RESUMEN
OBJECTIVE: Intervertebral Disc Degeneration (IVDD) is one of the leading causes of low back pain, significantly impacting both individuals and society. This study aimed to investigate the significance of macrophage infiltration and the role of macrophage-secreted platelet-derived growth factor-BB (PDGF-BB) in IVDD progression. METHODS: To confirm the protective function of macrophage-derived PDGF-BB on nucleus pulposus cells (NPCs), we employed Lysm-Cre transgenic mice to genetically ablate PDGF-B within the myeloid cells. Immunohistochemistry was utilized to detect the expression of glycolytic enzymes and pyroptosis-related proteins during the process of IVDD. Western blot, RT-PCR, ELISA and immunofluorescence were used to detect the protective effect of recombinant PDGF-BB on NPCs. RESULTS: Macrophage-derived PDGF-BB deficiency resulted in the loss of NPCs and the increased ossification of cartilage endplates during lumbar disc degeneration. Also, PDGF-BB deficiency triggered the inhibition of glycolytic enzymes' expression and the activation of pathways related to pyroptosis in the nucleus pulposus. Mechanistically, our results suggest that PDGF-BB predominantly conveys its protective influence on NPCs through the PDGF receptor- beta (PDGFR-ß)/ thioredoxin-interacting protein pathway. CONCLUSIONS: The absence of PDGF-BB originating from macrophages expedites the advancement of IVDD, whereas the application of PDGF-BB treatment holds the potential for retarding intervertebral disc degeneration in the human body.
RESUMEN
BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disease [1]. It has come to light that AZD8330 can suppress the generation of proinflammatory factors and deter the inflammatory response [2]. Given that inflammation is a primary causative factor in OA, it is posited that AZD8330 might exhibit superior efficacy in OA management. METHODS: In this study, we investigated the potential of intraperitoneal injection of AZD8330 to retard the progression of osteoarthritis in a murine model with surgically induced medial meniscus destruction (DMM). Concurrently, we employed ATDC5 cartilage cells to dissect the mechanism through which AZD8330 inhibits the TNF-α-induced NF-κB signaling pathway via modulation of RIP1. The findings revealed that AZD8330 mitigated cartilage degradation and the inflammatory response, leading to a substantial reduction in OARSI scores among DMM mice treated with AZD8330. Mechanistically, AZD8330 functioned as a suppressor of the TNF-α-induced NF-κB/p65 signaling pathway by facilitating the phosphorylation activation of cIAP1-mediated RIP1. The combination of data from both in vivo and in vitro experiments supports the conclusion that AZD8330 can attenuate chondrocyte degradation, thereby alleviating OA, by regulating the NF-κB/P65 signaling pathway through modulation of RIP1 activity. Consequently, the utilization of AZD8330 may hold potential in the prophylaxis of osteoarthritis. RESULTS: Our investigation delineates the role of AZD8330 in the regulation of inflammation in the context of OA treatment. Furthermore, we have unveiled that the inhibitory impact of AZD8330 on OA may hinge upon the activation of cIAP1, which in turn downregulates RIP1, thereby restraining the NF-κB/P65 signaling pathway. This study lends credence to the notion that AZD8330 may be a promising contender for osteoarthritis therapy. CONCLUSIONS: Our study provides compelling evidence attesting to the capacity of AZD8330 in managing inflammation within the realm of OA treatment. Likewise, our study has elucidated that the attenuation of OA by AZD8330 relies on the activation of cIAP1 to inhibit RIP1, consequently suppressing the NF-κB signaling pathway. On the strength of our present study, we may have identified a viable drug candidate for OA treatment.
