Clinical efficacy of unilateral laminotomy for bilateral decompression in the treatment of adjacent segment disease after lumbar fusion.

Objective: To assess the clinical impact of unilateral laminotomy for bilateral decompression (ULBD) in managing patients with adjacent vertebrae following lumbar fusion. Methods: A retrospective analysis was conducted on 21 patients, with a mean age of 67.4 years, who underwent ULBD for adjacent vertebra disease at our department from January 2021 to November 2023. We reviewed demographic data, surgical techniques, imaging studies, and patient-reported outcomes. The study compared Visual Analog Scale (VAS) scores, Numeric Rating Scale (NRS) scores, Japanese Orthopaedic Association (JOA) scores, Short Form-36 (SF-36) scores, and imaging outcomes before surgery, immediately post-surgery, and at 1 month, 6 months, and 12 months post-surgery. Results: Evaluation of 21 patients with adjacent segment disease (ASD) (13 males, 8 females; mean age 67.42 years) was performed with follow-ups at various intervals post-surgery. Postoperative VAS, NRS, JOA, and SF-36 scores showed significant improvements compared to preoperative scores. Immediately after surgery, there were significant improvements in NRS score (2.76 ± 0.70 vs. 3.71 ± 0.85, P < 0.05) and JOA score (15.38 ± 1.02 vs. 9.29 ± 1.01, P < 0.05) compared to preoperative scores. Similarly, at 12 months post-surgery, significant improvements were observed in NRS score (1.52 ± 0.51 vs. 3.71 ± 0.85, P < 0.05) and JOA score (25.0 ± 1.10 vs. 9.29 ± 1.01, P < 0.05) compared to preoperative scores. The clinical satisfaction rate was 95.0% among all patients, with postoperative imaging examinations revealing a significant decompression effect. No complications were reported among the surgical patients. Conclusions: This study suggests that endoscopic ULBD can be a safe and effective technique for managing symptomatic ASD, providing satisfactory clinical outcomes for patients with ASD. Endoscopic ULBD may serve as an alternative treatment option for ASD with lumbar stenosis.

Posterior Percutaneous Endoscopic Cervical Discectomy for Single-Level Soft, Huge Central Disc Herniation.

BACKGROUND: Posterior percutaneous endoscopic cervical discectomy (PPECD) has been proven safe and effective for foraminal cervical disc herniation (CDH). However, central CDH has long been considered as the contraindication of PPECD, because the path is obstructed by the spinal cord and nerve root. OBJECTIVES: To preliminarily assess the feasibility, safety, and effectiveness of PPECD for single-level soft, huge central CDH. STUDY DESIGN: A retrospective cohort study. SETTING: Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College). METHODS: Between 2017 and 2020, 31 patients diagnosed with single-level soft, huge central CDH were treated by PPECD. Primary outcomes included the measures of neck and radicular pain based on the numeric rating scale (NRS) and cervical neurologic status based on the Japanese Orthopedic Association (JOA) score. The global outcome was assessed using the Odom's criteria at one-year follow-up. RESULTS: Compared to the baseline, there was a constant and significant reduction of NRS-rated pain and improvement of JOA-rated cervical neurologic status postoperatively (P < 0.01). According to the Odom's criteria, 96.8% (30/31) of patients had satisfactory postoperative clinical improvement (excellent or good outcomes) at one-year follow-up. Complications included C5 nerve root palsy and spinal cord injury. The total complication rate was 16.5% (2/31), but these complications were temporary and not catastrophic. LIMITATIONS: The limitations of this study include the volume of the sample, a short follow-up period, and the lack of a control group. CONCLUSIONS: Our preliminary experience indicates that PPECD is a feasible and promising alternative for symptomatic single-level soft, huge central CDH.

Recent advances of CREKA peptide-based nanoplatforms in biomedical applications.

Nanomedicine technology is a rapidly developing field of research and application that uses nanoparticles as a platform to facilitate the diagnosis and treatment of diseases. Nanoparticles loaded with drugs and imaging contrast agents have already been used in clinically, but they are essentially passive delivery carriers. To make nanoparticles smarter, an important function is the ability to actively locate target tissues. It enables nanoparticles to accumulate in target tissues at higher concentrations, thereby improving therapeutic efficacy and reducing side effects. Among the different ligands, the CREKA peptide (Cys-Arg-Glu-Lys-Ala) is a desirable targeting ligand and has a good targeting ability for overexpressed fibrin in different models, such as cancers, myocardial ischemia-reperfusion, and atherosclerosis. In this review, the characteristic of the CREKA peptide and the latest reports regarding the application of CREKA-based nanoplatforms in different biological tissues are described. In addition, the existing problems and future application perspectives of CREKA-based nanoplatforms are also addressed.

