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1.
Curr Opin Rheumatol ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34652292

RESUMO

PURPOSE OF THE REVIEW: Osteoarthritis (OA) is a painful disease for which drug development has proven difficult. One major reason for this is the heterogeneity of the disease and the current lack of operationalized means to distinguish various disease endotypes (molecular subtypes). Biomarkers measured in blood or urine, reflecting joint tissue turnover, have been developed and tested during the last decades. In this narrative review, we provide highlights on biomarkers derived from the two most studied and abundant cartilage proteins - type II collagen and aggrecan. RECENT FINDINGS: Multiple biomarkers assessing type II collagen degradation and formation, and aggrecan turnover have been developed. Several markers, such as uCTX-II, have been validated for their association with disease severity and prognosis, as well as pharmacodynamically used to describe the mode of action and efficacy of drugs in development. There is a great need for biomarkers for subdividing patients (i.e., endotyping) and recent scientific advances have not yet come closer to achieving this goal. SUMMARY: There is strong support for using biomarkers for understanding OA, reflecting degradation and formation of the joint tissues, focused on type II collagen and aggrecan. There is still a lack of in vitro diagnostics, in all contexts of use.

2.
Heliyon ; 7(9): e08032, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34611563

RESUMO

The main nerves in the knee region are the tibial nerve, the common peroneal nerve, and the saphenous nerve. These three nerves innervate the lower leg and foot, providing sensory and motor function. The large sciatic nerve splits just above the knee to form the tibial and common peroneal nerves. The tibial nerve travels down in the posterior region, while the common peroneal nerve runs around the lateral side of the knee and runs down the front of the leg to the foot. Although all these nerves can be affected by injuries of the knee, the infrapatellar branch of the saphenous nerve (IPBSN) and the common peroneal nerve (CPN) are most affected. In this narrative review we focus on neuropathies associated with nerves located in the region of the knee joint in the context of their injuries and possible iatrogenic damage during reconstructive surgery.

3.
Nat Rev Rheumatol ; 17(10): 621-632, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34465902

RESUMO

Osteoarthritis (OA) remains the most challenging arthritic disorder, with a high burden of disease and no available disease-modifying treatments. Symptomatic early-stage OA of the knee (the focus of this Review) urgently needs to be identified and defined, as efficient early-stage case finding and diagnosis in primary care would enable health-care providers to proactively and substantially reduce the burden of disease through proper management including structured education, exercise and weight management (when needed) and addressing lifestyle-related risk factors for disease progression. Efforts to define patient populations with symptomatic early-stage knee OA on the basis of validated classification criteria are ongoing. Such criteria, as well as the identification of molecular and imaging biomarkers of disease risk and/or progression, would enable well-designed clinical studies, facilitate interventional trials, and aid the discovery and validation of cellular and molecular targets for novel therapies. Treatment strategies, relevant outcomes and ethical issues also need to be considered in the context of the cost-effective management of symptomatic early-stage knee OA. To move forwards, a multidisciplinary and sustained international effort involving all major stakeholders is required.

4.
Cells ; 10(9)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34571845

RESUMO

Knee osteoarthritis (OA) is one of the most prevalent chronic conditions affecting the adult population. OA is no longer thought to come from a purely biomechanical origin but rather one that has been increasingly recognized to include a persistent low-grade inflammatory component. Intra-articular corticosteroid injections (IACSI) have become a widely used method for treating pain in patients with OA as an effective symptomatic treatment. However, as the disease progresses, IACSI become ineffective. FKBP51 is a regulatory protein of the glucocorticoid receptor function and have been shown to be dysregulated in several pathological scenario's including chronic inflammation. Despite of these facts, to our knowledge, there are no previous studies of the expression and possible role of FKBP51 in OA. We investigated by double and triple immunofluorescence confocal microscopy the cellular and subcellular expression of FKBP51 and its relations with inflammation factors in osteoarthritic knee joint tissues: specifically, in the tibial plateau knee cartilage, Hoffa's fat pad and suprapatellar synovial tissue of the knee. Our results show co-expression of FKBP51 with TNF-α, IL-6, CD31 and CD34 in OA chondrocytes, synovial membrane cells and adipocytes in Hoffa's fat pad. FKBP51 is also abundant in nerve fibers within the fat pad. Co-expression of FKBP51 protein with these markers may be indicative of its contribution to inflammatory processes and associated chronic pain in OA.