Asunto(s)
FN-kappa B , Osteoartritis , Ratones , Animales , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Regulación hacia Arriba , Transducción de Señal , Inflamación/tratamiento farmacológico , Condrocitos/metabolismo , Meniscos Tibiales , Necrosis/metabolismo , Interleucina-1beta/metabolismoRESUMEN
OBJECTIVES: Limonin has received significant attention due to its multiple biological effects, intervertebral disc degeneration (IDD) is also of interest due to the high prevalence of this disease. In this study, we determined the effects of limonin on IDD and the underlying mechanism of action to find novel ways to treat IDD. METHODS: An IL-1ß-induced cell inflammation model and a lumbar instability model inducing IDD were established to assess the progression of IDD with or without limonin treatment. We further evaluated MAPK/NF-κB and necroptosis pathways and alterations in the extracellular matrix specific within the disc. KEY FINDINGS: Limonin suppresses inflammation in the nucleus pulposus in vitro by reducing the production of pro-inflammatory markers such as iNOS and COX-2. Limonin reduced the activation of the MAPK/NF-κB signalling pathway and the RIP1/RIP3/MLKL necroptosis pathway in the NP cells. Moreover, limonin delays the IDD progression in the lumbar instability model. CONCLUSIONS: Limonin could potentially delay IDD by inhibiting NP cell necroptosis and modulating peripheral matrix proteins within the intervertebral disc and is a potential pharmacological research direction for the therapy in patients with IDD.
Asunto(s)
Degeneración del Disco Intervertebral , Limoninas , Inflamación , Degeneración del Disco Intervertebral/tratamiento farmacológico , Limoninas/farmacología , Limoninas/uso terapéutico , Necroptosis , FN-kappa B/metabolismo , Animales , RatasRESUMEN
As a degenerative disease, the pathogenesis and treatment of osteoarthritis (OA) are still being studied. The prevailing view is that articular cartilage dysfunction plays an essential role in the development of osteoarthritis. Similarly, dynamic bone remodeling dramatically influences the development of osteoarthritis. The inflammatory response is caused by the overexpression of inflammatory factors, among which tumor necrosis factor-α is one of the main causes of OA, and its sources include the secretion of chondrocytes themselves and osteoclast secretion of subchondral bone. Moreover, TNF-α-induced activation of RIP1, RIP3, and MLKL has been shown to play an important role in cell necroptosis and inflammatory responses. In vitro, AZ-628 alleviates chondrocyte inflammation and necroptosis by inhibiting the NF-κB signaling pathway and RIP3 activation instead of RIP1 activation. AZ-628 also reduces osteoclast activity, proliferation and differentiation, and release of inflammatory substances by inhibiting autophagy, MAPK, and NF-κB pathways. Similarly, the in vivo study demonstrated that AZ-628 could inhibit chondrocyte breakdown and lower osteoclast formation and bone resorption, thereby slowing down subchondral bone changes induced by dynamic bone remodeling and reversing the progression of osteoarthritis in mice. The results of this study indicate that AZ-628 could be used to treat OA byinhibiting chondrocyte necroptosis and regulating osteoclast formation.
Asunto(s)
Condrocitos , Osteoartritis , Animales , Condrocitos/metabolismo , Ratones , FN-kappa B/metabolismo , Necroptosis , Osteoartritis/metabolismo , Osteoclastos/metabolismo , Quinazolinas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: Cerebrospinal fluid leakage (CSFL) is a common complication during spinal surgery. This study aimed to compare dural closure with different suture types, sizes, and techniques, and adhesives to reduce the occurrence of CSFL. MATERIALS AND METHODS: Using a pig spine model, the PDS II 4-0, 5-0, 6-0, Vicryl 4-0, 5-0, 6-0, and Prolene 4-0, 5-0, 6-0 sutures were compared by calculating the permeability after suturing. Spraying bioprotein glue was also tried. Next, 120 patients who underwent surgery for intraspinal subdural tumors were enrolled and received 5-0 PDSII, Vicryl, or Prolene for dura repair. RESULTS: In the animal model study, Vicryl 5-0 showed a reduced leakage flow rate compared with 5-0 Prolene and 5-0 PDS II. In the clinical study, postoperative drainage in the Vicryl group was smaller than that in the other groups during the first 3 days after surgery (p < 0.05). Drainage volume of patients with postoperative cerebrospinal fluid leakage in the Vicryl group was smaller than that in the other groups during the first 3 days after surgery (p < 0.05).There were 12 patients (23.1%, 12/52) in the Vicryl group, 20 patients (55.6%, 20/36) in the PDS group, and 16 patients (50.0%, 16/32) in the Prolene group who had CSFL.The incidence of CSFL was significantly reduced in Vicryl group compared with the other groups(P < 0.05). CONCLUSIONS: 5-0 Vicryl sutures significantly reduced the dural leakage flow rate in an animal spine model. Fibrin glue can reinforce dural repair after surgery. 5-0 Vicryl was associated with a lower occurrence of CSFL in patients.
