Cartilage calcification in osteoarthritis: mechanisms and clinical relevance

Bernabei, I.; So, Alexander; Busso, Nathalie; Nasi, Sonia

doi:10.1038/s41584-022-00875-4

Cited by 60 publications

(33 citation statements)

References 252 publications

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“…Mounting evidence has revealed that the number of apoptotic chondrocytes in OA articular cartilage is substantially higher than that in healthy cartilage, [ 23 ] and a strong correlation has been observed between apoptosis and the severity of cartilage damage; [ 24 ] therefore, apoptosis may be a potential target for OA therapy. IL‐1β, as a major catabolic cytokine in OA, is reported to stimulate matrix‐degrading enzymes (MMPs) and inducible nitric oxide synthase.…”

Section: Resultsmentioning

confidence: 99%

Amelioration of Osteoarthritis via Tetrahedral Framework Nucleic Acids Delivering Microrna‐124 for Cartilage Regeneration

Shi,

Chen,

et al. 2023

Adv Funct Materials

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MicroRNAs (miRNAs) regulate several physiological and pathological processes involved in various diseases, including osteoarthritis (OA). OA is the most common global musculoskeletal disorder, characterized by the irreversible progressive destruction of articular cartilage. Supplementation with exogenous miRNAs may represent a promising therapeutic OA treatment, with miRNA‐124 (miR‐124) being a prime candidate for its anti‐inflammatory ability; however, an effective drug delivery system is urgently required to enhance miR‐124 stability and capacity to enter chondrocytes. To this end, tetrahedral framework nucleic acids’ (tFNAs) self‐assembled 3D DNA nanostructures possess superior inherent biocompatibility, versatile functionality, unsurpassed editability, and strong cellular internalization ability. In this study, tFNAs carrying one or three miR‐124 (T‐miR1 or T‐miR3) are successfully synthesized. T‐miR3 is largely absorbed via induced inflammatory chondrocytes by IL‐1β. With reactive oxygen species’ scavenging ability and inflammation‐suppressive miR‐124 release behavior, T‐miR3 efficiently protects chondrocytes against IL‐1β injury in vitro. Additionally, T‐miR3 effectively prevents OA progression by inhibiting chondrocyte apoptosis, smoothing cartilage surfaces, suppressing extracellular matrix degradation, and increasing synovial thickness, effectively protecting in vivo articular cartilage, and illustrating the therapeutic ability of T‐miR3 in OA treatment. This study provides experimental evidence and novel therapeutic strategies for OA treatment in the clinical setting.

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Section: Resultsmentioning

confidence: 99%

Amelioration of Osteoarthritis via Tetrahedral Framework Nucleic Acids Delivering Microrna‐124 for Cartilage Regeneration

Shi,

Chen,

et al. 2023

Adv Funct Materials

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“…Collagens are main components in cartilage and their healthy turnover is essential for the integrity of articular cartilage. Degeneration and damage of cartilage during OA is associated with loss of type II collagen (Col2a1) and upregulation of type X collagen (Col10a1) (Bernabei et al, 2023; van der Kraan & van den Berg, 2012). As RUNX2 controls the differentiation of articular chondrocytes into hypertrophic chondrocytes that produce high levels of Col10a1, we performed fluorescent IHC to determine if RUNX2 accumulation in the chondrocytes of dKO TMJ resulted in degenerative changes of collagen production.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, our results suggest that the deficiency of miR-204 and miR-211 in TMJ upregulates RUNX2, which induces the expression of cartilagedegrading enzymes such as MMP13 and ADAMTS5 and reduces the expression of lubricin, a key factor maintaining joint integrity, both contributing to a profound pathogenesis of TMJ OA.Collagens are main components in cartilage and their healthy turnover is essential for the integrity of articular cartilage. Degeneration and damage of cartilage during OA is associated with loss of type II collagen (Col2a1) and upregulation of type X collagen (Col10a1)(Bernabei et al, 2023;van der Kraan & van den Berg, 2012).As RUNX2 controls the differentiation of articular chondrocytes into hypertrophic chondrocytes that produce high levels of Col10a1, we performed fluorescent IHC to determine if RUNX2 accumulation in the chondrocytes of dKO TMJ resulted in degenerative changes of collagen production. Our results demonstrated that Col10a1 increased robustly in the dKO condylar cartilage, while Col2a1 decreased significantly (Figure5a,c).…”

mentioning

confidence: 99%

Loss ofmiR‐204andmiR‐211shifts osteochondral balance and causes temporomandibular joint osteoarthritis