LONP1 downregulation with ageing contributes to osteoarthritis via mitochondrial dysfunction.

Osteoarthritis (OA) is an age-related disorder and an important cause of disability that is characterized by a senescence-associated secretory phenotype and matrix degradation leading to a gradual loss of articular cartilage integrity. Mitochondria, as widespread organelles, are involved in regulation of complex biological processes such as energy synthesis and cell metabolism, which also have bidirectional communication with the nucleus to help maintain cellular homeostasis and regulate adaptation to a broad range of stressors. In light of the evidence that OA is strongly associated with mitochondrial dysfunction. In addition, mitochondria are considered to be the culprits of cell senescence, and mitochondrial function changes during ageing are considered to have a controlling role in cell fate. Mitochondrial dysfunction is also observed in age-related OA, however, the internal mechanism by which mitochondrial function changes with ageing to lead to the development of OA has not been elucidated. In this study, we found that the expression of Lon protease 1 (LONP1), a mitochondrial protease, was decreased in human OA cartilage and in ageing rat chondrocytes. Furthermore, LONP1 knockdown accelerated the progression and severity of osteoarthritis, which was associated with aspects of mitochondrial dysfunction including oxidative stress, metabolic changes and mitophagy, leading to downstream MAPK pathway activation. Antioxidant therapy with resveratrol suppressed oxidative stress and MAPK pathway activation induced by LONP1 knockdown to mitigate OA progression. Therefore, our findings demonstrate that LONP1 is a central regulator of mitochondrial function in chondrocytes and reveal that downregulation of LONP1 with ageing contributes to osteoarthritis.

Irisin promotes the proliferation and tenogenic differentiation of rat tendon-derived stem/progenitor cells via activating YAP/TAZ.

Tendinopathy is a common tendon disorder characterized by pain, swelling, and dysfunction. Current evidence has demonstrated that the depletion of stem cell pool and non-tenogenic differentiation of tendon-derived stem/progenitor cells (TSPCs) might account for the pathogenesis of tendinopathy. FNDC5/Irisin, as a novel exercise-induced myokine, is proved to be involved in the exercise-induced protective effects on musculoskeletal disorders. However, whether irisin can affect TSPCs fate is still unknown. To ascertain the roles of irisin on the proliferation and tenogenic differentiation of TSPCs, rat TSPCs were isolated and incubated with irisin. Cell viability, phenotypic changes, and related signaling pathways were evaluated by CCK-8 assay, colony formation assay, real-time PCR, Western blot, immunofluorescence, and proteasome activity assay. We found that irisin treatment increased the proliferative and colony-forming abilities, and promoted the tenogenic differentiation of TSPCs by upregulating the expression of YAP/TAZ. In conclusion, our work showed for the first time that irisin promotes the proliferation and tenogenic differentiation of rat TSPCs in vitro by activating YAP/TAZ, and the process was associated with a ubiquitin-proteasome proteolytic pathway. In conclusion, irisin and agents targeting YAP/TAZ may be promising therapeutic options for tendinopathy.

Computed tomography-guided radiofrequency ablation of cervical intervertebral discs for the treatment of refractory cervicogenic headache: A retrospective chart review.

