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Cell Proliferation Dec 2023Osteoarthritis is a progressive and heterogeneous joint disease with complex pathogenesis. The various phenotypes associated with each patient suggest that better... (Review)
Review
Osteoarthritis is a progressive and heterogeneous joint disease with complex pathogenesis. The various phenotypes associated with each patient suggest that better subgrouping of tissues associated with genotypes in different phases of osteoarthritis may provide new insights into the onset and progression of the disease. Recently, single-cell RNA sequencing was used to describe osteoarthritis pathogenesis on a high-resolution view surpassing traditional technologies. Herein, this review summarizes the microstructural changes in articular cartilage, meniscus, synovium and subchondral bone that are mainly due to crosstalk amongst chondrocytes, osteoblasts, fibroblasts and endothelial cells during osteoarthritis progression. Next, we focus on the promising targets discovered by single-cell RNA sequencing and its potential applications in target drugs and tissue engineering. Additionally, the limited amount of research on the evaluation of bone-related biomaterials is reviewed. Based on the pre-clinical findings, we elaborate on the potential clinical values of single-cell RNA sequencing for the therapeutic strategies of osteoarthritis. Finally, a perspective on the future development of patient-centred medicine for osteoarthritis therapy combining other single-cell multi-omics technologies is discussed. This review will provide new insights into osteoarthritis pathogenesis on a cellular level and the field of applications of single-cell RNA sequencing in personalized therapeutics for osteoarthritis in the future.
Topics: Humans; Endothelial Cells; Osteoarthritis; Cartilage, Articular; Bone and Bones; Chondrocytes; Sequence Analysis, RNA
PubMed: 37317049
DOI: 10.1111/cpr.13517 -
Journal of Orthopaedic Surgery and... Jul 2023Osteoarthritis (OA) and sarcopenia are common musculoskeletal disorders in the aged population, and a growing body of evidence indicated that they mutually influence one...
BACKGROUND
Osteoarthritis (OA) and sarcopenia are common musculoskeletal disorders in the aged population, and a growing body of evidence indicated that they mutually influence one another. Nevertheless, there was still substantial controversy and uncertainty about the causal relationship between sarcopenia and OA. We explored the complex association between sarcopenia-related traits and OA using cross-sectional analysis and Mendelian randomization (MR).
METHODS
The cross-sectional study used the data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Weighted multivariable-adjusted logistic regression and subgroup analyses were used to evaluate the correlation between sarcopenia, grip, appendicular lean mass (ALM) and the risk of OA. Then, we further performed MR analysis to examine the causal effect of sarcopenia-related traits (grip strength, ALM) on OA. Instrumental variables for grip strength and ALM were from the UK Biobank, and the summary-level data for OA was derived from the Genetics of Osteoarthritis (GO) Consortium GWAS (n = 826,690).
RESULTS
In this cross-sectional analysis, we observed that sarcopenia, grip were significantly linked with the risk of OA (OR 1.607, 95% CI 1.233-2.094, P < 0.001), (OR 0.972, 95% CI 0.964-0.979, P < 0.001). According to subgroup analyses stratified by gender, body mass index (BMI), and age, the significant positive relationship between sarcopenia and OA remained in males, females, the age (46-59 years) group, and the BMI (18.5-24.9 kg/m) group (P < 0.05). Furthermore, MR analysis and sensitivity analyses showed causal associations between right grip, left grip and KOA (OR 0.668; 95% CI 0.509 to 0.877; P = 0.004), (OR 0.786; 95% CI 0.608 to 0.915; P = 0.042). Consistent directional effects for all analyses were observed in both the MR-Egger and weighted median methods. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy or outliers for the causal effect of grip strength on KOA (P > 0.05).
CONCLUSIONS
Our research provided evidence that sarcopenia is correlated with an increased risk of OA, and there was a protective impact of genetically predicted grip strength on OA. These findings needed to be verified in further prospective cohort studies with a large sample size.
Topics: Male; Female; Humans; Aged; Middle Aged; Cross-Sectional Studies; Sarcopenia; Nutrition Surveys; Mendelian Randomization Analysis; Prospective Studies; Osteoarthritis
PubMed: 37454213
DOI: 10.1186/s13018-023-03960-w -
Osteoarthritis and Cartilage Sep 2023Early-stage knee osteoarthritis (KOA) classification criteria will enable consistent identification and trial recruitment of individuals with knee osteoarthritis (OA) at... (Review)
Review
BACKGROUND
Early-stage knee osteoarthritis (KOA) classification criteria will enable consistent identification and trial recruitment of individuals with knee osteoarthritis (OA) at an earlier stage of the disease when interventions may be more effective. Toward this goal, we identified how early-stage KOA has been defined in the literature.
