Aims. Knee osteoarthritis (OA) involves a variety of tissues in the joint. Gene expression profiles in different tissues are of great importance in order to understand OA. Methods. First, we obtained gene expression profiles of cartilage, synovium, subchondral bone, and meniscus from the Gene Expression Omnibus (GEO). Several datasets were standardized by merging and removing batch effects. Then, we used unsupervised clustering to divide OA into three subtypes. The gene ontology and pathway enrichment of three subtypes were analyzed. CIBERSORT was used to evaluate the infiltration of immune cells in different subtypes. Finally, OA-related genes were obtained from the Molecular Signatures Database for validation, and diagnostic markers were screened according to clinical characteristics. Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) was used to verify the effectiveness of markers. Results. C1 subtype is mainly concentrated in the development of skeletal muscle organs, C2 lies in metabolic process and immune response, and C3 in pyroptosis and cell death process. Therefore, we divided OA into three subtypes: bone remodelling subtype (C1), immune metabolism subtype (C2), and cartilage degradation subtype (C3). The number of macrophage M0 and activated mast cells of C2 subtype was significantly higher than those of the other two subtypes. COL2A1 has significant differences in different subtypes. The expression of COL2A1 is related to age, and trafficking protein particle complex subunit 2 is related to the sex of OA patients. Conclusion. This study linked different tissues with gene expression profiles, revealing different molecular subtypes of patients with knee OA. The relationship between clinical characteristics and OA-related genes was also studied, which provides a new concept for the diagnosis and treatment of OA. Cite this article: Bone Joint Res 2023;12(12):702–711

Aims. This study aimed, through bioinformatics analysis, to identify the potential diagnostic markers of osteoarthritis, and analyze the role of immune infiltration in synovial tissue. Methods. The gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified by R software. Functional enrichment analyses were performed and protein-protein interaction networks (PPI) were constructed. Then the hub genes were screened. Biomarkers with high value for the diagnosis of early osteoarthritis (OA) were validated by GEO datasets. Finally, the CIBERSORT algorithm was used to evaluate the immune infiltration between early-stage OA and end-stage OA, and the correlation between the diagnostic marker and infiltrating immune cells was analyzed. Results. A total of 88 DEGs were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that DEGs were significantly enriched in leucocyte migration and interleukin (IL)-17 signalling pathways. Disease ontology (DO) indicated that DEGs were mostly enriched in rheumatoid arthritis. Six hub genes including FosB proto-oncogene, AP-1 transcription factor subunit (FOSB); C-X-C motif chemokine ligand 2 (CXCL2); CXCL8; IL-6; Jun proto-oncogene, AP-1 transcription factor subunit (JUN); and Activating transcription factor 3 (ATF3) were identified and verified by GEO datasets. ATF3 (area under the curve = 0.975) turned out to be a potential biomarker for the diagnosis of early OA. Several infiltrating immune cells varied significantly between early-stage OA and end-stage OA, such as resting NK cells (p = 0.016), resting dendritic cells (p = 0.043), and plasma cells (p = 0.043). Additionally, ATF3 was significantly correlated with resting NK cells (p = 0.034), resting dendritic cells (p = 0.026), and regulatory T cells (Tregs, p = 0.018). Conclusion. ATF3 may be a potential diagnostic marker for early diagnosis and treatment of OA, and immune cell infiltration provides new perspectives for understanding the mechanism during OA progression. Cite this article: Bone Joint Res 2022;11(9):679–689

Aims. Osteoarthritis (OA) is a common degenerative joint disease. The osteocyte transcriptome is highly relevant to osteocyte biology. This study aimed to explore the osteocyte transcriptome in subchondral bone affected by OA. Methods. Gene expression profiles of OA subchondral bone were used to identify disease-relevant genes and signalling pathways. RNA-sequencing data of a bone loading model were used to identify the loading-responsive gene set. Weighted gene co-expression network analysis (WGCNA) was employed to develop the osteocyte mechanics-responsive gene signature. Results. A group of 77 persistent genes that are highly relevant to extracellular matrix (ECM) biology and bone remodelling signalling were identified in OA subchondral lesions. A loading responsive gene set, including 446 principal genes, was highly enriched in OA medial tibial plateaus compared to lateral tibial plateaus. Of this gene set, a total of 223 genes were identified as the main contributors that were strongly associated with osteocyte functions and signalling pathways, such as ECM modelling, axon guidance, Hippo, Wnt, and transforming growth factor beta (TGF-β) signalling pathways. We limited the loading-responsive genes obtained via the osteocyte transcriptome signature to identify a subgroup of genes that are highly relevant to osteocytes, as the mechanics-responsive osteocyte signature in OA. Based on WGCNA, we found that this signature was highly co-expressed and identified three clusters, including early, late, and persistently responsive genes. Conclusion. In this study, we identified the mechanics-responsive osteocyte signature in OA-lesioned subchondral bone. Cite this article: Bone Joint Res 2022;11(6):362–370

