Aims

Mesenchymal stem cells (MSCs) are usually cultured in a normoxic atmosphere (21%) in vitro, while the oxygen concentrations in human tissues and organs are 1% to 10% when the cells are transplanted in vivo. However, the impact of hypoxia on MSCs has not been deeply studied, especially its translational application.

Aims

Osteoarthritis (OA) is a common degenerative disease. PA28γ is a member of the 11S proteasome activator and is involved in the regulation of several important cellular processes, including cell proliferation, apoptosis, and inflammation. This study aimed to explore the role of PA28γ in the occurrence and development of OA and its potential mechanism.

Introduction. Osteoarthritis (OA) causes pain, stiffness, and loss of function due to degenerative changes in joint cartilage and bone. In some forms of OA, exercise can alleviate symptoms by improving joint mobility and stability. However, excessive training after joint injury may have negative consequences for OA development. Sensory nerve fibers in joints release neuropeptides like alpha-calcitonin gene-related peptide (alpha-CGRP), potentially affecting OA progression. This study investigates the role of alpha-CGRP in OA pathogenesis under different exercise regimen in mice. Method. OA was induced in C57Bl/6J WT mice and alpha-CGRP KO mice via surgical destabilization of the medial meniscus (DMM) at 12 weeks of age (N=6). Treadmill exercise began 2 weeks post-surgery and was performed for 30 minutes, 5 days a week, for 2 or 6 weeks at intense (16 m/min, 15° incline) or moderate (10 m/min, 5° incline) levels. Histomorphometric assessment of cartilage degradation (OARSI scoring), serum cytokine analysis, immunohistochemistry, and nanoCT analysis were conducted. Result. OARSI scoring confirmed OA induction 4 weeks post-DMM surgery, with forced exercise exacerbating cartilage degradation regardless of intensity. No significant genotype-dependent differences were observed. Serum analysis revealed elevated cytokine levels associated with OA and inflammation in KO mice compared to WT mice 4 and 8 weeks post-surgery (VEGF-A, MCP-1, CXCL10, RANTES, MIP1-alpha, MIP1-beta, and RANKL). The observed effects were often exacerbated by intense exercise but rarely by DMM surgery. NanoCT analysis demonstrated increased sclerotic bone changes after 6 weeks of forced exercise in KO mice compared to WT mice. Conclusion. Our results suggest an OA promoting effect of exercise in early disease stages of posttraumatic OA. Intense exercise induced inflammatory processes correlated to increased cytokine levels in the serum that might exacerbate OA pathogenesis in later stages. The neuropeptide alpha-CGRP might play a role in protecting against these adverse effects

Aims

This study aimed to define the histopathology of degenerated humeral head cartilage and synovial inflammation of the glenohumeral joint in patients with omarthrosis (OmA) and cuff tear arthropathy (CTA). Additionally, the potential of immunohistochemical tissue biomarkers in reflecting the degeneration status of humeral head cartilage was evaluated.

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Adenosine, lidocaine, and Mg²⁺ (ALM) therapy exerts differential immuno-inflammatory responses in males and females early after anterior cruciate ligament (ACL) reconstruction (ACLR). Our aim was to investigate sex-specific effects of ALM therapy on joint tissue repair and recovery 28 days after surgery.

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Pigment epithelium-derived factor (PEDF) is known to induce several types of tissue regeneration by activating tissue-specific stem cells. Here, we investigated the therapeutic potential of PEDF 29-mer peptide in the damaged articular cartilage (AC) in rat osteoarthritis (OA).

Aims

Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear.

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cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect.

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Therapeutic agents that prevent chondrocyte loss, extracellular matrix (ECM) degradation, and osteoarthritis (OA) progression are required. The expression level of epidermal growth factor (EGF)-like repeats and discoidin I-like domains-containing protein 3 (EDIL3) in damaged human cartilage is significantly higher than in undamaged cartilage. However, the effect of EDIL3 on cartilage is still unknown.

