Damaged deoxyribonucleic acid (DNA) is a primary pathologic factor for osteoarthritis (OA); however, the mechanism by which DNA damage drives OA is unclear. Previous research demonstrated that the ...cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) participates in DNA damage response. As a result, the current study aimed at exploring the role STING, which is the major effector in the cGAS-STING signaling casacde, in OA progress in vitro, as well as in vivo. In this study, the expression of STING was evaluated in the human and mouse OA tissues, and in chondrocytes exposed to interleukin-1 beta (IL-1β). The influences of STING on the metabolism of the extracellular matrix (ECM), apoptosis, and senescence, were assessed in STING overexpressing and knocking-down chondrocytes. Moreover, the NF-κB-signaling casacde and its role in the regulatory effects of STING on ECM metabolism, apoptosis, and senescence were explored. The STING knockdown lentivirus was intra-articularly injected to evaluate its therapeutic impact on OA in mice in vivo. The results showed that the expression of STING was remarkably elevated in the human and mouse OA tissues and in chondrocytes exposed to IL-1β. Overexpression of STING promoted the expression of MMP13, as well as ADAMTS5, but suppressed the expression of Aggrecan, as well as Collagen II; it also enhanced apoptosis and senescence in chondrocytes exposed to and those untreated with IL-1β. The mechanistic study showed that STING activated NF-κB signaling cascade, whereas the blockage of NF-κB signaling attenuated STING-induced apoptosis and senescence, and ameliorated STING-induced ECM metabolism imbalance. In in vivo study, it was demonstrated that STING knockdown alleviated destabilization of the medial meniscus-induced OA development in mice. In conclusion, STING promotes OA by activating the NF-κB signaling cascade, whereas suppression of STING may provide a novel approach for OA therapy.
Diabetes (DB) is a risk factor for osteoarthritis progression. High glucose (HG) is one of the key pathological features of DB and has been demonstrated to induce apoptosis and senescence in ...chondrocytes. Autophagy is an endogenous mechanism that can protect cells against apoptosis and senescence. The effects of HG on autophagy in cells including chondrocytes have been studied; however, the results have been inconsistent. The current study aimed to elucidate the underlying mechanisms, which could be associated with the contrasting outcomes. The present study revealed that HG can induce apoptosis and senescence in chondrocytes, in addition to regulating autophagy dynamically. The present study demonstrated that HG can cause oxidative stress in chondrocytes and suppress the AMPK pathway in a dose-dependent manner. Elimination of oxidative stress by Acetylcysteine, also called N-acetyl cysteine (NAC), downregulated autophagy and alleviated HG-stimulated apoptosis and senescence, while activation of the AMPK signaling pathway by AICAR not only upregulated autophagy but also alleviated HG-stimulated apoptosis and senescence. A combined treatment of NAC and AICAR was superior to treatment with either NAC or AICAR. The study has demonstrated that HG can suppress autophagy through the AMPK pathway and induce autophagy via oxidative stress in chondrocytes.
Intervertebral disc degeneration (IDD) is a complicated pathological condition blamed for low back pain. Mitochondrion is of vital importance for cellular homeostasis, and mitochondrial dysfunction ...is considered to be one of the major causes of cellular damage. Mitophagy is a cellular process to eliminate impaired mitochondria and showed protective effects in various diseases; however, its role in IDD is still not clear. Here, we explore the role of Parkin-mediated mitophagy in IDD. In this study, we found that Parkin was upregulated in degenerative nucleus pulposus (NP) tissues in vivo as well as in TNF-α stimulated NP cells in vitro. Knockdown of Parkin by siRNA showed that Parkin is crucial for apoptosis and mitochondrion homeostasis in NP cells. Further study showed that upregulation of Parkin by salidroside may eliminate impaired mitochondria and promote the survival of NP cells through activation of mitophagy in vitro. In in vivo study, we found that salidroside could inhibit the apoptosis of NP cells and ameliorate the progression of IDD. These results suggested that Parkin is involved in the pathogenesis of IDD and may be a potential therapeutic target for IDD.
