altogether, our findings suggest a pivotal role of MMP12 in myofibroblast generation, thereby regulating NP fibrosis in IDD.

Chronic low back pain (LBP) is the leading cause of global disability. Vertebral bone marrow lesions (BMLs), one etiological factor for chronic LBP, are MRI signal changes in the vertebral bone marrow that extend from the disc endplate. The adipogenesis of bone marrow mesenchymal stem cells (BM-MSCs) could explain fatty replacement (FR) in normal bone marrow. FR is the most common type of BMLs. Here we show how the gut microbiome and serum metabolome change and how they interact in LBP patients with or without FR. The serum metabolome of chronic LBP patients with FR is characterized by decreased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has important capability to regulate BCAA degradation pathway. Ruminococcus gnavus, Roseburia hominis and Lachnospiraceae bacterium 8 1 57FAA are identified as the main species driving the association between biosynthesis of BCAAs and BM-MSCs metabolism in LBP with FR individuals. In vitro work demonstrates that BCAAs can induce the adipogenesis of BM-MSCs by activating the SIRT4 pathway. Our findings provide a deep insight into understanding the role of the disturbed gut ecosystem in FR and LBP.

Background: We aimed to propose the apical vertebras distribution modifier to supplement the coronal balance (CB) classification for adult idiopathic scoliosis (AdIS). An algorithm to predict postoperative coronal compensation and avoid postoperative coronal imbalance (CIB) was proposed. Methods: Patients were categorized into CB and CIB groups according to the preoperative coronal balance distance (CBD). The apical vertebras distribution modifier was defined as negative (−) if the centers of the apical vertebras (CoAVs) were on either side of the central sacral vertical line (CSVL) and positive (+) if the CoAVs were on the same side of the CSVL. Results: A total of 80 AdIS patients, with an average age of 25.97 ± 9.20 years, who underwent posterior spinal fusion (PSF) were prospectively recruited. The mean Cobb angle of the main curve was 107.25 ± 21.11 degrees at preoperation. The mean follow-up time was 3.76 ± 1.38 (2–8) years. At postoperation and follow-up, CIB occurred in 7 (70%) and 4 (40%) CB− patients, 23 (50%) and 13 (28.26%) CB+ patients, 6 (60%) and 6 (60%) CIB− patients, and 9 (64.29%) and 10 (71.43%) CIB+ patients. Health-related quality of life (HRQoL) was significantly better in the CIB− group compared with that of the CIB+ group in the dimension of back pain. To avoid postoperative CIB, the correction rate of the main curve (CRMC) should match the compensatory curve for CB−/+ patients; the CRMC should be greater than the compensatory curve for CIB− patients; and the CRMC should be less than the compensatory curve for CIB+ patients, and the inclination of the LIV needs to be reduced. Conclusions: CB+ patients have the least postoperative CIB rate and the best coronal compensatory ability. CIB+ patients are at a high risk of postoperative CIB and have the poorest coronal compensatory capacity in the event of postoperative CIB. The proposed surgical algorithm facilitates the handling of each type of coronal alignment.

Study Design: This was a retrospective clinical study.Purpose: This study aimed to evaluate the effect of combination therapy with zoledronic acid and teriparatide on the risk of new vertebral fracture (NVF) in type 2 diabetes mellitus (T2DM) patients after percutaneous kyphoplasty (PKP).Overview of Literature: Although T2DM had been associated with bone fragility and increased fracture risk, it remains unknown whether patients with T2DM could expect similar benefit from the combination therapy with zoledronic acid and teriparatide following PKP.Methods: Total 106 diabetic patients who had undergone PKP and had received anti-osteoporosis treatment for osteoporotic vertebral compression fracture were enrolled and allocated into the following two groups: group I (n=52, zoledronic acid) and group II (n=54, zoledronic acid plus teriparatide). The operating time, bone cement volume, and complications related to anti-osteoporosis treatment or PKP, if any, were recorded. The Visual Analog Scale (VAS) score and Oswestry Disability Index (ODI) were assessed at admission, at discharge, and at the final follow-up. Dual-energy X-ray absorptiometry scan of the hip for the measurement of the bone mineral density (BMD) was performed preoperatively and at the final follow-up for all the patients.Results: There was no significant difference in the age, body mass index, bone cement volume, or follow-up time of the groups. The mean follow-up duration was 22.5±1.6 months. All the patients had improved VAS and ODI, and group II had significantly better clinical outcomes than group I. All the patients had increased BMD at the latest follow-up, while group II exhibited significantly more improvement. The prevalence of NVF was lower in group II (11.5% vs. 7.4%, p=0.523). Male patients had a higher prevalence of NVF although the difference was not statistically significant.Conclusions: Combination therapy with zoledronic acid and teriparatide could improve the clinical outcomes, and BMD and had the potential to reduce NVF in diabetic patients following PKP.

