Osteoarthritis and Cartilage最新文献

Objective: People with osteoarthritis (OA) commonly experience flares. Whether COVID-19 vaccination triggers OA flares is unknown.

Design: Adults with OA enrolled in a COVID-19 Rheumatology Registry were invited to participate in a case-crossover study. Vaccine data were ascertained from self-report and electronic health records (EHR). OA was identified using coding algorithms and validated via EHR. Participants reported flare and non-flare periods. Vaccine exposures in the 2-, 7-, and 14-day "lookback windows" prior to OA flares were compared to vaccine exposures during similar non-flare ("control") periods.

Results: 279 participants had validated OA, and 136 (49%) contributed at least one flare and one control period. Mean age was 68 years [SD ±8], 82% female, 87% White, 62% knee OA, 56% hip OA, 37% hand/wrist OA and 60% had >= one anatomic location of OA. 525 COVID-19 vaccine doses were recorded, and participants reported 374 OA flares: 30% were mild, 55% were moderate, and 14% were severe. OA flares were not associated with COVID-19 vaccination 2 or 7 days prior (odds ratios [OR] 0.69 [95% confidence interval (CI): 0.28, 1.66], OR 0.54 [95% CI: 0.27, 1.07], respectively). In the 14-day lookback window, fewer flares occurred after vaccination (OR 0.57 [95% CI: 0.34, 0.97], p=0.039). Analyses stratified on sex, age, knee or hand OA, vaccine brand, and dose showed no increased association between COVID-19 vaccination and OA flares.

Conclusion: The lack of positive association between COVID-19 vaccination and OA flare in any primary or secondary analysis provides reassurance regarding the use of COVID-19 vaccines in people with OA.

Objective: Macrophages play a crucial role in various physiological processes. In intervertebral disc degeneration (IDD), macrophage infiltration has been observed in human intervertebral disc (IVD) specimens, but how macrophages influence IDD remains unclear.

Methods: According to the single-cell transcriptome expression profiles from GSE165722, we verified the infiltration of macrophages in IDD and the possible interaction between infiltrated macrophages and nucleus pulposus cells (NPCs). The expression of macrophage-associated markers was verified in specimens of human nucleus pulposus, lumbar spinal instability mice and annulus fibrosus puncture mice. By treating NPCs cocultured with M2 macrophages with osteopontin (OPN) neutralization antibody and siCD44, we demonstrated that both in vitro and in vivo macrophages regulated IDD through the OPN-CD44 axis. Using transforming growth factor beta 1 and siCD44 treatment, we verified that CD44 regulated the pSMAD2/3 pathway.

Results: IDD engaged macrophage infiltration, mainly gathered in the endplate, and induced macrophage M2 polarization. Infiltrated macrophages showed high-level expression of OPN, and NPCs showed upregulated CD44. Depletion of macrophages significantly decreased the expression of OPN and CD44 in degenerative IVD, concurrently exacerbating IDD. The co-culture of macrophages and NPCs in vitro demonstrated that the conditioned media from NPCs induced macrophage M2 polarization. Further, M2 macrophages rescued NPCs extracellular matrix (ECM) phenotype through the OPN-CD44 axis, by regulating pSMAD2/3 nuclear translocation.

Conclusions: Our findings suggest that macrophages regulate NPC ECM expression in IDD through the OPN-CD44 axis, emphasizing the therapeutic potential of targeting macrophages and the OPN-CD44 axis for IDD prevention and treatment.

Objective: The pivotal role of mitophagy in the initiation and progression of intervertebral disc (IVD) degeneration (IDD) has become increasingly apparent due to a growing body of research on its pathogenesis. This review summarizes the role of mitophagy in IDD and the therapeutic potential of targeting this process.

Design: This narrative review is divided into three parts: the regulatory mechanisms of mitophagy, the role of mitophagy in IDD, and the applications and prospects of mitophagy for the treatment of IDD.

Results: Mitophagy protects cells against harmful external stimuli and plays a crucial protective role by promoting extracellular matrix (ECM) production, inhibiting ECM degradation, and reducing apoptosis, senescence, and cartilage endplate calcification. However, excessive mitophagy is often detrimental to cells. Currently, the regulatory mechanisms governing appropriate and excessive mitophagy remain unclear.

Conclusions: Proper mitophagy effectively maintains IVD cell homeostasis and slows the progression of IDD. Conversely, excessive mitophagy may accelerate IDD development. Further research is needed to elucidate the regulatory mechanisms underlying appropriate and excessive mitophagy, which could provide new theoretical support for the application of mitophagy targeting to the treatment of IDD.

Objective: This study aims to link aberrant endogenous retroviruses (ERVs) activation and osteoarthritis (OA) progression by comparing the chromatin accessibility and transcriptomic landscapes of diseased or intact joint tissues of OA patients.

Method: We performed ERVs-centric analysis on published ATAC-seq and RNA-seq data from OA patients' cartilage tissues. Here, we compared the outer region of the lateral tibial plateau, representing intact cartilage, to the inner region of the medial tibial plateau, representing damaged cartilage. In addition, cartilage tissue sections from OA patients and post-traumatic OA mouse models were assayed for global H3K9me3 abundance through immunohistochemistry staining.

Results: Chromatin accessibility and transcription of ERVs, particularly from evolutionarily "intermediate age" ERVs families (ERV1 and ERVL), were enriched and elevated in OA cartilage. This integrative analysis suggests that H3K9me3-related heterochromatin loss might be mechanistically connected to ERV activation in OA tissue. We further verified that global H3K9me3 levels were reduced in diseased cartilage relative to intact tissue in OA patients and injury-induced OA mice.