Aims. To assess the alterations in cell-specific DNA methylation associated with chondroitin sulphate response using peripheral blood collected from Kashin-Beck disease (KBD) patients before initiation of chondroitin sulphate treatment. Methods. Peripheral blood samples were collected from KBD patients at baseline of chondroitin sulphate treatment. Methylation profiles were generated using reduced representation bisulphite sequencing (RRBS) from peripheral blood. Differentially methylated regions (DMRs) were identified using MethylKit, while DMR-related genes were defined as those annotated to the gene body or 2.2-kilobase upstream regions of DMRs. Selected DMR-related genes were further validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to assess expression levels. Tensor composition analysis was performed to identify cell-specific differential DNA methylation from bulk tissue. Results. This study revealed 21,060 hypermethylated and 44,472 hypomethylated DMRs, and 13,194 hypermethylated and 22,448 hypomethylated CpG islands for differential global methylation for chondroitin sulphate treatment response. A total of 12,666 DMR-related genes containing DMRs were identified in their promoter regions, such as CHL1 (false discovery rate (FDR) = 2.11 × 10. -11. ), RIC8A (FDR = 7.05 × 10. -4. ), and SOX12 (FDR = 1.43 × 10. -3. ). Additionally, RIC8A and CHL1 were hypermethylated in responders, while SOX12 was hypomethylated in responders, all showing decreased gene expression. The patterns of cell-specific differential global methylation associated with chondroitin sulphate response were observed. Specifically, we found that DMRs located in TESPA1 and ATP11A exhibited differential DNA methylation between responders and non-responders in granulocytes, monocytes, and B cells. Conclusion. Our study identified cell-specific changes in DNA methylation associated with chondroitin sulphate response in KBD patients. Cite this article: Bone Joint Res 2024;13(5):237–246

Aims. Minimally manipulated cells, such as autologous bone marrow concentrates (BMC), have been investigated in orthopaedics as both a primary therapeutic and augmentation to existing restoration procedures. However, the efficacy of BMC in combination with tissue engineering is still unclear. In this study, we aimed to determine whether the addition of BMC to an osteochondral scaffold is safe and can improve the repair of large osteochondral defects when compared to the scaffold alone. Methods. The ovine femoral condyle model was used. Bone marrow was aspirated, concentrated, and used intraoperatively with a collagen/hydroxyapatite scaffold to fill the osteochondral defects (n = 6). Tissue regeneration was then assessed versus the scaffold-only group (n = 6). Histological staining of cartilage with alcian blue and safranin-O, changes in chondrogenic gene expression, microCT, peripheral quantitative CT (pQCT), and force-plate gait analyses were performed. Lymph nodes and blood were analyzed for safety. Results. The results six months postoperatively showed that there were no significant differences in bone regrowth and mineral density between BMC-treated animals and controls. A significant upregulation of messenger RNA (mRNA) for types I and II collagens in the BMC group was observed, but there were no differences in the formation of hyaline-like cartilage between the groups. A trend towards reduced sulphated glycosaminoglycans (sGAG) breakdown was detected in the BMC group but this was not statistically significant. Functional weightbearing was not affected by the inclusion of BMC. Conclusion. Our results indicated that the addition of BMC to scaffold is safe and has some potentially beneficial effects on osteochondral-tissue regeneration, but not on the functional endpoint of orthopaedic interest. Cite this article: Bone Joint Res 2021;10(10):677–689

Aims. Osteoarthritis (OA) is characterized by persistent destruction of articular cartilage. It has been found that microRNAs (miRNAs) are closely related to the occurrence and development of OA. The purpose of the present study was to investigate the mechanism of miR-486 in the development and progression of OA. Methods. The expression levels of miR-486 in cartilage were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of collagen, type II, alpha 1 (COL2A1), aggrecan (ACAN), matrix metalloproteinase (MMP)-13, and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) in SW1353 cells at both messenger RNA (mRNA) and protein levels was determined by qRT-PCR, western blot, and enzyme-linked immunosorbent assay (ELISA). Double luciferase reporter gene assay, qRT-PCR, and western blot assay were used to determine whether silencing information regulator 6 (SIRT6) was involved in miR-486 induction of chondrocyte-like cells to a more catabolic phenotype. Results. Compared with osteonecrosis, the expression of miR-486 was significantly upregulated in cartilage from subjects with severe OA. In addition, overexpressed miR-486 promoted a catabolic phenotype in SW1353 cells by upregulating the expressions of ADAMTS4 and MMP-13 and down-regulating the expressions of COL2A1 and ACAN. Conversely, inhibition of miR-486 had the opposite effect. Furthermore, overexpression of miR-486 significantly inhibited the expression of SIRT6, confirming that SIRT6 is a direct target of miR-486. Moreover, SW1353 cells were transfected with small interfering RNA (si)-SIRT6 and it was found that SIRT6 was involved in and inhibited miR-486-induced changes to SW1353 gene expression. Conclusion. Our results indicate that miR-486 promotes a catabolic phenotype in SW1353 cells in OA by targeting SIRT6. Our findings might provide a potential therapeutic target and theoretical basis for OA. Cite this article: Bone Joint Res 2021;10(7):459–466

