Cervical nerve root variant: report of two cases under the cervical endoscopy and review of clinical literature.

BACKGROUND: We know of five cases of cervical nerve root variants that have been reported, all of which were found during posterior cervical surgery. We reported two cases of cervical nerve root variants. One had two anomalous branches of the C7 root, is the other had a C5, C6 nerve root communication branch. CASE DESCRIPTION: A 62-year-old female presented with neck and right upper extremity pain, accompanied by hypaesthesia in her right forearm for 4 months. Preoperative X-ray film, magnetic resonance imaging (MRI) and computed tomography (CT) scan demonstrated C6-7 uncovertebral joint hyperplasia and foraminal stenosis. She underwent posterior cervical endoscopic foraminoplasty. The right C7 nerve root was observed to have two anomalous branches originated from a proximal trunk. After the surgery, the symptoms resolved. A 54-year-old female presented with radiating pain and numbness in her right arm and hand for 4 months. Preoperative MRI showed a C5/6 intervertebral disc herniation. She had hypaesthesia in radial side of her right arm and 1st-3rd fingers. Posterior cervical endoscopic foraminalplasty was performed for the patient. After decompression of the bony wall of the posterior nerve root canal, a 2-mm thick communicating nerve was observed emerging from the dura with the C6 nerve root and exiting to the caudal level. After the surgery, the symptoms resolved immediately. CONCLUSIONS: Cervical nerve root variant may be more apparent on edoscopic approaches to the cervical foraminae than at open surgery.

Suspected allergy to titanium after anterior cervical discectomy and fusion using a Zero-P device: a case report.

PURPOSE: Cases of allergy to large surgical implants have been reported. However, few studies have reported allergy to small titanium-containing implants (e.g. Zero-P device). METHODS: We reported the case of a 51-year old male patient who underwent the anterior cervical discectomy and fusion (ACDF) procedure using a Zero-P device and exhibited allergic symptoms 1 month after the surgery. RESULTS: The allergic symptoms included intermittent tingling and itches in the throat induced by speaking. Systemic rashes over the skin surface and congestion of the eyeball, and dysphagia were also present. Anti-allergic treatment did not resolve the symptoms. Patch tests revealed negative reactions to the rested reagents including titanium. Radiographic results showed solid bone fusion and no signs of chronic inflammation or hypotoxic infection in the surrounding tissues. Upon the patient's request, we removed the titanium screws and plate of the Zero-P device. No allergic reactions were observed after the surgery and at a 6-month follow-up. CONCLUSIONS: Even with a small implant such as the Zero-P device, allergy to titanium may still occur. This case demonstrated the need to screen for the presence of allergy to metals including titanium before the surgery.

Thoracic de-kyphosis for revision surgery of a failure case of endoscopic discectomy: a case report and literature review.

BACKGROUND: Indications and clinical outcomes of percutaneous endoscopic thoracic discectomy(PETD) in treating thoracic disc herniation is rarely reported and still controversial. We reported an unsatisfied recovery of thoracic disc herniation with PETD, treated by a second posterior thoracic laminectomy and Ponte osteotomy. CASE DESCRIPTION: A male presented with lower extremity weakness and stagger caused by T3/4 intervertebral disc herniation. The upper thoracic curve was in excessive kyphosis with T2-5 Cobb angle of 34.3 degrees. The preoperative ODI score was 34 and Roelzs's JOA score was 14. Percutaneous transforaminal endoscopic thoracic discectomy (PETD) from a posterior lateral approach was performed. At five-month follow-up, his thoracic back pain and staggering gait did not improve. The postoperative T2-5 Cobb angle was 32.1 degrees, the ODI score was 24 and Roelzs's JOA score was 14. A second posterior thoracic decompression this time with fixation was performed, but no disc herniation was detected. A Ponte osteotomy was performed to correct the kyphosis. One month after the second surgery, muscle strength of the lower limbs was improving with the T2-5 Cobb angle decreased to 19.4 degrees, the ODI score decreased to 10 and Roelzs's JOA score increase to 16. Six month later, the ODI score decreased to 0 and Roelzs's JOA score improved to 18. In review of the literature, PETD doesn't guarantee the patient a satisfactory neurological recovery for kyphotic thoracic disc herniation. Posterior decompression with Ponte osteotomy may be beneficial to release the tension and decompression of the spinal cord tension. CONCLUSIONS: Thoracic disc herniation with kyphosis angle >20 degrees (T2-5), percutaneous endoscopic thoracic discectomy is not likely to get good neurologic results. Posterior laminectomy with ponte osteotomy might be beneficial for these patients to induce dorsal drifting of the spinal cord from anterior herniation.