OBJECTIVE: To evaluate the feasibility and efficacy of computed tomography (CT)-guided radiofrequency ablation (RFA) of cervical intervertebral discs for the treatment of discogenic cervicogenic headache (CEH). BACKGROUND: Some patients with CEH experience no obvious therapeutic effect after conventional therapy, particularly patients with refractory CEH originating from abnormal cervical intervertebral discs. Treatment for this type of CEH remains poorly characterized. METHODS: Using a single intervention arm, pretest/posttest design, we retrospectively analyzed the data of patients who underwent CT-guided RFA of cervical intervertebral discs for CEH at the Pain Medicine Center of Zhejiang Provincial People's Hospital from January 2017 to April 2021. If conservative treatment failed in patients with discogenic CEH, we classified the patients as having refractory CEH and performed RFA of cervical intervertebral discs. We used a numeric rating scale (NRS) to assess pain intensity for 6 months. We also compared therapeutic outcome of patients with different characteristics. RESULTS: A total of 44 patients who underwent CT-guided RFA of cervical intervertebral discs were enrolled and 41 of them were analyzed in the present study. The preoperative median (25th, 75th) NRS score was 4 (4, 5), and it was significantly reduced to 1 (0, 4) 6 months after RFA (p < 0.001). The number of patients with ≥50% of their pain relieved after 6 months was 28 of 41 (68%). No serious treatment-related complications occurred in this study. Compared with single-level RFA, multi-level RFA shows greater effects on pain intensity reduction (p = 0.032) and pain relief rate (p = 0.047) of patients. CONCLUSION: In patients who have discogenic CEH, CT-guided RFA of the cervical intervertebral discs appears to be a promising treatment with no serious complications.

The effect of mitochondrial fusion on chondrogenic differentiation of cartilage progenitor/stem cells via Notch2 signal pathway.

BACKGROUND: Osteoarthritis (OA) is a debilitating disease that inflicts intractable pain, a major problem that humanity faces, especially in aging populations. Stem cells have been used in the treatment of many chronic diseases, including OA. Cartilage progenitor/stem cells (CPSCs) are a type of stem cells with the ability to self- renew and differentiate. They hold a promising future for the understanding of the progression of OA and for its treatment. Previous studies have reported the relationship between mitochondrial dynamics and mesenchymal stem cell (MSC) proliferation, differentiation and aging. Mitochondrial dynamic and morphology change during stem cell differentiation. METHODS: This study was performed to access the relationship between mitochondrial dynamics and chondrogenic differentiation of CPSCs. Mitochondrial fusion and fission levels were measured during the chondrogenic differentiation process of CPSCs. After that, we used mitochondrial fusion promoter to induce fusion in CPSCs and then the chondrogenic markers were measured. Transmission electron microscopy (TEM) and confocal microscopy were used to capture the mass and fusion status of mitochondria. Lentiviruses were used to detect the role of mitofusin 2 (Mfn2) in CPSC chondrogenic differentiation. In vivo, Mfn2 was over-expressed in sheets of rat CPSCs, which were then injected intra-articularly into the knees of rats. RESULTS: Mitochondrial fusion markers were upregulated during the chondrogenic induction process of CPSCs. The mass of mitochondria was higher in differentiated CPSC, and the fusion status was obvious relative to un-differentiated CPSC. Chondrogenesis of CPSCs was upregulated with the induction by mitochondrial fusion promoter. Mfn2 over-expression significantly increased chondrocyte-specific gene expression and reversed OA through NOTCH2 signal pathway. CONCLUSIONS: Our study demonstrated that the mitochondrial fusion promotes chondrogenesis differentiation of CPSCs. Mfn2 accelerates the chondrogenesis differentiation of CPSCs through Notch2. In vivo, Mfn2-OE in sheets of rCPSCs ameliorated OA in the rat model.

DUSP5 suppresses interleukin-1ß-induced chondrocyte inflammation and ameliorates osteoarthritis in rats.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by deterioration of articular cartilage. Dual specificity phosphatase 5 (DUSP5), a member of the DUSP subfamily, is known to regulate cellular inflammation. Here, we studied the relationship between DUSP5 and OA by knockdown and overexpression DUSP5, respectively. Results from in vitro experiments demonstrated that the knockdown of DUSP5 increased interleukin-1ß (IL-1ß)-induced expression of inflammatory genes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), and matrix metalloproteinases (MMPs) in chondrocytes, whereas it decreased the expression of anti-inflammatory genes, such as tissue inhibitor of metalloproteinase 3 (TIMP3) and IL-10. Conversely, the overexpression of DUSP5 suppressed the IL-1ß-induced expression of iNOS, COX-2, and MMPs, and upregulated the expression of TIMP3 and IL-10. Moreover, knockdown of DUSP5 enhanced the IL-1ß-induced activation of NF-κB and ERK pathways, whereas its overexpression inhibited these pathways. DUSP5 overexpression prevented cartilage degeneration in a rat OA model, while its knockdown reversed that effect. Our findings reveal that DUSP5 suppresses IL-1ß-induced chondrocyte inflammation by inhibiting the NF-κB and ERK signaling pathways and ameliorates OA.