Conclusion: The findings suggest a compelling hypothesis that the loss of H3K9me3, either due to aging or cellular stressors, may lead to ERVs reactivation that contributes to tissue inflammation and OA progression. This study unveils the intricate relationship between epigenetic alterations, ERVs activation, and OA, paving the way for potential therapeutic interventions targeting these pathogenic mechanisms.

Objective: Distal radius fractures (DRFs) with dorsal malunion increase the risk of osteoarthritis (OA), although the cause of post-DRF OA is yet to be elucidated. To clarify the abnormal effects of a post-DRF dorsal radius deformity, we evaluated the bone density (BD) and stress-distribution patterns of the articular surface in dorsally malunited DRFs.

Design: In 36 cases of dorsally malunited DRFs following extra-articular fractures, we generated three-dimensional computerized models of the malunited distal radius from computed tomography data and extracted the subchondral bones of the radiocarpal joint (RCJ) and distal radioulnar joint (DRUJ). Both BD and stress distribution in the subchondral bones were quantitatively evaluated by comparing the affected and normal sides. Correlations of alterations in high-BD distribution and deformation angles were analyzed.

Results: The center of high-BD distribution from the center of the RCJ in the volar(-)-dorsal(+) direction was dorsal (0.56 ± 0.72 mm) on the affected side compared with the normal side (-0.15 ± 0.63 mm) [95% CI: 0.43, 1.00, P < 0.0001]. The maximum stress distribution was also dorsal on the affected side (2.34 ± 3.52 mm) compared with the normal side (-2.49 ± 1.62 mm) [95% CI: 0.89, 1.79, P < 0.0001]. The alterations in BD and stress distribution correlated with the dorsiflexion and radial deviation angles. In the DRUJ, there was no significant difference in BD between the affected and normal sides.

Conclusions: In dorsally malunited DRFs, the alignment change of the RCJ resulted in high BD-concentration areas and stress distribution on the dorsal side of the radius, which may constitute a precursor for OA.

Objective: To provide a comprehensive and insightful summary of studies on molecular biomarkers at the gene, protein, and metabolite levels across different sample types and joints affected by osteoarthritis (OA).

Methods: A literature search using the PubMed database for publications on OA biomarkers published between April 1, 2023 and April 30, 2024 was performed. Publications were then screened, examined at length, and summarized in a narrative review.

Results: Out of the 364 papers initially identified, 44 publications met inclusion criteria, were relevant to OA, and were further examined for data extraction and discussion. These studies included 1 genomic analysis, 22 on protein markers, 6 on metabolite markers, 9 on inflammatory mediators, and 6 integrating multiple molecular levels.

Conclusions: Significant advancements have been made in identifying molecular biomarkers for OA, encompassing various joints, sample types, and molecular levels. Despite this progress, gaps remain, particularly in the need for validation, larger sample sizes, the integration of more clinical data, and consideration of covariates. For early detection and improved treatment of OA, continued efforts in biomarker identification are needed. This effort should seek to identify effective biomarkers that advance early detection, support prevention, evaluate interventions, and improve patient outcomes.

Objective: The purpose of this narrative review is to highlight the advances made in the past 12 months in the field of osteoarthritis genetics, genomics and epigenetics.

Methods: The Medline and Embase databases were systematically searched for original publications using terminology, and combinations of terminology, relating to: "osteoarthritis", "genetics", "genomics", and "epigenetics". Only original research articles published in the English language between the OARSI congresses of April 2032 and April 2024 were considered.

Results: This narrative review focuses only on studies using genome-wide omics techniques in human material. There was a rise in functional genomics studies across different osteoarthritis-relevant tissues, which have robustly identified an additional 26 genes involved in osteoarthritis pathology. Two of such previously identified genes (MGP, ALDH1A2) are currently the target of ongoing clinical trials for osteoarthritis. This past year also saw the use of single-cell transcriptomics and two relatively new omics: epitranscriptomics and mitochondrial genomics.

Conclusion: This past year of genomics research has led to multiple exciting findings involving genes and mechanisms linked to osteoarthritis. Moreover, the comprehensive genome-wide omics datasets generated for diverse osteoarthritis tissues will prove invaluable for future research aimed at elucidating more causal biological mechanisms and possible therapeutic targets for osteoarthritis.

Objective: To assess the longitudinal stability of biomarker-based molecular endotypes of knee osteoarthritis (KOA) participants from APPROACH and to evaluate the consistency of findings in an independent KOA population.

Methods: Nineteen biomarkers were measured longitudinally in 295 KOA participants from the APPROACH cohort. K-means clustering was used to identify the structural damage, inflammation, and low tissue turnover endotypes at the six-, 12-, and 24-month follow-ups. Endotype stability was defined as having the same independent endotype assignment longitudinally for patients with complete data (n = 226). Clinical and biochemical characteristics were compared between participants with longitudinally stable and unstable endotypes. The presence and longitudinal stability of the endotypes were evaluated in a different KOA population from the placebo arm of the oral salmon calcitonin trials.

Results: An average overall longitudinal endotype stability of 55% (Fleiss' Kappa of 0.53; 95% confidence interval [CI]: 0.46, 0.60) was demonstrated. An average stability of 59% (range: 54-59%) was observed for the structural damage endotype (Fleiss' Kappa 0.52; 95% CI: 0.45, 0.60), 54% (52-56%) for the inflammatory (Fleiss' Kappa 0.61; 95% CI: 0.53, 0.68), and 50% (49-52%) for the low tissue turnover endotype (Fleiss' Kappa 0.46; 95% CI: 0.39, 0.54). Participants with longitudinally unstable endotypes exhibited molecular properties of more than one endotype, which were detectable already at the first visit.

Conclusions: Our study showed for the first time that more than half of KOA participants exhibited a longitudinally stable endotype, highlighting the applicability of biomarker-based endotyping in a clinical trial setting.