Aims. Osteoarthritis (OA) is the most prevalent joint disease. However, the specific and definitive genetic mechanisms of OA are still unclear. Methods. Tissue-related transcriptome-wide association studies (TWAS) of hip OA and knee OA were performed utilizing the genome-wide association study (GWAS) data of hip OA and knee OA (including 2,396 hospital-diagnosed hip OA patients versus 9,593 controls, and 4,462 hospital-diagnosed knee OA patients versus 17,885 controls) and gene expression reference to skeletal muscle and blood. The OA-associated genes identified by TWAS were further compared with the differentially expressed genes detected by the messenger RNA (mRNA) expression profiles of hip OA and knee OA. Functional enrichment and annotation analysis of identified genes was performed by the DAVID and FUMAGWAS tools. Results. We detected 33 common genes, eight common gene ontology (GO) terms, and one common pathway for hip OA, such as calcium and integrin-binding protein 1 (CIB1) (PTWAS = 0.025, FCmRNA = -1.575 for skeletal muscle), adrenomedullin (ADM) (PTWAS = 0.022, FCmRNA = -4.644 for blood), Golgi apparatus (PTWAS <0.001, PmRNA = 0.012 for blood), and phosphatidylinositol 3' -kinase-protein kinase B (PI3K-Akt) signalling pathway (PTWAS = 0.033, PmRNA = 0.005 for blood). For knee OA, we detected 24 common genes, eight common GO terms, and two common pathways, such as histocompatibility complex, class II, DR beta 1 (HLA-DRB1) (PTWAS = 0.040, FCmRNA = 4.062 for skeletal muscle), Follistatin-like 1 (FSTL1) (PTWAS = 0.048, FCmRNA = 3.000 for blood), cytoplasm (PTWAS < 0.001, PmRNA = 0.005 for blood), and complement and coagulation cascades (PTWAS = 0.017, PmRNA = 0.001 for skeletal muscle). Conclusion. We identified a group of OA-associated genes and pathways, providing novel clues for understanding the genetic mechanism of OA. Cite this article:Bone Joint Res. 2020;9(3):130–138

Aims. This study aimed to uncover the hub long non-coding RNAs (lncRNAs) differentially expressed in osteoarthritis (OA) cartilage using an integrated analysis of the competing endogenous RNA (ceRNA) network and co-expression network. Methods. Expression profiles data of ten OA and ten normal tissues of human knee cartilage were obtained from the Gene Expression Omnibus (GEO) database (GSE114007). The differentially expressed messenger RNAs (DEmRNAs) and lncRNAs (DElncRNAs) were identified using the edgeR package. We integrated human microRNA (miRNA)-lncRNA/mRNA interactions with DElncRNA/DEmRNA expression profiles to construct a ceRNA network. Likewise, lncRNA and mRNA expression profiles were used to build a co-expression network with the WGCNA package. Potential hub lncRNAs were identified based on an integrated analysis of the ceRNA network and co-expression network. StarBase and Multi Experiment Matrix databases were used to verify the lncRNAs. Results. We detected 1,212 DEmRNAs and 49 DElncRNAs in OA and normal knee cartilage. A total of 75 dysregulated lncRNA-miRNA interactions and 711 dysregulated miRNA-mRNA interactions were obtained in the ceRNA network, including ten DElncRNAs, 69 miRNAs, and 72 DEmRNAs. Similarly, 1,330 dysregulated lncRNA-mRNA interactions were used to construct the co-expression network, which included ten lncRNAs and 407 mRNAs. We finally identified seven hub lncRNAs, named MIR210HG, HCP5, LINC00313, LINC00654, LINC00839, TBC1D3P1-DHX40P1, and ISM1-AS1. Subsequent enrichment analysis elucidated that these lncRNAs regulated extracellular matrix organization and enriched in osteoclast differentiation, the FoxO signalling pathway, and the tumour necrosis factor (TNF) signalling pathway in the development of OA. Conclusion. The integrated analysis of the ceRNA network and co-expression network identified seven hub lncRNAs associated with OA. These lncRNAs may regulate extracellular matrix changes and chondrocyte homeostasis in OA progress. Cite this article:Bone Joint Res. 2020;9(3):90–98

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Rheumatoid arthritis (RA) is a common chronic immune disease. Berberine, as its main active ingredient, was also contained in a variety of medicinal plants such as Berberaceae, Buttercup, and Rutaceae, which are widely used in digestive system diseases in traditional Chinese medicine with anti-inflammatory and antibacterial effects. The aims of this article were to explore the therapeutic effect and mechanism of berberine on rheumatoid arthritis.