Tectorigenin Alleviates Inflammation, Apoptosis, and Ossification in Rat Tendon-Derived Stem Cells via Modulating NF-Kappa B and MAPK Pathways.

Tendinopathy is a common musculoskeletal disorder that mainly affects athletes and people of older age. Tumor necrosis factor-α (TNF-α) plays an important role in initiating tendinopathy. Tectorigenin, an extract component of Belam-canda Chinesis, possesses anti-inflammatory and anti-apoptosis activity. The present study was established to investigate the role of tectorigenin against the pathogenetic effects of TNF-α on tendon-derived stem cells (TDSCs) in vivo and in vitro. The findings indicated that TNF-α is able to induce TDSC inflammation, apoptosis, and ossification, as well as activate nuclear factor-kappa B and mitogen-activated protein kinase (MAPK). Furthermore, the results confirmed that tectorigenin is able to inhibit the TNF-α-induced inflammation, apoptosis, and ossification. Tectorigenin treatment decreases activation of NF-kappa B and MAPK signaling in TDSCs. Tectorigenin ameliorates tendinopathy in the in vivo rat model. Thus, these data reveal that tectorigenin can serve as a potential treatment for tendinopathy.

The role of SIRT3-mediated mitochondrial homeostasis in osteoarthritis.

Osteoarthritis is the most common degenerative joint disease and causes major pain and disability in adults. It has been reported that mitochondrial dysfunction in chondrocytes is associated with osteoarthritis. Sirtuins are a family of nicotinamide adenine dinucleotide-dependent histone deacetylases that have the ability to deacetylate protein targets and play an important role in the regulation of cell physiological and pathological processes. Among sirtuin family members, sirtuin 3, which is mainly located in mitochondria, can exert its deacetylation activity to regulate mitochondrial function, regeneration, and dynamics; these processes are presently recognized to maintain redox homeostasis to prevent oxidative stress in cell metabolism. In this review, we provide present opinions on the effect of mitochondrial dysfunction in osteoarthritis. Furthermore, the potential protective mechanism of SIRT3-mediated mitochondrial homeostasis in the progression of osteoarthritis is discussed.

Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats.

Osteoarthritis (OA) is the most prevalent joint disease and uncontrolled inflammation is now recognized to play vital roles in OA development. Targeting the endogenous counterpart of inflammation may develop new therapeutic approaches in resolving inflammation persistence and treating inflammatory disease including OA. The orphan nuclear receptor 4A1 (NR4A1) is a key negative regulator of inflammatory responses but its role in osteoarthritis remains unclear. In the present study, we found that the NR4A1 expression was elevated in human osteoarthritis cartilage and in vitro OA model, which could be blocked by NF-κB signal inhibitor JSH23. The overexpression of NR4A1 inhibited, whereas knockdown of NR4A1 enhanced IL-1ß induced COX-2, iNOS, MMP3, MMP9 and MMP13 expression, and luciferase reporter activity of NF-κB response element. Though NR4A1 was upregulated in inflammatory stimulation and creates a negative feedback loop, persistent inflammatory stimulation inhibited NR4A1 expression and activation. The expression of NR4A1 declined rapidly after an initial peak in conditions of chronic IL-1ß stimulation, which could be partially restored by HDACs inhibitor SAHA. The phosphorylation of NR4A1 was increased in human osteoarthritis cartilage, and p38 inhibitor SB203580, JNK inhibitor SP600125 and ERK inhibitor FR180204 could significantly inhibited IL-1ß induced NR4A1 phosphorylation. Reactivation of NR4A1 by its agonist cytosporone B could inhibit IL-1ß induced chondrocyte inflammation and expression of COX-2, iNOS, MMP3, MMP9, and MMP13. In rat OA model, intra-articular injection of cytosporone B protected cartilage damage and ameliorated osteoarthritis. Thus, our study demonstrated that the NR4A1 is a key endogenous inhibitor of chondrocyte inflammation, which was relatively inactivated under chronic inflammatory stimulation through HDACs mediated transcriptional suppression and MAKP dependent phosphorylation in osteoarthritis. NR4A1 agonist cytosporone B could reactivate and restore the inhibitory regulatory ability of NR4A1, prevent excessive inflammation, and ameliorates osteoarthritis.

Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis.