Low back pain (LBP), as a leading cause of disability, is a common musculoskeletal disorder that results in major social and economic burdens. Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration, a significant contributor to LBP. Inflammatory mediators also play an indispensable role in discogenic LBP. The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies. Here, an overview of the advances in inflammation-related pain in disc degeneration is provided, with a discussion on the role of inflammation in IVD degeneration and pain induction. Puncture models, mechanical models, and spontaneous models as the main animal models to study painful disc degeneration are discussed, and the underlying signaling pathways are summarized. Furthermore, potential drug candidates, either under laboratory investigation or undergoing clinical trials, to suppress discogenic LBP by eliminating inflammation are explored. We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.

Visfatin reportedly induces the expression of proinflammatory cytokines. Severe grades of intervertebral disc disease (IVDD) exhibit higher expression of visfatin than mild ones. However, the direct relationship between visfatin and IVDD remains to be elucidated. This study aimed to clarify whether stimulation of visfatin in IVDD is mediated by IL-6. To investigate the role of visfatin in IVDD, a rat model of anterior disc puncture was established by injecting visfatin or PBS using a 27-gauge needle. Results revealed an obvious aggravation of the histological morphology of IVDD in the visfatin group. On treating human NP cellswith visfatin, the levels of collagenII and aggrecan decreased and those of matrix metallopeptidase 3 and IL-6 gradually increased. A rapid increase in ERK, JNK, and p38 phosphorylation was also noted after visfatin treatment. Compared to those treated with visfatin alone, NP cells pretreated with ERK1/2, JNK, and p38 inhibitors or siRNA targeting p38, ERK, and JNK exhibited a significant suppression of IL-6. Our data represent the first evidence that visfatin promotes IL-6 expression in NP cells via the JNK/ERK/p38-MAPK signalling pathways. Further, our findings suggest epidural fat and visfatin as potential therapeutic targets for controlling IVDD-associated inflammation.

Purpose To analyze correlations between the realistic surgical difficulty of LaLIF and anatomic characteristics in radiographic images, in order to develop a simple classification to provide guiding information for case selection and evaluate the potential risks of the technique. Methods Ninety-six consecutive cases who underwent LaLIF surgeries at the L4-5 level with MR T2-weighted images were analyzed. A novel classification based on the anatomic relationships among the disk, great vessels, and psoas muscle was used for grouping. Clinical outcomes and realistic surgical difficulty parameters were recorded, and comparisons were made among different types of classifications. Results Of the 96 analyzed cases, the time of surgical exposure was significantly longer for type C than for type B, and both of these were longer than that of type A. The VAS and ODI were significantly improved at a 1-year follow-up. There was no statistically significant difference among the three types. Type C had the highest incidence of complications, while Type A had the lowest. Analyses of another 304 MRI cases obtained in outpatient clinics showed that the distribution of the three types among these cases was consistent with that of the surgical cohort. Conclusion Our novel and simple classification provides useful information for case selection. Type A provided the best indication and is most appropriate for a beginner in this technique. Type C includes the most challenging situations, which may have a high incidence of complications and require sophisticated surgical skills to achieve satisfactory outcomes and avoid approach-related complications.

Previous studies have indicated that growth differentiation factor 6 (GDF6) is a potential candidate for intervertebral disc (IVD) degeneration (IDD) treatment. Here, we investigated the effect of GDF6 on IDD by examining changes in disc structure and the expression of inflammatory and pain‐related factors. A rat posterior disc puncture model of single segments and three consecutive segments was constructed, and GDF6 or phosphate‐buffered solution was administered via intradiscal injection 1 or 2 weeks after surgery. Magnetic resonance imaging showed a clear degeneration signal in the punctured disc, which was inhibited by GDF6. Histological staining revealed that GDF6 did not significantly improve the structure of IVDs in rats 8 weeks after puncture surgery, but it had an inhibitory effect on expression of the tumor necrosis factor‐alpha (TNF‐α) and interleukin (IL)‐1β in the IVD. Furthermore, GDF6 was found to protect the morphology and structure of the IVD 32 weeks after surgery. Mechanical and thermal hyperalgesia tests suggested that GDF6 injection can significantly improve mechanical and thermal‐stimulated pain behavior in rats and inhibit the expression of inflammatory factors TNF‐α and IL‐1β and the pain factor calcitonin gene‐related peptide in the dorsal root ganglion. A rat protein array test indicated that GDF6 could reduce the expression of cytokines IL‐6, intercellular cell adhesion molecule‐1, matrix metalloproteinase‐13, IL‐1β, and TNF‐α and increase the expression of tissue inhibitor of metalloproteinases 1, Transforming growth factor‐beta 2, IL‐10, and resistin in a TNF‐α‐induced IDD cell model. Thus, our study demonstrates that GDF6 can improve the structure of the IVD, inhibit the expression of inflammatory and pain‐related factors, and improve pain behavior in rats. Clinical Significance: To establish further preclinical research and clinical trials, comprehensive data are needed to validate the regenerative properties of GDF6. Ideally, a regenerative agent should also be able to relieve discogenic pain, achieving the best clinical outcomes.