Cartilage degeneration and loss are key events in the initiation and progression of osteoarthritis (OA). Changes to chondrocyte volume and morphology (in the form of cytoplasmic processes) and thus cell phenotype are implicated, as they lead to the production of a mechanically-weakened extracellular matrix. The chondrocyte cytoskeleton is intimately linked to cell volume and morphology and hence we have investigated alterations to levels and distribution of chondrocyte F-actin that occur during early OA. The femoral heads (FH) from hip joints (N=16) were obtained with ethical permission and patient consent following femoral neck fracture. Cartilage was assessed as grade 0 (non-degenerate) and grade 1 (superficial fibrillation) using OARSI criteria. In situ chondrocyte volume and F-actin distribution were assessed using the fluorescent indicators (5-chloromethyl fluorescein diacetate (CMFDA)) and phalloidin, and imaged and quantified by confocal microscopy, Imaris. TM. and ImageJ software. There were no differences between the volume or total F-actin levels of in situ chondrocytes within the superficial zone of grade 0 (n=164 cells) compared to grade 1 (n=145) cartilage (P>0.05). However, a more detailed analysis of phalloidin labelling was performed, which demonstrated significant increases in both intense punctuate (IP) or intense areas (IA) (P<0.0001; P=0.0175 respectively). A preliminary analysis of IP and IA F-actin labelling suggested that while the former did not appear to be associated with changes to chondrocyte morphology, most of the cytoplasmic processes were associated with the presence of IA at the starting point of the protrusion. These results demonstrate marked changes to F-actin distribution in chondrocytes in the very early stages of cartilage degeneration as occurs in OA. These subtle changes are probably an early indication of a change to the chondrocyte phenotype and thus worthy of further study as they may lead to deleterious alterations to matrix metabolism and ultimately cartilage weakening

Aims

Osteoarthritis (OA) is a prevalent joint disorder with inflammatory response and cartilage deterioration as its main features. Dihydrocaffeic acid (DHCA), a bioactive component extracted from natural plant (gynura bicolor), has demonstrated anti-inflammatory properties in various diseases. We aimed to explore the chondroprotective effect of DHCA on OA and its potential mechanism.

Senescent chondrocyte and subchondral osteoclast overburden aggravate inflammatory cytokine and pro-catabolic proteinase overproduction, accelerating extracellular matrix degradation and pain during osteoarthritis (OA). Fibronectin type III domain containing 5 (FNDC5) is found to promote tissue homeostasis and alleviate inflammation. This study aimed to characterize what role Fndc5 may play in chondrocyte aging and OA development. Serum and macroscopically healthy and osteoarthritic cartilage were biopsied from patients with knee OA who received total knee replacement. Murine chondrocytes were transfected with Fndc5 RNAi or cDNA. Mice overexpressing Fndc5 (Fndc5Tg) were operated to have destabilized medial meniscus mediated (DMM) joint injury as an experimental OA model. Cellular senescence was characterized using RT-PCR analysis of p16INK4A, p21CIP1, and p53 expression together with ß-galactosidase activity staining. Articular cartilage damage and synovitis were graded using OARSI scores. Osteophyte formation and mechanical allodynia were quantified using microCT imaging and von Frey filament, respectively. Osteoclast formation was examined using tartrate-resistant acid phosphatase staining. Senescent chondrocyte and subchondral osteoclast overburden together with decreased serum FNDC5 levels were present in human osteoarthritic cartilage. Fndc5 knockdown upregulated senescence program together with increased IL-6, MMP9 and Adamts5 expression, whereas Alcian blue-stained glycosaminoglycan production were inhibited. Forced Fndc5 expression repressed senescence, apoptosis and IL-6 expression, reversing proliferation and extracellular matrix production in inflamed chondrocytes. Fndc5Tg mice showed few OA signs, including articular cartilage erosion, synovitis, osteophyte formation, subchondral plate sclerosis and mechanical allodynia together with decreased IL-6 production and few senescent chondrocytes and subchondral osteoclast formation during DMM-induced joint injury. Mechanistically, Fndc5 reversed histone H3K27me3-mediated IL-6 transcription repression to reduce reactive oxygen species production. Fndc5 loss correlated with OA development. It was indispensable in chondrocyte growth and anabolism. This study sheds light onto the anti-ageing and anti-inflammatory actions of Fndc5 to chondrocytes; and highlights the chondroprotective function of Fndc5 to compromise OA

