The role of macrophages in osteoarthritis and cartilage repair.
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ABSTRACT:
SUBMITTER: Wu CL
PROVIDER: S-EPMC7214213 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Osteoarthritis (OA) is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extracellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived 'mesenchymal stem cells' or 'mesenchymal stromal cells', with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. BMSCs can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local microenvironment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. This review broadly describes the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.
| S-EPMC3580463 | biostudies-literature
Project description:Osteoarthritis (OA) is the most common joint condition and, with a burgeoning ageing population, is due to increase in prevalence. Beyond conventional medical and surgical interventions, there are an increasing number of 'alternative' therapies. These alternative therapies may have a limited evidence base and, for this reason, are often only afforded brief reference (or completely excluded) from current OA guidelines. Thus, the aim of this review was to synthesize the current evidence regarding autologous chondrocyte implantation (ACI), mesenchymal stem cell (MSC) therapy, platelet-rich plasma (PRP), vitamin D and other alternative therapies. The majority of studies were in knee OA or chondral defects. Matrix-assisted ACI has demonstrated exceedingly limited, symptomatic improvements in the treatment of cartilage defects of the knee and is not supported for the treatment of knee OA. There is some evidence to suggest symptomatic improvement with MSC injection in knee OA, with the suggestion of minimal structural improvement demonstrated on MRI and there are positive signals that PRP may also lead to symptomatic improvement, though variation in preparation makes inter-study comparison difficult. There is variability in findings with vitamin D supplementation in OA, and the only recommendation which can be made, at this time, is for replacement when vitamin D is deplete. Other alternative therapies reviewed have some evidence (though from small, poor-quality studies) to support improvement in symptoms and again there is often a wide variation in dosage and regimens. For all these therapeutic modalities, although controlled studies have been undertaken to evaluate effectiveness in OA, these have often been of small size, limited statistical power, uncertain blindness and using various methodologies. These deficiencies must leave the question as to whether they have been validated as effective therapies in OA (or chondral defects). The conclusions of this review are that all alternative interventions definitely require clinical trials with robust methodology, to assess their efficacy and safety in the treatment of OA beyond contextual and placebo effects.
| S-EPMC7170824 | biostudies-literature
Project description:IntroductionThere is currently no disease-modifying drug for osteoarthritis (OA), and some safety concerns have been identified about the leading traditional drugs. Therefore, research efforts have focused on alternatives such as supplementation with collagen derivatives. The objective of this scoping review is to examine the extent, range, and nature of research, and to summarize and disseminate research findings on the effects of collagen derivatives in OA and cartilage repair. The purpose is to identify gaps in the current body of evidence in order to further help progress research in this setting.MethodsThe databases Medline, Scopus, CENTRAL, TOXLINE, and CDSR were comprehensively searched from inception to search date. After studies selection against eligibility criteria, following recommended methods, data were charted from the retrieved articles and these were subsequently synthesized. Numerical and graphical descriptive statistical methods were used to show trends in publications and geographical distribution of studies.ResultsThe systematic literature search identified a total of 10,834 records. Forty-one published studies were ultimately included in the review, 16 of which were preclinical studies and 25 were clinical studies (including four systematic reviews/meta-analyses). Collagen hydrolysate (CH) and undenatured collagen (UC) were the two types of collagen derivatives studied, with a total of 28 individual studies on CH and nine on UC. More than a third of studies originated from Asia, and most of them have been published after 2008. Oral forms of collagen derivatives were mainly studied; three in vivo preclinical studies and three clinical trials investigated intra-articularly injected CH. In most of the clinical trials, treatment durations varied between 3 and 6 months, with the shortest being 1.4 months and the longest 11 months. All in vivo preclinical studies and clinical trials, regardless of their quality, concluded on beneficial effects of collagen derivatives in OA and cartilage repair, whether used as nutritional supplement or delivered intra-articularly, and whatever the manufacturers of the products, the doses and the outcomes considered in each study.ConclusionsAlthough current evidence shows some potential for the use of CH and UC as an option for management of patients with OA, there is still room for progress in terms of laboratory and clinical research before any definitive conclusion can be made. Harmonization of outcomes in preclinical studies and longer randomized placebo-controlled trials in larger populations with the use of recommended and validated endpoints are warranted before collagen derivatives can be recommended by large scientific societies.