Low back pain, triggered by intervertebral disc degeneration (IVDD), is one of the most common causes of disability and financial expenditure worldwide. However, except for surgical interventions, ...effective medical treatment to prevent the progression of IVDD is lacking. This study aimed to investigate the effects of circKIF18A, a novel circRNA, on IVDD progression and to explore its underlying mechanism in IVDD. In this study, we found that oxidative stress was positively correlated with nucleus pulposus cell (NPC) senescence in IVDD and that circKIF18A was downregulated in IVDD and attenuated senescent phenotypes such as cell cycle arrest and extracellular matrix degradation in NPCs. Mechanistically, circKIF18A competitively suppressed ubiquitin-mediated proteasomal degradation of MCM7, and the protective effects of circKIF18A on NPCs were partially mediated by MCM7 under oxidative stress. Intradiscal injection of adenoviral circKIF18A ameliorated IVDD in a rat model. This study revealed that circKIF18A regulates NPC degeneration by stabilizing MCM7 and identified a novel signaling pathway, the circKIF18A-MCM7 axis, for anti-senescence molecular therapy in IVDD.
Intervertebral disk degeneration (IDD) is the major cause of low back pain (LBP), which affects 80% of the world's population. Interleukin 1 beta (IL-1β) is a major inflammatory factor that ...accelerates disk degeneration, and IL-1β levels increase in degenerative disks. It has recently been reported that luteoloside-a type of flavonoid glycoside-has anti-inflammatory properties. In the present study, we investigated the protective potential of luteoloside in IDD. We found that luteoloside maintains cell morphology and inhibits apoptosis (indicated by the reduced expression of cleaved caspase 3) in IL-1β-treated nucleus pulposus (NP) cells. It also suppresses inflammatory mediators-nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS)-in IL-1β-treated NP cells. Furthermore, we found increased collagen II and aggrecan expression and reduced MMP13 and ADAMTS5 expression in luteoloside-treated NP cells in the presence of IL-1β. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is involved in apoptosis, inflammation, and extracellular matrix (ECM) homeostasis. Mechanistic studies revealed that the NF-κB signaling pathway is inhibited by luteoloside, and Nrf2 is involved in the regulation of luteoloside in NF-κB signaling because Nrf2 knockdown reduced the suppressive effect of luteoloside on NF-κB signaling. We also established a puncture-induced rat IDD model and demonstrated that the persistent intraperitoneal injection of luteoloside ameliorates the progression of IDD. In conclusion, we demonstrated that luteoloside activates the Nrf2/HO-1 signaling axis and is a potential therapeutic medicine for IDD.
•The incidence rates of bone lymphoma had sharply increased for the early decades.•The incidence trend of bone lymphoma has stabilized in recent years.•The mortality had sharply increased from 1985 ...to 2016 without a turn point.•The incidence and mortality by various characteristics had similar patterns.
In recent years, studies on bone lymphoma and its histologic types have reached a mature stage. However, reports on the incidence and incidence-based mortality trends of bone lymphoma are scanty.
Patients with bone lymphoma in the U.S. were selected from Surveillance, Epidemiology, and End Results (SEER) database (1975–2016), and categorized based on age, sex, race, tumor location, SEER Historic Stage A and histologic type. Data on the incidence (1975–2016) and incidence-based mortality (1985–2016) were directly obtained from the SEER program. Annual percentage change (APC) and 95% confidence intervals (CIs) were calculated using the joinpoint regression analysis program.
Overall, 13,058 bone lymphoma cases diagnosed in resident patients of the U.S. were included in incidence analysis between 1975 and 2016 as follows: 6080 cases in 1975–1999, 3796 cases in 2000–2009, and 3182 cases in 2010–2016. Of these cases, 6888 died of bone lymphoma between 1985 and 2016. The overall incidence rates dramatically increased from 0.89 per 100,000 person-years in 1975 to 1.36 per 100,000 person-years in 2016. Incidence trend sharply increased from 1975 to 2009, and then stabilized between 2009 and 2016. Overall incidence-based mortality trends sharply increased from 1985 to 2016 without a joinpoint. Following the demographic and tumor characteristics, the trends of incidence and incidence-based mortality exhibited similar patterns.
Considering various characteristics (age, sex, race, tumor location, SEER Historic Stage A, and histologic type), we established that the incidence trend of bone lymphoma has sharply been increasing over the decades, however, in the recent years, the trend has stabilized. Besides, between 1985 and 2016, the incidence-based mortality had been sharply increasing without a turning point. These findings could give insights for clinicians to elaborately assess the epidemiology and risk factors of bone lymphoma.
Purpose
To determine the incidence of and risk factors for residual back pain in osteoporotic vertebral compression fracture (OVCF) patients after percutaneous kyphoplasty (PKP) treatment, we ...performed a retrospective analysis of prospective data.