TGF-β/Smad2 signaling is considered to be one of the important pathways involved in osteoarthritis (OA) and protein phosphatase magnesium-dependent 1A (PPM1A) functions as an exclusive phosphatase of Smad2 and regulates TGF-β signaling, here, we investigated the functional role of PPM1A in OA pathogenesis. PPM1A expressions in both human OA cartilage and experimental OA mice chondrocytes were analyzed immunohistochemically. Besides, the mRNA and protein expression of PPM1A induced by IL-1β treatment were also detected by q-PCR and immunofluorescence in vitro. OA was induced in PPM1A knockout (KO) mice by destabilization of the medial meniscus (DMM), and histopathological examination was performed. OA was also induced in wild-type (WT) mice, which were then treated with an intra-articular injection of a selective PPM1A inhibitor for 8 weeks. PPM1A protein expressions were increased in both human OA cartilage and experimental OA mice chondrocytes. We also found that treatment with IL-1β in mouse primary chondrocytes significantly increased both mRNA and protein expression of PPM1A in vitro. Importantly, our data showed that PPM1A deletion could substantially protect against surgically induced OA. Concretely, the average OARSI score and quantification of BV/TV of subchondral bone in KO mice were significantly lower than that in WT mice 8 weeks after DMM surgery. Besides, TUNEL staining revealed a significant decrease in apoptotic chondrocytes in PPM1A-KO mice with DMM operation. With OA induction, the rates of chondrocytes positive for Mmp-13 and Adamts-5 in KO mice were also significantly lower than those in WT mice. Moreover, compared with WT mice, the phosphorylation of Smad2 in chondrocytes was increased in KO mice underwent DMM surgery. However, articular-injection with SD-208, a selective inhibitor of TGF-β/Smad2 signaling could significantly abolish the chondroprotective phenotypes in PPM1A-KO mice. Additionally, both cartilage degeneration and subchondral bone subchondral bone sclerosis in DMM model were blunted following intra-articular injection with BC-21, a small-molecule inhibitor for PPM1A. Our study demonstrated that PPM1A inhibition attenuates OA by regulating TGF-β/Smad2 signaling. Furthermore, PPM1A is a potential target for OA treatment and BC-21 may be employed as alternative therapeutic agents for the management of OA

Aims

Pellino1 (Peli1) has been reported to regulate various inflammatory diseases. This study aims to explore the role of Peli1 in the occurrence and development of osteoarthritis (OA), so as to find new targets for the treatment of OA.

Aims. To evaluate inducing osteoarthritis (OA) by surgical destabilization of the medial meniscus (DMM) in mice with and without a stereomicroscope. Methods. Based on sample size calculation, 70 male C57BL/6 mice were randomly assigned to three surgery groups: DMM aided by a stereomicroscope; DMM by naked eye; or sham surgery. The group information was blinded to researchers. Mice underwent static weightbearing, von Frey test, and gait analysis at two-week intervals from eight to 16 weeks after surgery. Histological grade of OA was determined with the Osteoarthritis Research Society International (OARSI) scoring system. Results. Surgical DMM with or without stereomicroscope led to decrease in the mean of weightbearing percentages (-20.64% vs -21.44%, p = 0.792) and paw withdrawal response thresholds (-21.35% vs -24.65%, p = 0.327) of the hind limbs. However, the coefficient of variation (CV) of weight-bearing percentages and paw withdrawal response thresholds in naked-eye group were significantly greater than that in the microscope group (19.82% vs 6.94%, p < 0.001; 21.85% vs 9.86%, p < 0.001). The gait analysis showed a similar pattern. Cartilage degeneration was observed in both DMM-surgery groups, evidenced by increased OARSI scores (summed score: 11.23 vs 11.43, p = 0.842), but the microscope group showed less variation in OARSI score than the naked-eye group (CV: 21.03% vs 32.44%; p = 0.032). Conclusion. Although surgical DMM aided by stereomicroscope is technically difficult, it produces a relatively more homogeneous OA model in terms of the discrete degree of pain behaviours and histopathological grading when compared with surgical DMM without stereomicroscope. Cite this article: Bone Joint Res 2022;11(8):518–527

Aims

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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Post-traumatic osteoarthritis (PTOA) is a subset of osteoarthritis (OA). The gut microbiome is shown to be involved in OA. However, the effect of exercise on gut microbiome in PTOA remains elusive.