Bi-needle technique versus transforaminal endoscopic spine system technique for percutaneous endoscopic lumbar discectomy in treating intervertebral disc calcification: a propensity score matched cohort analysis.

OBJECTIVE: The aim of this study was to evaluate the clinical results of a Bi-needle technique and conventional transforaminal endoscopic spine system (TESSYS) technique for percutaneous endoscopic lumbar discectomy (PELD) in treating patients with intervertebral disc calcification (IDC). BACKGROUND: PELD has gained acceptance for treating patients with IDC. The Bi-needle technique was designed to improve the efficiency and safety of PELD. METHOD: Bi-needle and TESSYS group within each cohort were balanced using 1:1 propensity score matching. Finally, 32 patients with IDC treated by Bi-needle technique from December 2015 to September 2017 were enrolled and 25 patients treated by TESSYS technique from the same spine surgery center between January 2013 and October 2017 were enrolled as controls. RESULTS: Propensity score matching generated 22 Bi-needle and 22 TESSYS patients. There were no significant differences in visual analog scale and lumbar Japanese Orthopaedic Association scores between Bi-needle and TESSYS group. Operative time and rate of complications in the Bi-needle was significantly better than the TESSYS group (p < 0.01). CONCLUSIONS: Both surgical methods achieved good clinical outcomes. However, compared with the TESSSY technique, operative time of the Bi-needle technique is shorter, and rate of complications is lower.

Absence of VEGFR-1/Flt-1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model.

Although degenerative disc disease (DDD) and related low back pain (LBP) are growing public health problems, the underlying disease mechanisms remain unclear. An increase in the vascular endothelial growth factor (VEGF) levels in DDD has been reported. This study aimed to examine the role of VEGF receptors (VEGFRs) in DDD, using a mouse model of DDD. Progressive DDD was induced by anterior stabbing of lumbar intervertebral discs in wild type (WT) and VEGFR-1 tyrosine-kinase deficient mice (vegfr-1TK-/- ). Pain assessments were performed weekly for 12 weeks. Histological and immunohistochemical assessments were made for discs, dorsal root ganglions, and spinal cord. Both vegfr-1TK-/- and WT mice presented with similar pathological changes in discs with an increased expression of inflammatory cytokines and matrix-degrading enzymes. Despite the similar pathological patterns, vegfr-1TK-/- mice showed insensitivity to pain compared with WT mice. This insensitivity to discogenic pain was related to lower levels of pain factors in the discs and peripheral sensory neurons and lower spinal glial activation in the vegfr-1TK- /- mice than in the WT mice. Exogenous stimulation of bovine disc cells with VEGF increased inflammatory and cartilage degrading enzyme. Silencing vegfr-1 by small-interfering-RNA decreased VEGF-induced expression of pain markers, while silencing vegfr-2 decreased VEGF-induced expression of inflammatory and metabolic markers without changing pain markers. This suggests the involvement of VEGFR-1 signaling specifically in pain transmission. Collectively, our results indicate that the VEGF signaling is involved in DDD. Particularly, VEGFR-1 is critical for discogenic LBP transmission independent of the degree of disc pathology.

Is selective nerve root block necessary for learning percutaneous endoscopic lumbar discectomy: a comparative study using a cumulative summation test for learning curve.

PURPOSE: The aim of this study was to investigate the effect of lumbar spine selective nerve root block (SNRB) experience on the learning efficiency of percutaneous endoscopic lumbar discectomy (PELD) for junior trainees. METHODS: A total of 480 patients undergoing single-level PELD performed by eight junior trainees were included. The trainees were divided into two groups based on whether they had previous SNRB experience (group A, yes; group B, no). Surgical proficiency was defined as total operation time less than 65 minutes and cumulative radiation exposure time no more than 40 seconds. The learning curve was analyzed by cumulative summation (CUSUM) test. Clinical evaluations included Macnab classification, visual analog scale (VAS)-low back score, VAS-leg score, and Oswestry Disability Index (ODI). Follow-up information at 12 months was also obtained. RESULTS: Integral number of cases before achieving an acceptable surgical level in group A (47.75 ± 2.50 cases) was significantly smaller than that in group B (56.50 ± 1.29 cases, p < 0.05), along with less accumulated failure (18.75 ± 0.96 cases vs. 25.50 ± 1.75 cases, p < 0.05). The two groups were comparable in clinical outcomes. Forty-seven cases of complications were observed, with 17 in group A and 30 in group B (p < 0.05). CONCLUSION: Previous experience of SNRB improved the performance of PELD with shorter operation time and less radiation exposure. SNRB practice may reduce the complication rate without a significant effect on the recurrence of symptoms and reoperation.