Huang,

Lai,

et al. 2023

Journal Cellular Physiology

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Temporomandibular joint (TMJ) osteoarthritis (OA) is a common type of TMJ disorders causing pain and dysfunction in the jaw and surrounding tissues. The causes for TMJ OA are unknown and the underlying mechanism remains to be identified. In this study, we generated genetically‐modified mice deficient of two homologous microRNAs, miR‐204 and miR‐211, both of which were confirmed by in situ hybridization to be expressed in multiple TMJ tissues, including condylar cartilage, articular eminence, and TMJ disc. Importantly, the loss‐of‐function of miR‐204 and miR‐211 caused an age‐dependent progressive OA‐like phenotype, including cartilage degradation and abnormal subchondral bone remodeling. Mechanistically, the TMJ joint deficient of the two microRNAs demonstrated a significant accumulation of RUNX2, a protein directly targeted by miR‐204/‐211, and upregulations of β‐catenin, suggesting a disrupted balance between osteogenesis and chondrogenesis in the TMJ, which may underlie TMJ OA. Moreover, the TMJ with miR‐204/‐211 loss‐of‐function displayed an aberrant alteration in both collagen component and cartilage‐degrading enzymes and exhibited exacerbated orofacial allodynia, corroborating the degenerative and painful nature of TMJ OA. Together, our results establish a key role of miR‐204/‐211 in maintaining the osteochondral homeostasis of the TMJ and counteracting OA pathogenesis through repressing the pro‐osteogenic factors including RUNX2 and β‐catenin.

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“…Continual proteoglycan loss and type II collagen degradation lead to net cartilage attrition, and this is a major cause of joint space narrowing in disease [ 25 ]. Cartilage calcification is common (reviewed in [ 26 ]) with deposits of calcium crystals such as basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPP) frequently found in cartilage as well as other joint tissues in OA [ 26 ]. These changes in the cartilage are accompanied by altered activity of chondrocytes within the affected tissue.…”

Section: Histological Appearance Of Oa In Human Disease Vs Mouse Modelsmentioning

confidence: 99%

Re-thinking osteoarthritis pathogenesis: what can we learn (and what do we need to unlearn) from mouse models about the mechanisms involved in disease development

2023

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Efforts to develop effective disease-modifying drugs to treat osteoarthritis have so far proved unsuccessful with a number of promising drug candidates from pre-clinical studies failing to show efficacy in clinical trials. It is therefore timely to re-evaluate our current understanding of osteoarthritis pathogenesis and the similarities and differences in disease development between commonly used pre-clinical mouse models and human patients. There is substantial heterogeneity between patients presenting with osteoarthritis and mounting evidence that the pathways involved in osteoarthritis (e.g. Wnt signalling) differ between patient sub-groups. There is also emerging evidence that the pathways involved in osteoarthritis differ between the STR/ort mouse model (the most extensively studied mouse model of spontaneously occurring osteoarthritis) and injury-induced osteoarthritis mouse models. For instance, while canonical Wnt signalling is upregulated in the synovium and cartilage at an early stage of disease in injury-induced osteoarthritis mouse models, this does not appear to be the case in the STR/ort mouse. Such findings may prove insightful for understanding the heterogeneity in mechanisms involved in osteoarthritis pathogenesis in human disease. However, it is important to recognise that there are differences between mice and humans in osteoarthritis pathogenesis. A much more extensive array of pathological changes are evident in osteoarthritic joints in individual mice with osteoarthritis compared to individual patients. There are also specified differences in the pathways involved in disease development. For instance, although increased TGF-β signalling is implicated in osteoarthritis development in both mouse models of osteoarthritis and human disease, in mice, this is mainly mediated through TGF-β3 whereas in humans, it is through TGF-β1. Studies in other tissues have shown TGF-β1 is more potent than TGF-β3 in inducing the switch to SMAD1/5 signalling that occurs in osteoarthritic cartilage and that TGF-β1 and TGF-β3 have opposing effects on fibrosis. It is therefore possible that the relative contribution of TGF-β signalling to joint pathology in osteoarthritis differs between murine models and humans. Understanding the similarities and differences in osteoarthritis pathogenesis between mouse models and humans is critical for understanding the translational potential of findings from pre-clinical studies.

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Cartilage calcification in osteoarthritis: mechanisms and clinical relevance

Cited by 60 publications

References 252 publications

Amelioration of Osteoarthritis via Tetrahedral Framework Nucleic Acids Delivering Microrna‐124 for Cartilage Regeneration

Amelioration of Osteoarthritis via Tetrahedral Framework Nucleic Acids Delivering Microrna‐124 for Cartilage Regeneration

Loss ofmiR‐204andmiR‐211shifts osteochondral balance and causes temporomandibular joint osteoarthritis

Re-thinking osteoarthritis pathogenesis: what can we learn (and what do we need to unlearn) from mouse models about the mechanisms involved in disease development

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