METHODS
We performed a scoping literature review in PubMed, EMBASE, Cochrane, and Web of Science, including human studies where early-stage KOA was included as a study population or outcome. Extracted data included demographics, symptoms/history, examination, laboratory, imaging, performance-based measures, gross inspection/histopathologic domains, and the components of composite early-stage KOA definitions.
RESULTS
Of 6142 articles identified, 211 were included in data synthesis. An early-stage KOA definition was used for study inclusion in 194 studies, to define study outcomes in 11 studies, and in the context of new criteria development or validation in six studies. The element most often used to define early-stage KOA was Kellgren-Lawrence (KL) grade (151 studies, 72%), followed by symptoms (118 studies, 56%), and demographic characteristics (73 studies, 35%); 14 studies (6%) used previously developed early-stage KOA composite criteria. Among studies defining early-stage KOA radiographically, 52 studies defined early-stage KOA by KL grade alone; of these 52, 44 (85%) studies included individuals with KL grade 2 or higher in their definitions.
CONCLUSION
Early-stage KOA is variably defined in the published literature. Most studies included KL grades of 2 or higher within their definitions, which reflects established or later-stage OA. These findings underscore the need to develop and validate classification criteria for early-stage KOA.
Topics: Humans; Osteoarthritis, Knee; Knee Joint
PubMed: 37225053
DOI: 10.1016/j.joca.2023.04.015 -
Osteoarthritis and Cartilage Feb 2024Great progress continues to be made in our understanding of the multiple facets of osteoarthritis (OA) biology. Here, we review the major advances in this field and... (Review)
Review
Great progress continues to be made in our understanding of the multiple facets of osteoarthritis (OA) biology. Here, we review the major advances in this field and progress towards therapy development over the past year, highlighting a selection of relevant published literature from a PubMed search covering the year from the end of April 2022 to the end of April 2023. The selected articles have been arranged in themes. These include 1) molecular regulation of articular cartilage and implications for OA, 2) mechanisms of subchondral bone remodelling, 3) role of synovium and inflammation, 4) role of age-related changes including cartilage matrix stiffening, cellular senescence, mitochondrial dysfunction, metabolic dysfunction, and impaired autophagy, and 5) peripheral mechanisms of OA pain. Progress in the understanding of the cellular and molecular mechanisms responsible for the multiple aspects of OA biology is unravelling novel therapeutic targets for disease modification.
Topics: Humans; Osteoarthritis; Inflammation; Cartilage, Articular; Bone and Bones; Biology
PubMed: 37944663
DOI: 10.1016/j.joca.2023.11.002 -
Nature Communications Oct 2023As the unique cell type in articular cartilage, chondrocyte senescence is a crucial cellular event contributing to osteoarthritis development. Here we show that...
As the unique cell type in articular cartilage, chondrocyte senescence is a crucial cellular event contributing to osteoarthritis development. Here we show that clathrin-mediated endocytosis and activation of Notch signaling promotes chondrocyte senescence and osteoarthritis development, which is negatively regulated by myosin light chain 3. Myosin light chain 3 (MYL3) protein levels decline sharply in senescent chondrocytes of cartilages from model mice and osteoarthritis (OA) patients. Conditional deletion of Myl3 in chondrocytes significantly promoted, whereas intra-articular injection of adeno-associated virus overexpressing MYL3 delayed, OA progression in male mice. MYL3 deficiency led to enhanced clathrin-mediated endocytosis by promoting the interaction between myosin VI and clathrin, further inducing the internalization of Notch and resulting in activation of Notch signaling in chondrocytes. Pharmacologic blockade of clathrin-mediated endocytosis-Notch signaling prevented MYL3 loss-induced chondrocyte senescence and alleviated OA progression in male mice. Our results establish a previously unknown mechanism essential for cellular senescence and provide a potential therapeutic direction for OA.