Development of an in vivo mouse model of discogenic low back pain.

Discogenic low back pain (DLBP) is extremely common and costly. Effective treatments are lacking due to DLBP's unknown pathogenesis. Currently, there are no in vivo mouse models of DLBP, which restricts research in this field. The aim of this study was to establish a reliable DLBP model in mouse that captures the pathological changes in the disc and allows longitudinal pain testing. The model was generated by puncturing the mouse lumbar discs (L4/5, L5/6, and L6/S1) and removing the nucleus pulposus using a microscalpel under the microscope. Histology, molecular pathways, and pain-related behaviors were examined. Over 12 weeks post-surgery, animals displayed the mechanical, heat, and cold hyperalgesia along with decreased burrowing and rearing. Histology showed progressive disc degeneration with loss of disc height, nucleus pulposus reduction, proteoglycan depletion, and annular fibrotic disorganization. Immunohistochemistry revealed a substantial increase in inflammatory mediators at 2 and 4 weeks. Nerve growth factor was upregulated from 2 weeks to the end of the experiment. Nerve fiber ingrowth was induced in the injured discs after 4 weeks. Disc-puncture also produced an upregulation of neuropeptides in dorsal root ganglia neurons and an activation of glial cells in the spinal cord dorsal horn. These findings indicate that the cellular and structural changes in discs, as well as peripheral and central nervous system plasticity, paralleled persistent, and robust behavioral pain responses. Therefore, this mouse DLBP model could be used to investigate mechanisms underlying discogenic pain, thereby facilitating effective drug screening and development of treatments for DLBP.

TGF-ß Stimulates Expression of Chondroitin Polymerizing Factor in Nucleus Pulposus Cells Through the Smad3, RhoA/ROCK1, and MAPK Signaling Pathways.

The enzyme chondroitin polymerizing factor (ChPF) is primarily involved in extension of the chondroitin sulfate backbone required for the synthesis of sulfated glycosaminoglycan (sGAG). Transforming growth factor beta (TGF-ß) upregulates sGAG synthesis in nucleus pulposus cells; however, the mechanisms mediating this induction are incompletely understood. Our study demonstrated that ChPF expression was negatively correlated with the grade of degenerative intervertebral disc disease. Treatment of nucleus pulposus cells with TGF-ß induced ChPF expression and enhanced Smad2/3, RhoA/ROCK activation, and the JNK, p38, and ERK1/2 MAPK signaling pathways. Selective inhibitors of Smad2/3, RhoA or ROCK1/2, and knockdown of Smad3 and ROCK1 attenuated ChPF expression and sGAG synthesis induced by TGF-ß. In addition, we showed that RhoA/ROCK1 signaling upregulated ChPF via activation of the JNK pathway but not the p38 and ERK1/2 signaling pathways. Moreover, inhibitors of JNK, p38 and ERK1/2 activity also blocked ChPF expression and sGAG synthesis induced by TGF-ß in a Smad3-independent manner. Collectively, our data suggest that TGF-ß stimulated the expression of ChPF and sGAG synthesis in nucleus pulposus cells through Smad3, RhoA/ROCK1 and the three MAPK signaling pathways. J. Cell. Biochem. 119: 566-579, 2018. © 2017 Wiley Periodicals, Inc.

Nicotinamide Phosphoribosyltransferase Inhibitor APO866 Prevents IL-1ß-Induced Human Nucleus Pulposus Cell Degeneration via Autophagy.