8.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071037

RESUMO

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.


Assuntos
Plasma Rico em Plaquetas , Animais , Células Cultivadas , Microambiente Celular , Condrócitos/efeitos dos fármacos , Condrogênese , Citocinas/administração & dosagem , Citocinas/uso terapêutico , Grânulos Citoplasmáticos/química , Cobaias , Humanos , Ácido Hialurônico/farmacologia , Ácido Hialurônico/uso terapêutico , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Injeções Intra-Articulares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Neurotransmissores/administração & dosagem , Neurotransmissores/uso terapêutico , Osteoartrite do Joelho , Plasma Rico em Plaquetas/química , Resultado do Tratamento
9.
Inflammopharmacology ; 29(3): 695-704, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34085175

RESUMO

OBJECTIVE: NLRP3 inflammasome may play a key role in OA pathogenesis. Stromal cell-derived factor-1 (SDF-1) is a homeostatic CXC chemokine. Since the role of SDF-1 in OA has not been explored, this study aimed to examine the effect of SDF-1 on NLRP3 inflammasome and pyroptosis in synoviocytes from OA joints. MATERIALS AND METHODS: Human synovium was obtained from OA patients for isolation of primary synoviocytes and a murine model of collagenase-induced OA was established for testing intra-articular injections of SDF-1. Immunoblotting assays were used to examine the effects and underlying mechanism of action of SDF-1 on NLRP3 inflammasome and synoviocyte pyroptosis in synoviocytes. Inhibitors of AMPK and PI3K-mTOR were utilized to investigate the key signaling pathways involved in SDF-1-mediated OA inflammasome formation and pyroptosis. RESULTS: Synoviocytes from OA joints exhibited significantly higher expression of NLRP3 inflammasome and biomarkers of synoviocyte pyroptosis relative to healthy individuals. This was confirmed in the collagenase-induced OA model, where OA synoviocytes had a significantly lower SDF-1 expression than healthy ones. SDF-1 treatment in synoviocytes of OA patients and collagenase-induced OA led to significant downregulation in the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Inhibition of the AMPK signaling pathway significantly suppressed the inhibitory effect of SDF-1 on NLRP3 inflammasome expression of OA synoviocytes. However, blocking the SDF-1-activated PI3K-mTOR signaling pathway could still suppress the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. CONCLUSIONS: SDF-1 ameliorates NLRP3 inflammasome and pyroptosis in OA synoviocytes through activation of the AMPK signaling pathway. Therefore, SDF-1 may be a novel therapeutic target for OA.

10.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
11.
J Cell Physiol ; 236(11): 7421-7439, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34008188

RESUMO

Chondrogenic progenitor cells (CPCs) may be used as an alternative source of cells with potentially superior chondrogenic potential compared to mesenchymal stem cells (MSCs), and could be exploited for future regenerative therapies targeting articular cartilage in degenerative diseases such as osteoarthritis (OA). In this study, we hypothesised that CPCs derived from OA cartilage may be characterised by a distinct channelome. First, a global transcriptomic analysis using Affymetrix microarrays was performed. We studied the profiles of those ion channels and transporter families that may be relevant to chondroprogenitor cell physiology. Following validation of the microarray data with quantitative reverse transcription-polymerase chain reaction, we examined the role of calcium-dependent potassium channels in CPCs and observed functional large-conductance calcium-activated potassium (BK) channels involved in the maintenance of the chondroprogenitor phenotype. In line with our very recent results, we found that the KCNMA1 gene was upregulated in CPCs and observed currents that could be attributed to the BK channel. The BK channel inhibitor paxilline significantly inhibited proliferation, increased the expression of the osteogenic transcription factor RUNX2, enhanced the migration parameters, and completely abolished spontaneous Ca2+ events in CPCs. Through characterisation of their channelome we demonstrate that CPCs are a distinct cell population but are highly similar to MSCs in many respects. This study adds key mechanistic data to the in-depth characterisation of CPCs and their phenotype in the context of cartilage regeneration.