Methods
Patients who underwent bilateral PKP and met this study’s inclusion criteria were retrospectively reviewed. Back pain intensity was assessed using a visual analogue scale (VAS) after surgery. Residual back pain was defined as the presence of postoperative moderate-severe pain (average VAS score ≥ 4), and the variables included patient characteristics, baseline symptoms, radiological parameters and surgical factors. Univariate and multivariate logistic regression analyses were performed to identify risk factors.
Results
A total of 809 patients were included, and residual back pain was identified in 63 (7.8%) patients. Of these patients, 52 patients had complete data for further analysis. Multivariate logistic regression analysis showed that risk factors for back pain included the presence of an intravertebral vacuum cleft (OR 2.93,
P
= 0.032), posterior fascia oedema (OR 4.11,
P
= 0.014), facet joint violations (OR 12.19,
P
< 0.001) and a separated cement distribution (OR 2.23,
P
= 0.043).
Conclusion
The incidence of postoperative residual back pain was 7.8% among 809 OVCF patients following PKP. The presence of an intravertebral vacuum cleft, posterior fascia oedema, facet joint violations and a separated cement distribution were identified as independent risk factors for residual back pain.
Intervertebral disc degeneration is a multifactorial and complicated degenerative disease that imposes a huge economic burden on society. However, there is no effective treatment that can delay and ...reverse the progression of disc degeneration. The inflammatory response causes the death of nucleus pulposus cells and the degradation of extracellular matrix are main factors of intervertebral disc degeneration. Ligustilide is a bioactive phthalide that is said to have an anti-inflammatory effect and anti-apoptosis effect on various disorders. Therefore, we further explored the protective effect of ligustilide on intervertebral disc degeneration and its potential mechanism. In this study, we found that ligustilide inhibited apoptosis, suppressed the expression of related inflammatory mediators (iNOS and COX-2) and decreased the expression of inflammatory cytokines (TNF-a and IL-6) in nucleus pulposus cells under IL-1β stimulation. At the same time, the degradation of extracellular matrix of nucleus pulposus cells induced by IL-1β was inhibited. In addition, we also found that ligustilide inhibits the inflammation response by inhibiting the NF-κB signaling pathway. Moreover, TUNEL assay and histological analysis showed that ligustilide could inhibit the apoptosis of nucleus pulposus cells and ameliorate the progression of intervertebral disc degeneration in punctured Rat IDD model. In summary, ligustilide may become a new potential treatment for intervertebral disc degeneration.
•Ligustilide attenuated IL-1β induced apoptosis，inflammation response and ECM degradation in NP cells.•Potential protective mechanism of ligustilide was associated with the inhibition of NF-κB signaling pathway.•ligustilide ameliorate the IDD in vivo and become a new potential therapeutic for intervertebral disc degeneration
•We showed that Aloin may inhibit the IL-1β-induced inflammatory response and promote extracellular matrix homeostasis in osteoarthritic chondrocytes.•Mechanism study revealed that effect of Aloin on ...OA is through PI3K/Akt/NF-κB signaling pathway.•In vivo study showed that Aloin could ameliorate OA development in mice. In summary, we considered that Aloin might be a promising therapeutic strategy for the treatment of osteoarthritis.
Osteoarthritis (OA) is a progressive and degenerative joint disease. Aloin is a bitter and yellow-brown-coloured compound from the Aloe plant and is allowed for use in foods as a “natural flavour”. In our study, we examined the protective effects of Aloin on the inhibition of OA development as well as its underlying mechanism in both in vitro and vivo experiments. In in-vitro experiments, the protective effect of aloin on the anabolism and catabolism of the extracellular matrix (ECM) induced by IL-1 β in chondrocytes by inhibiting the expression of pro-inflammatory factors, including TNF-α (p = 0.016), IL-6 (p = 0.006), iNOS (p = 0.001) and COX-2 (p = 0.006). Mechanistically, Aloin suppressed the IL-1β-induced activation of the PI3K/Akt/NF-κB signalling pathway cascades. Moreover, molecular docking studies demonstrated that Aloin bound strongly to PI3K. In vivo, Aloin ameliorated the OA process in the destabilization of the medial meniscus (DMM) model.
In summary, our findings demonstrate that Aloin ameliorates the progression of OA via the PI3K/Akt/NF-κB signalling pathways, which supports Aloin as a promising therapeutic agent for the treatment of OA.
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