BACKGROUND/AIMS: Intervertebral discs consist of an extracellular matrix (ECM) with a central gelatinous nucleus pulposus (NP) enclosed in an outer layer known as the annulus fibrosus. ECM metabolic disorders result in loss of boundary between the annulus fibrosus and NP, which can lead to intervertebral disc degeneration (IDD). Proinflammatory cytokines, such as interleukin (IL)-1ß, mediate the progression of IDD. Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD) and is known to be induced by IL-1ß. APO866 is an inhibitor of NAD biosynthesis and is involved in autophagy. LC3 (microtubule-associated protein 1 light chain 3) is a key regulator of autophagy and is used as an indicator of increased autophagy. Herein, we investigate the role of APO866 in regulating autophagy in NP cells and IL-1ß mediated NP cell degeneration and apoptosis. METHODS: NP cells were extracted from IDD tissues and cultured in DMEM/F12 medium. Nampt was induced by different concentrations of IL-1ß (0, 0.5, 1, 5, 10 ng/mL) for 24 h or NP cells were treated with 10 ng/mL IL-1ß for 0, 6, 12, 48 h. QRT-PCR and western blots were used to detect Nampt and ECM-related protein expression in NP tissue of patients with IDD and in NP cells. Confocal analysis was used to detect membrane-bound LC3, Aggrecan, and Collagen II. RESULTS: Nampt is expressed in NP tissue at higher levels in severe grades of IDD (Grade IV and V) compared with low grades (Grade II and III). In NP cells, 10 ng/mL IL-1ß induced Nampt expression for 48 h, increased expression of the degradative-associated proteins, ADAMTS4/5 and MMP-3/13, and decreased expression of ECM-related proteins, Aggrecan and Collagen II. However, the Nampt inhibitor APO866 blocked IL-1ß induction, and the knockdown of Nampt expression increased the expression of ECM proteins that were inhibited by IL-1ß. Moreover, evidence provided by the autophagic markers LC3 and Beclin-1 indicated that APO866 induced NP cell autophagy. Furthermore, although APO866 inhibited the downregulated expression of ECM-related proteins by IL-1ß, this function was blocked by autophagy inhibitor, 3-methyladenine. CONCLUSION: APO866 protects NP cells and induces autophagy by inhibiting IL-1ß-induced NP cell degeneration and apoptosis, which may have therapeutic potential in IDD.

Effect of continuous positive airway pressure on glucose metabolism in adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

Obstructive sleep apnea (OSA) has many serious consequences, and one of these may be the exacerbation of type 2 diabetes mellitus (T2DM). Reports on the effect of continuous positive airway pressure (CPAP) on glucose metabolism in people with T2DM and OSA are conflicting. Therefore, the purpose of this review was to examine the effect of CPAP treatment on glucose metabolism by synthesizing findings from randomized controlled trials. The PRISMA review protocol was developed and registered in PROSPERO. A systematic search of PubMed, CINAHL, Embase, Web of Science, PsycInfo, and Cochrane was conducted from inception to March 2017. The Cochrane risk of bias tool was used to assess the study quality. Review Manager (v5.2) was used for the meta-analyses, and the standardized mean difference was calculated. Six studies consisting of 496 participants were included in this review. The meta-analyses indicated that CPAP treatment did not have significant impact on glucose metabolism measured by A1C (mean difference = 0.05, 95% CI - 0.14 to 0.24, P = 0.61), fasting insulin level (mean difference = - 2.34, 95% CI - 8.19 to 3.51, P = 0.43), and fasting glucose (mean difference = - 0.05, 95% CI - 0.52 to 0.42, P = 0.84). As expected, CPAP treatment can improve daytime sleepiness (mean difference = - 2.68, 95% CI - 3.91 to - 1.54, P < 0.001). Findings of this meta-analysis do not substantiate a positive effect of CPAP on glucose metabolism in people with T2DM and coexisting OSA. Future large-scale clinical trials with a longer treatment duration and better CPAP compliance are warranted.

TGF-ß Induces Up-Regulation of Chondroitin Sulfate Synthase 1 (CHSY1) in Nucleus Pulposus Cells Through MAPK Signaling.

BACKGROUND/AIMS: Chondroitin sulfate synthase 1 (CHSY1) is a glycosyltransferases involved in the biosynthesis of chondroitin and dermatan sulfate glycosaminoglycan (GAG). TGF-ß can stimulate sulfated GAG production in nucleus pulposus cells; however, the underlying mechanisms are poorly understood. METHODS: CHSY1 expression was examined in rat nucleus pulposus treated with TGF-ß using real-time PCR and Western blot analysis. Lentiviral knockdown was performed to determine the downstream effectors of TGF-ß and to measure the effect of c-Jun and Sp1 on TGF-ß mediated CHSY1 promoter activity and CHSY1 expression. RESULTS: TGF-ß increased CHSY1 expression and promoter activity in the nucleus pulposus partially through activation of canonical Smad signaling pathway. Knockdown of c-Jun and Sp1 decreased CHSY1 promoter activity, CHSY1 expression and sGAG accumulation induced by TGF-ß. Furthermore, we found that TGF-ß-induced expression of CHSY1 was mediated through the activation of MAPK signaling. Moreover, we showed that silencing CHSY1 decreased sGAG accumulation in nucleus pulposus cells induced by TGF-ß. CONCLUSION: Our results suggest that TGF-ß induced CHSY1 expression in the nucleus pulposus through the activation of MAPK signaling.