Interleukin 18 (IL-18) promotes inflammation and apoptosis in chondrocytes, thereby contributing to the development and progression of osteoarthritis (OA). Here, we investigated the effects of IL-18 treatment and inhibition in rat chondrocytes in vitro and in vivo. We used RT-PCR and Western blotting to measure the mRNA and protein levels of the chondrocyte-specific genes Collagen II and Aggrecan as well as the protein levels of apoptosis-related (Bax, Bcl2, Caspase3/9), autophagy-related (Atg5, Atg7, Beclin1, LC3), and mTOR pathway-related genes (PI3K, Akt, mTOR). We observed a decrease in Collagen II and Aggrecan mRNA and protein levels, upregulation of chondrocyte apoptosis, downregulation of chondrocyte autophagy, and activation of the PI3K/Akt/mTOR pathway upon IL-18 treatment. PI3K/Akt/mTOR pathway activation and inhibition tests using rat 740Y-P (PI3K activator), SC79 (AKT activator), 3BDO (mTOR activator), or LY294002 (PI3K inhibitor) revealed that activation of the PI3K/Akt/mTOR pathway enhances chondrocyte-specific gene degradation induced by IL-18, while its inhibition has protective effects on chondrocytes. We also found that treatment with rapamycin (a selective mTOR inhibitor) also exerts chondro-protective effects that ameliorate OA by promoting autophagy. These results suggest that inhibition of the mTOR pathway could be exploited for therapeutic benefits in the treatment of OA.

Rat Chondrocyte Inflammation and Osteoarthritis Are Ameliorated by Madecassoside.

As a joint disease, osteoarthritis (OA) is caused by the breakdown of subchondral bone and cartilage damage. Inflammatory factors, such as interleukin- (IL-) 1ß, mediate the progression of OA. Madecassoside (MA), a triterpenoid component derived from the gotu kola herb (Centella asiatica), exhibits various pharmacological effects, including antioxidative and anti-inflammatory properties. In the present study, the protective effects and possible mechanism of MA on the treatment of OA were investigated. MA was demonstrated to significantly suppress the IL-1ß-induced overexpression of matrix metalloproteinase- (MMP-) 3, MMP-13, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and to decrease the IL-1ß-induced degradation of type II collagen and sox9. Additionally, MA was able to reduce the IL-1ß-induced phosphorylation of p65 in osteoarthritic chondrocytes. Furthermore, in a rat OA model, MA prevented cartilage degeneration and reduced the OARSI score in the MA-treated group compared with the OA group. The present study showed that MA suppresses the nuclear factor-κB signaling pathway, reducing IL-1ß-induced chondrocyte inflammation, which indicates the therapeutic potential of MA in patients with OA.

Nesfatin-1 suppresses interleukin-1ß-induced inflammation, apoptosis, and cartilage matrix destruction in chondrocytes and ameliorates osteoarthritis in rats.

Osteoarthritis (OA) is a chronic degenerative joint disease, related to the overexpression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), inflammation, and chondrocyte apoptosis. Nesfatin-1 is an adipokine, which plays an important role in the development of OA, especially in obese people. In the present study, cartilage degradation and apoptosis observed in OA patients was evaluated. Furthermore, the anti-inflammatory and anti-apoptotic effects of nesfatin-1, and its underlying in vitro and in vivo mechanisms were investigated. The results showed that nesfatin-1 increased significantly the expression of collagen type II alpha 1 chain (Col2a1), and reduced the expression of MMPs, ADAMTS5, cyclooxygenase (COX)-2, caspase-3, nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), interleukin (IL)-6, and chondrocyte apoptosis rate, which may be induced by IL-1ß in rat chondrocytes. Furthermore, nesfatin-1 treatment prevented cartilage degeneration in the rat OA model. It was found that nesfatin-1 suppressed the IL-1ß-induced activation of NF-κB, the mitogen-activated protein kinase (MAPK), and the Bax/Bcl-2 signal pathway in chondrocytes. These results suggest that in vivo nesfatin-1 could play a protective role in the development of OA and can be potentially used for its treatment.

Pioglitazone attenuates advanced glycation end products-induced apoptosis and calcification by modulating autophagy in tendon-derived stem cells.