Topics: Humans; Male; Mice; Animals; Chondrocytes; Myosin Light Chains; Cellular Senescence; Osteoarthritis; Cartilage, Articular; Endocytosis
PubMed: 37794006
DOI: 10.1038/s41467-023-41858-7 -
Annals of Medicine Dec 2023Although there is an assertion that weather conditions affect osteoarthritis (OA) pain, the results from clinical studies remain inconsistent. This meta-analysis was... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although there is an assertion that weather conditions affect osteoarthritis (OA) pain, the results from clinical studies remain inconsistent. This meta-analysis was performed to evaluate the association between weather conditions and OA pain.
METHODS
Cochrane Library, Embase, PubMed, and Web of Science were searched from inception to September 30, 2022. Observational studies that explored all weather conditions associated with pain intensity were included. In the systematic review, the methodological quality of the selected studies was assessed and a best-evidence synthesis was used to make qualitative conclusions. Based on homogeneous results, Fisher's scores derived from the effect size of temperature (T), barometric pressure (BP) or relative humidity (RH) related to OA pain were synthesized and further transformed to the correlation coefficients (summary r) in meta-analysis.
RESULTS
A total of 14 studies were included in the best-evidence synthesis of a qualitative systematic review. There was strong evidence with 13 of 14 studies reporting consistent findings that weather factors in general, including any kind of meteorological condition, were associated with OA pain. Subsequently, 3 studies regarding BP or T, and 5 studies regarding RH with the pain of OA were included in quantitative meta-analyses. Both BP (pooled Fisher's = 0.37, 95% CI 0.15 to 0.59; summary = 0.35, 95% CI 0.15 to 0.53) and RH (pooled Fisher's = 0.10, 95% CI 0.01 to 0.18; summary = 0.086, 95% CI -0.05 to 0.22) were positively related to OA pain, while T was negatively related to OA pain (pooled Fisher's = -0.38, 95% CI -0.60 to -0.16; summary = -0.36, 95% CI -0.54 to -0.16).
CONCLUSIONS
In this study, weather factors in general were significantly associated with OA pain. It may provide useful references for the daily health management of OA. More studies designed with the consistent meteorological condition are warranted to validate the findings.KEY MESSAGEMany people with osteoarthritis think their joint pain is affected by the weather, while the association between OA pain and weather conditions is still unclear.This is a systematic review and meta-analysis of 14 observational studies for the association between weather conditions and OA pain.Weather conditions appear to be associated with OA pain. Barometric pressure and relative humidity were positively correlated to OA pain intensity, while temperature was negatively correlated to OA pain.
Topics: Humans; Osteoarthritis; Pain; Weather; Temperature; Observational Studies as Topic
PubMed: 37078741
DOI: 10.1080/07853890.2023.2196439 -
Nature Jan 2024Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain. Although...
Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Na1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Na1.7 channels, with a density of 0.1 to 0.15 channels per µm and 350 to 525 channels per cell. Serial genetic ablation of Na1.7 in multiple mouse models demonstrates that Na1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Na1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Na1.7 with selective or clinically used pan-Na channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Na1.7 blockers regulate intracellular Ca signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Na1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.
Topics: Animals; Humans; Mice; Calcium; Calcium Signaling; Chondrocytes; Disease Progression; Ganglia, Spinal; NAV1.7 Voltage-Gated Sodium Channel; Neurons; Osteoarthritis; Pain; Voltage-Gated Sodium Channel Blockers
PubMed: 38172636
DOI: 10.1038/s41586-023-06888-7 -
Arthritis Research & Therapy Dec 2023To investigate the causal relationship between low bone mineral density (BMD) and osteoarthritis (OA) using Mendelian randomization (MR) design.
OBJECTIVE
To investigate the causal relationship between low bone mineral density (BMD) and osteoarthritis (OA) using Mendelian randomization (MR) design.
METHODS
Two-sample bi-directional MR analyses were performed using summary-level information on OA traits from UK Biobank and arcOGEN. Sensitivity analyses including MR-Egger, simple median, weighted median, MR pleiotropy residual sum, and outlier approaches were utilized in conjunction with inverse variance weighting (IVW). Gene ontology (GO) enrichment analyses and expression quantitative trait locus (eQTL) colocalization analyses were used to investigate the potential mechanism and shared genes between osteoporosis (OP) and OA.