Factors that may affect outcome in cervical artificial disc replacement: a systematic review.

PURPOSE: To identify the factors that may affect outcome in C-ADR and provide the pooled results of postoperative success rate of implanted segment range of motion (ROM), incidence of heterotopic ossification (HO), incidence of radiographic adjacent segment degeneration (r-ASD)/adjacent segment disease (ASD), and surgery rate for ASD. METHODS: We systematically searched in PubMed, Embase, Cochrane library and Web of knowledge from 2001 to May 2015. Two independent reviewers screened the primary records. Eleven questions regarding the effect of patient selection issues and radiographic parameters issues on outcome were posed previously. Studies addressing the framed questions were included for analysis. RESULTS: Twenty-two studies were included for the final analysis. Results showed that number of surgical level (single versus double-level) had no effect on primary clinical outcome and radiographic outcome, surgical level had no effect on clinical and radiographic outcome, and smoking habits had negative effect on clinical outcome. No evidence for the effect of patient's age and pathology category (radiculopathy or myelopathy) on outcome was found. The overall success rate of ROM was 79.4%. ROM of the implanted segment and cervical sagittal alignment had no effects on clinical outcome. The pooled incidences of grade 1-4 HO and grade 3-4 HO were 27.7 and 7.8%, respectively. The pooled incidence of r-ASD and surgery rate for ASD were 42.4 and 3.8%, respectively. CONCLUSIONS: The available evidence showed that most of the pre-selected factors had no effect on outcome after C-ADR, and the ROM success rate, incidence of HO and r-ASD/ASD, and surgery rate for ASD are acceptable. There is a lack of evidence from RCTs for some factors.

Clinical Outcomes of Full-Endoscopic Visualized Foraminoplasty and Discectomy for Lumbar Disc Herniation with Bilateral Radiculopathy.

OBJECTIVE: The treatment of lumbar disc herniation (LDH) with bilateral radiculopathy using transforaminal endoscopic lumbar discectomy (TELD) remains challenging, especially at the L5/S1 level with narrow foramen or high iliac crest. Full-endoscopic visualized foraminoplasty and discectomy (FEVFD) is a newly developed technique for LDH and lumbar stenosis. However, there is limited evidence on the efficacy of FEVFD technique in the treatment of LDH with bilateral radiculopathy. This study was to assess the clinical outcomes and safety of using FEVFD in the treatment of LDH with bilateral radiculopathy. METHODS: This retrospective study enrolled 63 patients with LDH presenting with bilateral radiculopathy between January 2018 and January 2022. Patients enrolled before January 2020 were treated using a conventional transforaminal endoscopic surgical system (TESSYS) technique (TESSYS, n = 33) and treated using a FEVFD technique after that (FEVFD, n = 30). The total operation time and the number of intraoperative fluoroscopies were recorded. The Oswestry Disability Index (ODI) and visual analog scale (VAS) were evaluated preoperatively and postoperatively (at 1-month, 3-month, 6-month, and final follow-ups). Global outcomes at final follow-up were assessed using modified MacNab criteria. RESULTS: Compared with TESSYS, patients in FEVFD group had a shorter operation time (92.9 vs. 78.0 min). The intraoperative fluoroscopies in FEVFD group were significantly lower than those in TESSYS group (18.7 vs. 4.9). After the operation, the VAS and ODI scores at all follow-ups in the two groups were significantly lower than those before operation. For the L5/S1 level, the values of VAS and ODI scores in FEVFD group were significantly lower than those of in TESSYS group at 3-month, 6-month, and final follow-up. For the L4/5 level, however, no significant difference was found in VAS and ODI scores between these two groups at the follow-ups. According to the modified MacNab criteria, the excellent-to-good rate in TESSYS and FEVFD groups was 84.8% and 90.0%, respectively. CONCLUSION: For LDH with bilateral radiculopathy, using the FEVFD technique could not only reduce the operation time and radiation, but also improve the clinical outcomes at the L5/S1 level.

Validity and reliability of the sleep health index among patients with spinal degenerative diseases.