Diabetes mellitus (DM) is one of the prominent risk factors for pathological development and progression of tendinopathy. One feature of DM-related changes in tendinopathy is accumulation of advanced glycation end products (AGEs) in affected tendons. Pioglitazone (Pio), a peroxisome proliferator-activated receptor γ agonist, performs a protective effect against AGEs. The present study aimed to investigate the pathogenetic role of AGEs on tendon-derived stem cells (TDSCs) and to determine the effect of Pio on AGEs-induced TDSC dysfunctions. Results indicated that AGEs induced TDSC apoptosis as well as compensatory activation of autophagy. Pharmacologic activation/inhibition of autophagy leaded to alleviate/exacerbate apoptosis induced by AGEs. We further confirmed the effect of Pio on autophagy, which ameliorated apoptosis and abnormal calcification caused by AGEs both in vitro and in vivo. Thus, we suggest that Pio ameliorates the dysfunctions of TDSCs against AGEs by promoting autophagy, and we also reveal that Pio is a potential pharmacological choice for tendinopathy.

Laser Acupuncture for Patients with Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

OBJECTIVES: To provide updated evidence from randomized controlled trials (RCTs) on the effectiveness of laser acupuncture for patients with knee osteoarthritis (KOA). METHODS: A literature search in 9 databases was conducted from their inception through February 2019. Randomized controlled trials (RCTs) written in English that compared active laser acupuncture with placebo in KOA patients were included. Two authors independently extracted data from these trials. Meta-analysis software was used to analyze the data. Included studies were assessed in terms of the follow-up period, the methodological quality, and appropriateness of their technical features. RESULTS: Of 357 studies, seven RCTs (totaling 395 patients) met the inclusion criteria. The short-term outcomes showed that laser acupuncture offered significant pain relief over placebo when assessed by the 100 mm visual analog scale (VAS) pain score (p = 0.02), while there was no significant difference between laser acupuncture and placebo based on Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score (p = 0.25). For subgroup analysis, laser acupuncture had superiority over placebo in terms of both VAS and WOMAC pain scores in the appropriate technical features subgroup and the excellent methodological quality subgroup. But the effect of laser acupuncture on pain relief was not maintained in terms of either VAS (p = 0.19) or WOMAC pain score (p = 0.60). The pooled effect showed no significant difference between laser acupuncture and placebo at either time point according to WOMAC function scale, WOMAC stiffness scale, and quality of life outcome. CONCLUSIONS: Our findings indicate that laser acupuncture can effectively reduce knee pain for patients with KOA at short term when appropriate technical features are applied, but the effect likely fades away during the subsequent follow-up period.

Costunolide inhibits matrix metalloproteinases expression and osteoarthritis via the NF­κB and Wnt/ß­catenin signaling pathways.

Osteoarthritis (OA) is a chronic joint disease involving cartilage erosion and matrix degradation. Costunolide is a sesquiterpene lactone that has been demonstrated to exert anti­inflammatory activities in a wide variety of cells. The aim of the present study was to investigate the effect of costunolide in OA treatment, using rat chondrocytes and an OA rat model, in which animals were subjected to destabilization of the medial meniscus. The results revealed that costunolide (2­6 µM) had no effect on chondrocyte viability or phenotype maintenance. Costunolide decreased the interleukin (IL)­1ß­induced upregulation of matrix metalloproteinases (MMPs), inducible nitric oxide synthase, cyclooxygenase­2 and IL­6, and increased the expression of collagen II and transcription factor SOX­9, which were inhibited by IL­1ß. Costunolide significantly decreased p65 phosphorylation induced by IL­1ß and the translocation of p65 into the nucleus of rat chondrocytes, as observed by western blot analysis and immunofluorescence staining. In addition, activation of the Wnt/ß­catenin signaling pathway was inhibited by costunolide, as demonstrated by the level of activation of ß­catenin and the transfer of ß­catenin into the nucleus induced by IL­1ß. In vivo, cartilage treated with costunolide exhibited attenuated degeneration and lower Mankin scores compared with the OA group. The present study investigated the anti­osteoarthritic effects of costunolide, which exerted anti­inflammatory activities and inhibited MMPs expression. Taken together, these results indicate that costunolide may have a potential value in the treatment of OA.

Wogonin mitigates intervertebral disc degeneration through the Nrf2/ARE and MAPK signaling pathways.