RESUMEN
OBJECTIVE: To investigate the influence of total hip arthroplasty on the changes of spine pelvic parameters in patients with hip spine syndrome. METHODS: From January 2013 to October 2014, 22 patients (26 hips) with hip spine syndrome accompanied by necrosis of femoral head, hip osteoarthritis and congenital dysplasia of hip were treated with total hip arthroplasty. There were 12 males and 10 females with an average age of 58.4 years (range, 45 to 76 years). The course of disease was 1.5 to 25 years with an average of 12.8 years. Before and after the operation, the anteroposterior, full length radiographs of both lower limbs, thoracolumbar spine and pelvis in standing position were routinely taken. The balance parameters of spine pelvis coronal plane and sagittal plane before and after the replacement were measured. Visual analogue scale (VAS), Oswestry Disability Index (ODI) and Harris score were performed before and after the operation. RESULTS: All cases were followed up for 21 to 52 (32±8) months. No infection, prosthesis subsidence, loosening, prosthesis dislocation were found in the last follow up. After total hip arthroplasty, sagittal vertical axis(SVA), thoracic kyphosis(TK), lumbar lordosis(LL), pelvic tilt (PT) were significantly reduced(P<0.05), sacral slope(SS) was significantly increased(P<0.05), there was no significant difference in pelvic incidence(PI)(P>0.05); PT and scoliosis (coronal position) were significantly decreased after operation(P<0.05); VAS score of waist, VAS score of hip joint and ODI score of waist were significantly decreased before and after operation (P<0.05). Harris score of hip joint increased significantly after operation, and thedifference was statistically significant (P<0.05). CONCLUSION: After total hip arthroplasty, the coronal and historical balance parameters of spine and pelvis are significantly improved, and the short term and medium-term effects are satisfactory.
Asunto(s)
Artroplastia de Reemplazo de Cadera , Anciano , Artroplastia de Reemplazo de Cadera/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Vértebras Lumbares/cirugía , Masculino , Persona de Mediana Edad , Pacientes , Pelvis , Estudios Retrospectivos , Columna VertebralRESUMEN
Aseptic prosthetic loosening due to wear particle-induced inflammatory osteolysis is the main cause of failure for artificial joint replacement. The inflammatory response and the production of pro-osteoclastic factors lead to elevation of osteoclast formation and excessive activity results in extensive bone destruction around the bone-implant interface. Here we showed that Nepetin, a natural bioactive flavonoid with proven anti-inflammatory and anti-proliferative properties, potently inhibited RANKL-induced osteoclast differentiation, formation and bone resorption in vitro, and protected mice against the deleterious effects of titanium particle-induced calvarial osteolysis in vivo. Mechanistically, Nepetin attenuated RANKL-induced activation of NF-κB and MAPK signalling pathways and TRAF6-dependent ubiquitination of Beclin 1 which is necessary for the induction of autophagy. In brief, our study demonstrates the potential therapeutic application of Nepetin against osteoclast-mediated osteolytic diseases.