OBJECTIVE: To test the validity and reliability of the Sleep Health Index (SHI) in a Chinese clinical sample, and thereby provide more evidence for the assessment of sleep health in future research and clinical practice. METHODS: This study used a cross-sectional design. A convenient sample of 265 participants with spinal degenerative diseases was recruited from outpatient clinics. The SHI, Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Patient Health Questionnaire-9 (PHQ-9), Visual Analogue Scale (VAS), and EuroQoL 5-Dimension 5-Level (EQ-5D-5L) were administered via REDCap. Structural, concurrent, convergent, known-group validity, internal consistency, and test-retest reliability were evaluated. RESULTS: Confirmatory factor analysis confirmed a 3-factor structure (sleep duration, sleep quality, and disordered sleep). The overall SHI score had a high correlation with PSQI and ISI (r = -0.62 and -0.70, respectively) as well as a moderate correlation with PHQ-9 (r = -0.50, p<0.001). The overall SHI was significantly associated with VAS, ESS, and EQ-5D-5L (r = -0.15 to -0.23, p<0.05). Participants with pain had a lower score on the sleep quality sub-index than those without (p<0.001). Those with chronic diseases had a significantly lower score on the sleep duration sub-index than those without (p<0.05). Those with depression, poor sleep quality, and insomnia had lower scores on the overall scale and the three sub-indices than those without (p<0.05). The overall SHI showed acceptable internal consistency (Cronbach's α = 0.74) and test-retest reliability (intraclass correlation coefficient = 0.73). CONCLUSIONS: The Chinese version of SHI showed good validity and acceptable reliability and could be used to assess sleep health among clinical populations.

Does Focal Kyphotic Deformity at Non-responsible Levels Affect the Outcomes of Anterior Cervical Decompression and Fusion?

OBJECTIVE: Focal cervical kyphotic deformity (FCK) without neurologic compression is not uncommon in patients with cervical spondylotic myelopathy (CSM) who underwent anterior cervical decompression and fusion (ACDF) surgery. It remains unclear whether FCK at non-responsible levels needs to be treated simultaneously. This study aims to investigate whether FCK at non-responsible levels is the prognostic factor for CSM and elucidate the surgical indication for FCK. METHODS: Patients with CSM who underwent ACDF between January 2016 and April 2021 were included. Patients were divided into two groups according to the presence of FCK and two classifications according to global cervical sagittal alignment. Clinical outcomes were compared using Japanese Orthopaedic Association (JOA) scores and recovery rate (RR) of neurologic function. Univariate and multivariate analysis based on RR assessed the relationship between various possible prognostic factors and clinical outcomes. The receiver operating characteristic curve (ROC) was used to determine the optimal cutoff value of the focal Cobb angle to predict poor clinical outcomes. RESULTS: A total of 94 patients were included, 41 with FCK and 53 without. Overall, the RR of neurologic function was significantly lower in the FCK than in the non-FCK group. Further analysis showed that the RR difference between the two groups was only observed in hypo-lordosis classification (kyphotic and sigmoid alignment), but not in the lordosis classification. Multivariate analysis showed that the preoperative focal Cobb angle in the FCK level (OR = 0.42; 95% CI = 0.18-0.97) was independently associated with clinical outcomes in the hypo-lordosis classification. The optimal cutoff point of the preoperative focal kyphotic Cobb angle was calculated at 4.05°. CONCLUSION: For CSM with hypo-lordosis, FCK was a risk factor for poor postoperative outcomes. Surgeons may consider treating the FCK simultaneously if the focal kyphotic Cobb angle of FCK is greater than 4.05° and is accompanied by cervical global kyphotic or sigmoid deformity.

TMEM135 maintains the equilibrium of osteogenesis and adipogenesis by regulating mitochondrial dynamics.

BACKGROUND: Disturbance in the differentiation process of bone marrow mesenchymal stem cells (BMSCs) leads to osteoporosis. Mitochondrial dynamics plays a pivotal role in the metabolism and differentiation of BMSCs. However, the mechanisms underlying mitochondrial dynamics and their impact on the differentiation equilibrium of BMSCs remain unclear. METHODS: We investigated the mitochondrial morphology and markers related to mitochondrial dynamics during BMSCs osteogenic and adipogenic differentiation. Bioinformatics was used to screen potential genes regulating BMSCs differentiation through mitochondrial dynamics. Subsequently, we evaluated the impact of Transmembrane protein 135 (TMEM135) deficiency on bone homeostasis by comparing Tmem135 knockout mice with their littermates. The mechanism of TMEM135 in mitochondrial dynamics and BMSCs differentiation was also investigated in vivo and in vitro. RESULTS: Distinct changes in mitochondrial morphology were observed between osteogenic and adipogenic differentiation of BMSCs, manifesting as fission in the late stage of osteogenesis and fusion in adipogenesis. Additionally, we revealed that TMEM135, a modulator of mitochondrial dynamics, played a functional role in regulating the equilibrium between adipogenesis and osteogenesis. The TMEM135 deficiency impaired mitochondrial fission and disrupted crucial mitochondrial energy metabolism during osteogenesis. Tmem135 knockout mice showed osteoporotic phenotype, characterized by reduced osteogenesis and increased adipogenesis. Mechanistically, TMEM135 maintained intracellular calcium ion homeostasis and facilitated the dephosphorylation of dynamic-related protein 1 at Serine 637 in BMSCs. CONCLUSIONS: Our findings underscore the significant role of TMEM135 as a modulator in orchestrating the differentiation trajectory of BMSCs and promoting a shift in mitochondrial dynamics toward fission. This ultimately contributes to the osteogenesis process. This work has provided promising biological targets for the treatment of osteoporosis.