| S-EPMC7695755 | biostudies-literature
Project description:Purpose of reviewThe decreased contact area, edge loading, and increased stress in the adjacent area cartilage resulting from chondral defects are believed to predispose this tissue to degenerative changes that have significant economic implications, especially when considering its progression to osteoarthritis of the knee. Growth factors are considered therapeutic possibilities to enhance healing of chondral injuries and modify the progression to degenerative arthritis. Thus, the purposes of this review are to first to summarize important points for defect preparation and recent advances in techniques for marrow stimulation and second, and to identify specific growth factors and cytokines that have the capacity to advance cartilage regeneration and the treatment of osteoarthritis in light of recent laboratory and clinical studies.Recent findingsTGF-β, BMP-2, BMP-7, IGF-1, as IL-1 receptor antagonist, and recombinant human FGF-18 are some of the promising growth factor/cytokine treatments with pioneering and evolving clinical developments. The bulk of the review describes and discusses these developments in light of fundamental basic science. It is crucial to also understand the other underlying advances made in the surgical management of cartilage defects prior to onset of OA. These advances are in techniques for defect preparation and marrow stimulation, a common cartilage repair procedure used in combination with growth factor/cytokine augmentation. Multiple growth factor/cytokine modulation therapies are currently undergoing clinical trial investigation including Invossa (currently in phase III study), Kineret (currently in phase I study), and Sprifermin (currently in phase II study) for the treatment of symptomatic osteoarthritis.
| S-EPMC7661573 | biostudies-literature
Project description:Epigenetics plays an important role in the pathogenesis and treatment of osteoarthritis (OA). In recent decades, HDAC family members have been associated with OA. This paper aims to describe the different role of HDACs in the pathogenesis of OA through interaction with microRNAs and the regulation of relevant signaling pathways. We found that HDACs are involved in cartilage and chondrocyte development but also play a crucial role in OA. However, the distinct HDAC mechanism in the pathogenesis and treatment of OA require further investigation. Furthermore, HDAC inhibitors (HDACi) can protect cartilage from disease, which may represent a potential therapeutic approach against OA.
| S-EPMC7554620 | biostudies-literature
Project description:In the past decade, mesenchymal stem cells (MSCs) have been widely used for the treatment of osteoarthritis (OA), and extracellular vesicles (EVs) may play a major role in the efficacy of this treatment. Hypoxia can change the cargo and biological functions of MSC-derived EVs (MSC-EVs). The aim of the present study was to determine whether the effects of hypoxia-preconditioned MSC-EVs on OA cartilage repair are superior to normoxia-preconditioned MSC-EVs. By using in vitro and in vivo OA models, we verified that hypoxia-preconditioned MSC-EVs improved chondrocyte proliferation and migration and suppressed chondrocyte apoptosis to a greater extent than normoxia-preconditioned MSC-EVs. Furthermore, we found that hypoxia altered the microRNA expression in MSC-EVs and identified four differentially expressed microRNAs: hsa-miR-181c-5p, hsa-miR-18a-3p, hsa-miR-376a-5p, and hsa-miR-337-5p. Bioinformatics analysis revealed that hypoxic pretreatment may promote cartilage repair by stimulating chondrocyte proliferation and migration and suppressing chondrocyte apoptosis through the miRNA-18-3P/JAK/STAT or miRNA-181c-5p/MAPK signaling pathway. Therefore, hypoxia-preconditioned EVs may be a novel treatment for OA.
| S-EPMC8875566 | biostudies-literature
Project description:BackgroundOsteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation.Materials and methodsThe type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width.ResultsIn both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4-8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011).ConclusionSerum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug.Level of evidenceLevel III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.