12.
Res Involv Engagem ; 7(1): 24, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971982

RESUMO

APPROACH is an EU-wide research consortium with the goal to identify different subgroups of knee osteoarthritis to enable future differential diagnosis and treatment. During a 2-year clinical study images, biomarkers and clinical data are collected from people living with knee osteoarthritis and data are analyzed to confirm patterns that can indicate such different subgroups. A Patient Council (PC) has been set up at project initiation and consists of five people from Norway, The Netherlands and UK. Initially, this group of individuals had to learn how to effectively work with each other and with the researchers. Today, the PC is a strong team that is fully integrated in the consortium and acknowledged by researchers as an important sounding board. The article describes this journey looking at formal processes of involvement - organizational structure, budget, meetings - and more informal processes such as building relationships and changing researcher perceptions. It describes how the PC helped improve the experience and engagement of study participants by providing input to the clinical protocol and ensuring effective communication (e.g. through direct interactions with participants and newsletters). Furthermore, the PC is helping with dissemination of results and project advocacy, and overall provides the patient perspective to researchers. Additionally, the authors experienced and describe the intangible benefits such as a shift in researcher attitudes and a sense of community and purpose for PC members. Importantly, learnings reported in this article also include the challenges, such as effective integration of the PC with researchers' work in the early phase of the project. TRIAL REGISTRATION: US National Library of Medicine, NCT03883568 , retrospectively registered 21 March 2019.

13.
J Biochem Mol Toxicol ; 35(7): e22795, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33973313

RESUMO

The world is currently facing an unprecedented pandemic caused by a newly recognized and highly pathogenic coronavirus disease 2019 (COVID-19; induced by SARS-CoV-2 virus), which is a severe and ongoing threat to global public health. Since COVID-19 was officially declared a pandemic by the World Health Organization in March 2020, several drug regimens have rapidly undergone clinical trials for the management of COVID-19. However, one of the major issues is drug-induced organ injury, which is a prominent clinical challenge. Unfortunately, most drugs used against COVID-19 are associated with adverse effects in different organs, such as the kidney, heart, and liver. These side effects are dangerous and, in some cases, they can be lethal. More importantly, organ injury is also a clinical manifestation of COVID-19 infection. These adverse reactions are increasingly recognized as outcomes of COVID-19 infection. Therefore, the differential diagnosis of drug-induced adverse effects from COVID-19-induced organ injury is a clinical complication. This review highlights the importance of drug-induced organ injury, its known mechanisms, and the potential therapeutic strategies in COVID-19 pharmacotherapy. We review the potential strategies for the differential diagnosis of drug-induced organ injury. This information can facilitate the development of therapeutic strategies, not only against COVID-19 but also for future outbreaks of other emerging infectious diseases.


Assuntos
Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Biomarcadores/análise , COVID-19/metabolismo , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/lesões , Diagnóstico Diferencial , Humanos , Inflamação , Rim/efeitos dos fármacos , Rim/lesões , Fígado/efeitos dos fármacos , Fígado/lesões , Estresse Oxidativo
14.
Stem Cell Res Ther ; 12(1): 251, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926568

RESUMO

BACKGROUND: Due to its low capacity for self-repair, articular cartilage is highly susceptible to damage and deterioration, which leads to the development of degenerative joint diseases such as osteoarthritis (OA). Menstrual blood-derived mesenchymal stem/stromal cells (MenSCs) are much less characterized, as compared to bone marrow mesenchymal stem/stromal cells (BMMSCs). However, MenSCs seem an attractive alternative to classical BMMSCs due to ease of access and broader differentiation capacity. The aim of this study was to evaluate chondrogenic differentiation potential of MenSCs and BMMSCs stimulated with transforming growth factor ß (TGF-ß3) and activin A. METHODS: MenSCs (n = 6) and BMMSCs (n = 5) were isolated from different healthy donors. Expression of cell surface markers CD90, CD73, CD105, CD44, CD45, CD14, CD36, CD55, CD54, CD63, CD106, CD34, CD10, and Notch1 was analyzed by flow cytometry. Cell proliferation capacity was determined using CCK-8 proliferation kit and cell migration ability was evaluated by scratch assay. Adipogenic differentiation capacity was evaluated according to Oil-Red staining and osteogenic differentiation according to Alizarin Red staining. Chondrogenic differentiation (activin A and TGF-ß3 stimulation) was investigated in vitro and in vivo (subcutaneous scaffolds in nude BALB/c mice) by expression of chondrogenic genes (collagen type II, aggrecan), GAG assay and histologically. Activin A protein production was evaluated by ELISA during chondrogenic differentiation in monolayer culture. RESULTS: MenSCs exhibited a higher proliferation rate, as compared to BMMSCs, and a different expression profile of several cell surface markers. Activin A stimulated collagen type II gene expression and glycosaminoglycan synthesis in TGF-ß3 treated MenSCs but not in BMMSCs, both in vitro and in vivo, although the effects of TGF-ß3 alone were more pronounced in BMMSCs in vitro. CONCLUSION: These data suggest that activin A exerts differential effects on the induction of chondrogenic differentiation in MenSCs vs. BMMSCs, which implies that different mechanisms of chondrogenic regulation are activated in these cells. Following further optimization of differentiation protocols and the choice of growth factors, potentially including activin A, MenSCs may turn out to be a promising population of stem cells for the development of cell-based therapies with the capacity to stimulate cartilage repair and regeneration in OA and related osteoarticular disorders.