Dysfunction of Caveolae-Mediated Endocytic TßRI Degradation Results in Hypersensitivity of TGF-ß/Smad Signaling in Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder caused by mutations of type I collagen-related genes, and excessive transforming growth factor-beta (TGF-ß) signaling is a common mechanism. TGF-ß/Smad signaling has inhibitory effects on osteoblast differentiation and maturation and is mainly transduced and regulated by the internalization of a tetrameric receptor complex comprising types I and II TGF-ß receptors (TßRI and TßRII). During internalization, clathrin-mediated endocytosis enhances TGF-ß/Smad signaling via Smad2/3 phosphorylation and receptors recycling, while caveolae-mediated endocytosis turns off TGF-ß/Smad signaling by promoting receptor ubiquitination and degradation. In this study, using an animal model of OI (Colla2oim , osteogenesis imperfecta murine [oim]/oim mouse), we found that osteoblastic cells of oim/oim mice were more sensitive to the inhibitory effects of TGF-ß on osteoblast differentiation and maturation and had much higher cell membrane protein levels of TGF-ß receptors than those of wild-type (wt)/wt mice. Further results showed that clathrin-mediated endocytosis of TßRI was enhanced, whereas caveolae-mediated TßRI endocytic degradation was reduced in oim/oim mice, combined with reduced caveolin-1 (Cav-1) phosphorylation. In addition, type I collagen downregulated TßRI via focal adhesion kinase (FAK) and Src activation-dependent Cav-1 phosphorylation. To further examine this mechanism, 4-week-old oim/oim and wt/wt mice were treated with either TßRI kinase inhibitor (SD-208) or vehicle for 8 weeks. SD-208 treatment significantly reduced the fracture incidence in oim/oim mice. Micro-computed tomography and biomechanical testing showed that femoral bone mass and strength were significantly improved with SD-208 treatment in both genotypes. Additionally, SD-208 significantly promoted osteoblast differentiation and bone formation and inhibited bone resorption. In conclusion, dysfunction of caveolae-mediated endocytic TßRI degradation is a possible mechanism for the enhanced TGF-ß/Smad signaling in OI. Targeting this mechanism using a TßRI kinase inhibitor effectively reduced fractures and improved bone mass and strength in OI model and, thus, may offer a new strategy for the treatment of OI. © 2022 American Society for Bone and Mineral Research (ASBMR).

Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-ß/Smad signaling in a growing mouse model of osteogenesis imperfecta.

Objective: Osteogenesis imperfecta (OI) is a congenital disorder characterized by muscle defect and skeletal fragility, and no cure is yet available. Crosstalk between bone and muscle has become a new coming focus of therapeutic strategy in OI. Irisin, a secreted myokine, was found to be involved in regulating bone metabolism, and may be beneficial for the treatment of OI. However, its effects in OI have yet to be determined. This study sought to determine whether Irisin therapy is capable of reducing fracture risk in OI and to investigate the potential mechanisms of action. Methods: Fibronectin type III domain containing 5 (FNDC5)/Irisin expression was assessed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. In vivo, X-ray was used for fracture counting and micro-CT, dynamic histomorphometry analysis, immunohistochemistry, histomorphometry, and biomechanical test were used to evaluate the effects of Irisin on fracture frequency and bone quality in OI mouse model, oim/oim mouse. In vitro, osteogenesis-related gene expressions were determined by quantitative real-time PCR (qRT-PCR), western blot, and osteoblastogenesis assay were assessed by alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining. Mechanistically, cell immunofluorescence staining, co-immunoprecipitation (co-IP) (Co-IP), molecular docking, western blot, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were used for elucidating the mechanisms of how Irisin antagonized transforming growth factor-ß (TGF-ß)/Smad signaling in oim/oim osteoblasts and further attenuated the inhibitory effect of TGF-ß1 on osteogenic differentiation. Results: Musculoskeletal system-related FNDC5/Irisin was decreased in the serum, muscle, and bone in oim/oim mice. Irisin administration reduced bone fracture and attenuated bone abnormalities by improving bone mass and strength and facilitating the expression of osteogenic differentiation markers. In vivo study and in vitro experiments showed that Irisin antagonized TGF-ß/Smad signaling by interfering with TGF-ß1-TGF-ß receptor II (TßRII) binding. In oim/oim osteoblasts, Irisin alleviated TGF-ß1-induced suppression of osteogenic differentiation through both integrin-dependent and integrin-independent mechanisms. Independent of integrin receptors, Irisin affected osteogenesis by activating ERK/p38 signaling and counteracting TGF-ß/Smad2/3 signaling. In particular, Irisin alleviated TGF-ß1-induced inhibition of Runx2 function at the osteocalcin promoter through decreasing Smad2/3 signaling and inducing HADC4/5 degeneration. Conclusions: Collectively, Irisin could effectively reduce bone fracture in oim/oim mice through promoting osteogenesis and counteracting TGF-ß/Smad signaling. Translational potential statement: Findings from this study provided evidence for using Irisin as a potential therapeutic reagent to prevent the progression of OI.