RESULTS
The IVW method revealed that genetically predicted low femoral neck BMD was significantly linked with hip (β = 0.105, 95% CI: 0.023-0.188) and knee OA (β = 0.117, 95% CI: 0.049-0.184), but not with other site-specific OA. Genetically predicted low lumber spine BMD was significantly associated with OA at any sites (β = 0.048, 95% CI: 0.011-0.085), knee OA (β = 0.101, 95% CI: 0.045-0.156), and hip OA (β = 0.150, 95% CI: 0.077-0.224). Only hip OA was significantly linked with genetically predicted reduced total bone BMD (β = 0.092, 95% CI: 0.010-0.174). In the reverse MR analyses, no evidence for a causal effect of OA on BMD was found. GO enrichment analysis and eQTL analysis illustrated that DDN and SMAD-3 were the most prominent co-located genes.
CONCLUSIONS
These findings suggested that OP may be causally linked to an increased risk of OA, indicating that measures to raise BMD may be effective in preventing OA. More research is required to determine the underlying processes via which OP causes OA.
Topics: Humans; Osteoarthritis, Hip; Mendelian Randomization Analysis; Osteoporosis; Bone Diseases, Metabolic; Osteoarthritis, Knee; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Bone Density
PubMed: 38093316
DOI: 10.1186/s13075-023-03213-5 -
Arthritis Care & Research Sep 2023To evaluate the quality of clinical practice guidelines (CPGs) for interventions in management of osteoarthritis (OA) and to provide a synthesis of high-quality CPG...
OBJECTIVE
To evaluate the quality of clinical practice guidelines (CPGs) for interventions in management of osteoarthritis (OA) and to provide a synthesis of high-quality CPG recommendations.
METHODS
Five databases (OvidSP Medline, Cochrane, Cumulative Index to Nursing and Allied Health Literature [CINAHL], Embase, and the Physiotherapy Evidence Database [PEDro]) and 4 online guideline repositories were searched. CPGs for the management of OA were included if they were 1) written in English and published from January 2015 to February 2022, focused on adults age ≥18 years, and met the criteria of a CPG as defined by the Institute of Medicine; and 2) were rated as high quality on the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. CPGs for OA were excluded if they were available via institutional access only, only addressed recommendations for the system/organization of care and did not include interventional management recommendations, and/or included other arthritic conditions.
RESULTS
Of 20 eligible CPGs, 11 were appraised as high quality and included in the synthesis. Of interest were the hip, knee, hand, and glenohumeral joints and/or polyarticular OA. Consistent recommendations were that care should be patient centered and include exercise, education, and weight loss (where appropriate). Nonsteroidal antiinflammatory drugs and surgical interventions were recommended for disabling OA that had not improved with nonsurgical care. Hand orthoses should be recommended for patients with hand OA.
CONCLUSION
This synthesis of high-quality CPGs for OA management offers health care providers with clear, simple guidance of recommended OA care to improve patient outcomes.
Topics: Humans; Adolescent; Osteoarthritis; Physical Therapy Modalities; Hand; Knee Joint; Lower Extremity
PubMed: 36762545
DOI: 10.1002/acr.25101 -
Cellular & Molecular Biology Letters Sep 2023During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS),... (Review)
Review
During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS), damage-associated molecular patterns, and proinflammatory cytokines. This detrimental environment triggers cellular stress and subsequent dysfunction, which not only contributes to the development of associated diseases, that is, osteoporosis and osteoarthritis, but also impairs regenerative processes. To counter ROS-mediated stress and reduce the overall tissue damage, cells possess diverse defense mechanisms. However, cellular antioxidative capacities are limited and thus ROS accumulation can lead to aberrant cell fate decisions, which have adverse effects on cartilage and bone homeostasis. In this narrative review, we address oxidative stress as a major driver of pathophysiologic processes in cartilage and bone, including senescence, misdirected differentiation, cell death, mitochondrial dysfunction, and impaired mitophagy by illustrating the consequences on tissue homeostasis and regeneration. Moreover, we elaborate cellular defense mechanisms, with a particular focus on oxidative stress response and mitophagy, and briefly discuss respective therapeutic strategies to improve cell and tissue protection.
Topics: Humans; Reactive Oxygen Species; Oxidative Stress; Osteoarthritis; Cell Differentiation; Osteoporosis; Cellular Senescence
PubMed: 37777764
DOI: 10.1186/s11658-023-00489-y