Assuntos
Células-Tronco Mesenquimais , Ativinas , Animais , Células da Medula Óssea , Diferenciação Celular , Células Cultivadas , Condrogênese , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Osteogênese , Fenótipo , Fator de Crescimento Transformador beta3/genética
15.
Stem Cells Dev ; 30(13): 651-659, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33899526

RESUMO

The objective of this study was to compare the clinical efficacy of repeated doses of leucocyte-poor platelet-rich plasma (LP-PRP) plus hyaluronic acid (HA) to a single dose of autologous microfragmented adipose tissue (AMAT) injections in patients with early osteoarthritis (OA) symptoms. Eighty knees in 50 patients (mean age: 61.3 years) were randomly allocated into two equal groups in a nonblinded design and prospectively followed for 12 months. Group 1 received three intra-articular injections (1 month apart) using autologous LP-PRP+HA. Group 2 received a single dose of AMAT injection. Outcomes were measured by PROMs Tegner, Marx, visual analog scale, and Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months. Both groups had significant clinical and functional improvement at 6 and 12 months. The differences between groups were statistically significant in Tegner score and KOOS symptoms (both P < 0.05) at 6 months in group 2. The test with statistically significant differences (P < 0.05) at 12 months was Tegner (P < 0.001), with group 2 having a higher median than group 1. LP-PRP+HA and AMAT lead to clinical and functional improvement at 6 and 12 months. AMAT showed better clinical results in Tegner and KOOS symptoms at 6 months and Tegner at 12 months. Understanding which therapy offers the most benefits with the least risk can significantly improve the quality of life for millions of people affected by OA. Long-term randomized controlled studies are needed to verify differences in efficacy.

16.
Case Rep Womens Health ; 30: e00292, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33643856
17.
Lab Invest ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767361

RESUMO

C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytes. This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA). We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target. We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes. We concluded that mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.

18.
Int J Mol Sci ; 22(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673730

RESUMO

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration.


Assuntos
Cartilagem Articular/fisiopatologia , Leptina/metabolismo , Osteoartrite/patologia , Receptores para Leptina/metabolismo , Animais , Cartilagem Articular/metabolismo , Humanos , Osteoartrite/metabolismo , Transdução de Sinais
20.
Geroscience ; 43(2): 517-537, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33634362

RESUMO

The prevalence of rheumatic and musculoskeletal diseases (RMDs) including osteoarthritis (OA) and low back pain (LBP) in aging societies present significant cost burdens to health and social care systems. Intervertebral disc (IVD) degeneration, which is characterized by disc dehydration, anatomical alterations, and extensive changes in extracellular matrix (ECM) composition, is an important contributor to LBP. IVD cell homeostasis can be disrupted by mitochondrial dysfunction. Mitochondria are the main source of energy supply in IVD cells and a major contributor to the production of reactive oxygen species (ROS). Therefore, mitochondria represent a double-edged sword in IVD cells. Mitochondrial dysfunction results in oxidative stress, cell death, and premature cell senescence, which are all implicated in IVD degeneration. Considering the importance of optimal mitochondrial function for the preservation of IVD cell homeostasis, extensive studies have been done in recent years to evaluate the efficacy of small molecules targeting mitochondrial dysfunction. In this article, we review the pathogenesis of mitochondrial dysfunction, aiming to highlight the role of small molecules and a selected number of biological growth factors that regulate mitochondrial function and maintain IVD cell homeostasis. Furthermore, molecules that target mitochondria and their mechanisms of action and potential for IVD regeneration are identified. Finally, we discuss mitophagy as a key mediator of many cellular events and the small molecules regulating its function.


Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Senescência Celular , Humanos , Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Mitocôndrias
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