3D-printed gradient scaffolds for osteochondral defects: Current status and perspectives.

Articular osteochondral defects are quite common in clinical practice, and tissue engineering techniques can offer a promising therapeutic option to address this issue.The articular osteochondral unit comprises hyaline cartilage, calcified cartilage zone (CCZ), and subchondral bone.As the interface layer of articular cartilage and bone, the CCZ plays an essentialpart in stress transmission and microenvironmental regulation.Osteochondral scaffolds with the interface structure for defect repair are the future direction of tissue engineering. Three-dimensional (3D) printing has the advantages of speed, precision, and personalized customization, which can satisfy the requirements of irregular geometry, differentiated composition, and multilayered structure of articular osteochondral scaffolds with boundary layer structure. This paper summarizes the anatomy, physiology, pathology, and restoration mechanisms of the articular osteochondral unit, and reviews the necessity for a boundary layer structure in osteochondral tissue engineering scaffolds and the strategy for constructing the scaffolds using 3D printing. In the future, we should not only strengthen the basic research on osteochondral structural units, but also actively explore the application of 3D printing technology in osteochondral tissue engineering. This will enable better functional and structural bionics of the scaffold, which ultimately improve the repair of osteochondral defects caused by various diseases.

Alendronate modified mPEG-PLGA nano-micelle drug delivery system loaded with astragaloside has anti-osteoporotic effect in rats.

Astragaloside (AS) has an anti-osteoporotic effect, but its poor water solubility and low bioavailability limit its application. In this study, a novel nano-carrier with bone targeting was prepared by modifying mPEG-PLGA with alendronate (AL) before incorporation into astragaloside nano-micelles (AS-AL-mPEG-PLGA) to enhance the oral bioavailability, bone targeting and anti-osteoporosis effect of AS. The release behavior of AS-AL-mPEG-PLGA in vitro was investigated via dialysis. The pharmacokinetics of AS-AL-mPEG-PLGA was studied in Sprague-Dawley (SD) rats. The cytotoxicity of AS-AL-mPEG-PLGA in vitro (via MTT method), coupled with bone targeting ability in vitro and in vivo were evaluated. The therapeutic effects of free AS and AS-AL-mPEG-PLGA (ELISA, micro-CT, H&E staining) were compared in osteoporotic rats. AS-AL-mPEG-PLGA with smaller particle size (45.3 ± 3.8 nm) and high absolute zeta potential (-23.02 ± 0.51 mV) were successfully prepared, wherein it demonstrated higher entrapment efficiency (96.16 ± 0.18%), a significant sustained-release effect for 96 h and acceptable safety within 10-200 µg/mL. AS-AL-mPEG-PLGA could enhance the hydroxyapatite affinity and bone tissue concentration of AS. The relative bioavailability of AS-AL-mPEG-PLGA was 233.90% compared with free AS. In addition, the effect of AS in reducing serum levels of bone metabolism-related indicators, restoring the bone microarchitecture and improving bone injury could be enhanced by AS-AL-mPEG-PLGA. AS-AL-mPEG-PLGA with small particle size, good stability, remarkable sustained-release effect, safety and bone targeting was successfully constructed in this experiment to potentially improve the oral bioavailability and anti-osteoporosis effect of AS. Thus, AS-AL-mPEG-PLGA may be a promising strategy to prevent and treat osteoporosis.