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Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficiency of two major cytokines, namely interleukin (IL)-1 and IL-6, in this study double deficient mice for IL-1αβ and IL-6 were investigated in different tumour necrosis factor (TNF)-driven inflammatory bone disorders, namely peripheral arthritis and sacroiliitis, as well as systemic bone loss.

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The aim of this study was to explore the genetic correlation and causal relationship between blood plasma proteins and rheumatoid arthritis (RA).

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Osteoarthritis (OA) is a common degenerative joint disease characterized by chronic inflammatory articular cartilage degradation. Long noncoding RNAs (lncRNAs) have been previously indicated to play an important role in inflammation-related diseases. Herein, the current study set out to explore the involvement of lncRNA H19 in OA.

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To explore the synovial expression of mucin 1 (MUC1) and its role in rheumatoid arthritis (RA), as well as the possible downstream mechanisms.

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This study aimed to investigate the role and mechanism of meniscal cell lysate (MCL) in fibroblast-like synoviocytes (FLSs) and osteoarthritis (OA).

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Mendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies.

Rheumatoid arthritis (RA) is an autoimmune disease that involves T and B cells and their reciprocal immune interactions with proinflammatory cytokines. T cells, an essential part of the immune system, play an important role in RA. T helper 1 (Th1) cells induce interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2, which are proinflammatory cytokines, leading to cartilage destruction and bone erosion. Th2 cells primarily secrete IL-4, IL-5, and IL-13, which exert anti-inflammatory and anti-osteoclastogenic effects in inflammatory arthritis models. IL-22 secreted by Th17 cells promotes the proliferation of synovial fibroblasts through induction of the chemokine C-C chemokine ligand 2 (CCL2). T follicular helper (Tfh) cells produce IL-21, which is key for B cell stimulation by the C-X-C chemokine receptor 5 (CXCR5) and coexpression with programmed cell death-1 (PD-1) and/or inducible T cell costimulator (ICOS). PD-1 inhibits T cell proliferation and cytokine production. In addition, there are many immunomodulatory agents that promote or inhibit the immunomodulatory role of T helper cells in RA to alleviate disease progression. These findings help to elucidate the aetiology and treatment of RA and point us toward the next steps.

Cite this article: Bone Joint Res 2022;11(7):426–438.

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Deciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations.

Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by joint pain and physical disability. Aberrant subchondral bone induces pathological changes and is a major source of pain in OA. In the subchondral bone, which is highly innervated, nerves have dual roles in pain sensation and bone homeostasis regulation. The interaction between peripheral nerves and target cells in the subchondral bone, and the interplay between the sensory and sympathetic nervous systems, allow peripheral nerves to regulate subchondral bone homeostasis. Alterations in peripheral innervation and local transmitters are closely related to changes in nociception and subchondral bone homeostasis, and affect the progression of OA. Recent literature has substantially expanded our understanding of the physiological and pathological distribution and function of specific subtypes of neurones in bone. This review summarizes the types and distribution of nerves detected in the tibial subchondral bone, their cellular and molecular interactions with bone cells that regulate subchondral bone homeostasis, and their role in OA pain. A comprehensive understanding and further investigation of the functions of peripheral innervation in the subchondral bone will help to develop novel therapeutic approaches to effectively prevent OA, and alleviate OA pain.

Cite this article: Bone Joint Res 2022;11(7):439–452.

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Rheumatoid arthritis (RA) is a systematic autoimmune disorder, characterized by synovial inflammation, bone and cartilage destruction, and disease involvement in multiple organs. Although numerous drugs are employed in RA treatment, some respond little and suffer from severe side effects. This study aimed to screen the candidate therapeutic targets and promising drugs in a novel method.

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Circular RNA (circRNA) S-phase cyclin A-associated protein in the endoplasmic reticulum (ER) (circSCAPER, ID: hsa_circ_0104595) has been found to be highly expressed in osteoarthritis (OA) patients and has been associated with the severity of OA. Hence, the role and mechanisms underlying circSCAPER in OA were investigated in this study.