Intervertebral disc degeneration (IVDD) is a prevalent disease characterized by the progressive loss of the extracellular matrix in the local nucleus pulposus region. Metalloproteinases and pro-inflammatory cytokines play an important role in this process. Thus, anti-inflammatory strategies are an important component of IVDD treatment. Wogonin, a naturally existing monoflavonoid, has been reported to have potential anti-inflammatory effects in some inflammatory diseases. Hence, in our present study we investigated the protective effects and potential mechanisms of wogonin in rat nucleus pulposus cells that had been treated with interleukin-1beta (IL-1ß) to induce severe IVDD. An in vivo rat caudal vertebrae needle-stab model was also designed and its validity was evaluated as an IVDD model. The results demonstrated that wogonin suppressed IL-1ß-induced inflammatory mediators (iNOS, IL-6 and COX2) and matrix-degrading proteinases (MMP1, MMP3, MMP13 and ADAMTS4). Wogonin also upregulated some of the key components of the extracellular matrix, such as collagen II. Furthermore, we discovered that wogonin exerted anti-inflammatory effects by activating the Nrf2/HO-1-SOD2-NQO1-GCLC signaling axis. Moreover, the IL-1ß-induced stimulation of the MAPK signaling pathway was reversed by wogonin treatment. The in vivo MRI and histological results also revealed that wogonin protected the nucleus pulposus from the progression of IVDD. Therefore, wogonin may be a potential agent for the treatment of IVDD.

Polygalacic acid inhibits MMPs expression and osteoarthritis via Wnt/ß-catenin and MAPK signal pathways suppression.

Osteoarthritis (OA) is a chronic degenerative joint disease that has been shown to be closely related to the over expression of matrix metalloproteinases (MMPs). Polygalacic acid is a triterpene isolated from the root of Polygala tenuifolia Willd. In the present study, the anti-inflammatory effect of polygalacic acid in OA was investigated as well as its in vitro and in vivo mechanism. In vitro, rat chondrocytes were induced with interleukin-1beta (IL-1ß) and treated with different concentrations of polygalacic acid; real-time PCR and Western blotting were performed to evaluate the expressions of MMP-3, MMP-9, MMP-13, and COX-2. In addition, the MAPK and Wnt/ß-catenin signaling pathways were analyzed via Western blotting and immunofluorescence staining. In vivo, a rat OA model was treated with polygalacic acid. Gross morphological and histological assessments were performed to evaluate the resulting cartilage damage. Polygalacic acid significantly reduced the expression of MMPs and COX-2, which could be induced by IL-1ß in rat chondrocytes. Furthermore, polygalacic acid treatment prevented the degeneration of cartilage in the rat OA model. To investigate the underlying mechanism, we found that polygalacic acid suppressed both the IL-1ß-induced activation of Wnt/ß-catenin and the mitogen-activated protein kinase (MAPK) signal pathway in chondrocytes. These results suggest that polygalacic acid may have a therapeutic effect in OA treatment.

Schisandrin B ameliorated chondrocytes inflammation and osteoarthritis via suppression of NF-κB and MAPK signal pathways.

INTRODUCTION: Osteoarthritis (OA) is the most prevalent joint disorder in the elderly population, and inflammatory mediators like IL-1ß were thought to play central roles in its development. Schisandrin B, the main active component derived from Schisandra chinensis, exhibited anti-oxidative and antiinflammatory properties. METHODS: In the present study, the protective effect and the underlying mechanism of Schisan-drin B on OA was investigated in vivo and in vitro. RESULTS: The results showed that Schisandrin B decreased IL-1ß-induced upregulation of matrix metalloproteinase 3 (MMP3), MMP13, IL-6, and inducible nitric oxide synthase (iNOS) and increased IL-1ß-induced downregulation of collagen II, aggrecan, and sox9 as well. Schisandrin B significantly decreased IL-1ß-induced p65 phosphorylation and nuclear translocation of p65 in rat chondrocytes. Mitogen-activated protein kinase (MAPK) activation was also inhibited by Schisandrin B, as evidenced by the reduction of p38, extracellular signal-regulated kinase (Erk), and c-Jun amino-terminal kinase (Jnk) phosphorylation. In addition, Schisandrin B prevented cartilage degeneration in rat OA model with significantly lower Mankin's score than the control group. CONCLUSION: Our study demonstrated that Schisandrin B ameliorated chondrocytes inflammation and OA via suppression of nuclear factor-κB (NF-κB) and MAPK signal pathways, indicating a therapeutic potential in OA treatment.