| S-EPMC7943687 | biostudies-literature
Project description:BackgroundThe chondrogenic differentiation of mesenchymal stem cells (MSCs) to enhance cartilage repair and regeneration is a promising strategy to alleviate osteoarthritis (OA) progression.MethodThe potency of JD-312 in inducing chondrogenic differentiation of MSCs was assessed and verified. The efficacy of JD-312-treated MSCs was evaluated using a Sprague-Dawley rat DMM model. Additionally, the capacity of JD-312 to successfully recruit bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of OA in vitro was confirmed via intra-articular injection. The repair status of the articular cartilage was analyzed in vivo through histological examination.ResultIn this study, we identify JD-312 as a novel non-toxic small molecule that can promote chondrogenic differentiation in human umbilical cord-derived MSCs (hUCMSCs) and human bone marrow MSCS (hBMSCs) in vitro. We also show that transient differentiation of MSCs with JD-312 prior to in vivo administration remarkably improves the regeneration of cartilage and promotes Col2a1 and Acan expression in rat models of DMM, in comparison to kartogenin (KGN) pre-treatment or MSCs alone. Furthermore, direct intra-articular injection of JD-312 in murine model of OA showed reduced loss of articular cartilage and improved pain parameters. Lastly, we identified that the effects of JD-312 are at least in part mediated via upregulation of genes associated with the focal adhesion, PI3K-Akt signaling and the ECM-receptor interaction pathways, and specifically cartilage oligomeric matrix protein (COMP) may play a vital role.ConclusionOur study demonstrated that JD-312 showed encouraging repair effects for OA in vivo.The translational potential of this articleTogether, our findings demonstrate that JD-312 is a promising new therapeutic molecule for cartilage regeneration with clinical potential.
| S-EPMC10805627 | biostudies-literature
Project description:Loss of NOTCH signaling in postnatal murine joints results in osteoarthritis, indicating a requirement for NOTCH during maintenance of joint cartilage. However, NOTCH signaling components are substantially increased in abundance in posttraumatic osteoarthritis in humans and mice, suggesting either a reparative or a pathological role for NOTCH activation in osteoarthritis. We investigated a potential dual role for NOTCH in joint maintenance and osteoarthritis by generating two mouse models overexpressing the NOTCH1 intracellular domain (NICD) within postnatal joint cartilage. The first mouse model exhibited sustained NOTCH activation to resemble pathological NOTCH signaling, whereas the second model had transient NOTCH activation, which more closely reflected physiological NOTCH signaling. Sustained NOTCH signaling in joint cartilage led to an early and progressive osteoarthritic-like pathology, whereas transient NOTCH activation enhanced the synthesis of cartilage matrix and promoted joint maintenance under normal physiological conditions. Through RNA-sequencing, immunohistochemical, and biochemical approaches, we identified several targets that could be responsible for NOTCH-mediated cartilage degradation, fibrosis, and osteoarthritis progression. These targets included components of the interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase signaling pathways, which may also contribute to the posttraumatic development of osteoarthritis. Together, these data suggest a dual role for the NOTCH pathway in joint cartilage, and they identify downstream effectors of NOTCH signaling as potential targets for disease-modifying osteoarthritis drugs.
| S-EPMC4607068 | biostudies-literature
Project description:ObjectivesKnee joint distraction (KJD) is a novel, but poorly understood, treatment for osteoarthritis (OA) associated with remarkable 'spontaneous' cartilage repair in which resident synovial fluid (SF) multipotential mesenchymal stromal cells (MSCs) may play a role. We hypothesised that SF hyaluronic acid (HA) inhibited the initial interaction between MSCs and cartilage, a key first step to integration, and postulate that KJD environment favoured MSC/cartilage interactions.MethodsAttachment of dual-labelled SF-MSCs were assessed in a novel in vitro human cartilage model using OA and rheumatoid arthritic (RA) SF. SF was digested with hyaluronidase (hyase) and its effect on adhesion was observed using confocal microscopy. MRI and microscopy were used to image autologous dual-labelled MSCs in an in vivo canine model of KJD. SF-HA was investigated using gel electrophoresis and densitometry.ResultsOsteoarthritic-synovial fluid (OA-SF) and purified high molecular weight (MW) HA inhibited SF-MSC adhesion to plastic, while hyase treatment of OA-SF but not RA-SF significantly increased MSC adhesion to cartilage (3.7-fold, p<0.05) These differences were linked to the SF mediated HA-coat which was larger in OA-SF than in RA-SF. OA-SF contained >9?MDa HA and this correlated with increases in adhesion (r=0.880). In the canine KJD model, MSC adhesion to cartilage was evident and also dependent on HA MW.ConclusionsThese findings highlight an unappreciated role of SF-HA on MSC interactions and provide proof of concept that endogenous SF-MSCs are capable of adhering to cartilage in a favourable biochemical and biomechanical environment in OA distracted joints, offering novel one-stage strategies towards joint repair.
| S-EPMC4853581 | biostudies-literature