Aims

Osteoarthritis (OA) is the most prevalent systemic musculoskeletal disorder, characterized by articular cartilage degeneration and subchondral bone (SCB) sclerosis. Here, we sought to examine the contribution of accelerated growth to OA development using a murine model of excessive longitudinal growth. Suppressor of cytokine signalling 2 (SOCS2) is a negative regulator of growth hormone (GH) signalling, thus mice deficient in SOCS2 (Socs2^-/-) display accelerated bone growth.

Introduction and Objective. Osteoarthristis (OA) has been associated with many genes and yet the genetic basis for this disease has never formally been established. Recent realization that epigenetic changes could be the underlying pathological mechanisms has helped to explain many complex multifactorial diseases with no clear genetic cause. We therefore asked whether epigenetics could also play a role in OA. We have previously shown that the DNA epigenetic modification, specifically the hydroxymethylation on cytosine (5hmC), undergoes a fivefold increase on OA-associated genes which are activated at OA onset. In this study, we further uncovered a set of 5hmC-mediated gene targets and their mechanistic link to OA progression. Materials and Methods. We surgically induced OA on 4 to 6 months old Tet1−/− mice (Tet1tm1.1Jae, the Jackson laboratory) and wild-type littermates by performing destabilization of the medial meniscus (DMM) surgery. Joints were collected for histological assessment through blinded grading with the OARSI scoring system. Human articular chondrocytes were harvested from OA cartilage samples obtained during total knee arthroplasty or from grossly normal cartilage pieces obtained during notchplasty or debridement from patients undergoing anterior cruciate ligament (ACL) reconstruction with no history of OA symptoms, under approved Human subjects Institutional Review Board protocols. Bioinformatic analyses of RNA-sequencing and CCGG sequencing (reduced representation 5hmC profiling) were performed to identify TET1 target genes associated with OA progression. Several measurements were used to assess the effect of TET1 ablation on the phenotype of mouse cartilage tissue and human chondrocytes including, histological evaluation, and quantitative bone assessment by micro-CT imaging and multiplex cytokine analyses in the serum of mice in vivo (mouse 39-plex assay) and in the supernatant of human chondrocyte cultures (human 62-plex assay). Results. We used a mouse model with surgically induced OA and found that OA onset was accompanied by a gain of ∼40,000 differentially hydroxymethylated sites prior the notable histological onset of the disease. We additionally revealed that these changes are mediated by the ten-eleven-translocation enzyme 1 (TET1), since Tet1−/− mice lost 98% of 5hmC sites upon OA induction. Remarkably, Tet1−/− mice were protected from OA development including degeneration of the cartilage surface and osteophyte formation. Silencing of TET1 expression in human OA chondrocytes reduced the expression in a set of genes, which may represent the pathological gene targets that exacerbate OA including MMP3 and MMP13 and several inflammatory cytokines. Therefore, our study reveals the unexpected beneficial role of TET1 inhibition in blocking OA progression. In fact, intra-articular injections of a dioxygenases’ inhibitor, 2 hydroxyglutarate, on mice after surgical induction of OA stalled disease progression. Furthermore, treatment of human OA chondrocytes with the same inhibitor also phenocopied TET1 loss, implicating a therapeutic potential of TET inhibition in OA patients. Conclusions. Collectively, our study not only demonstrate the role of TET1 in OA; the 5hmC-mediated gene targets acting on multiple OA pathways were identified and can be modulated as therapeutic intervention to treat OA

Introduction and Objective. Malunion after trauma can lead to coronal plane malalignment in the lower limb. The mechanical hypothesis suggests that this alters the load distribution in the knee joint and that that this increased load may predispose to compartmental arthritis. This is generally accepted in the orthopaedic community and serves as the basis guiding deformity correction after malunion as well as congenital or insidious onset malalignment. Much of the literature surrounding the contribution of lower limb alignment to arthritis comes from cohort studies of incident osteoarthritis. There has been a causation dilemma perpetuated in a number of studies - suggesting malalignment does not contribute to, but is instead a consequence of, compartmental arthritis. In this investigation the relationship between compartmental (medial or lateral) arthritis and coronal plane malalignment (varus or valgus) in patients with post traumatic unilateral limb deformity was examined. This represents a specific niche cohort of patients in which worsened compartmental knee arthritis after extra-articular injury must rationally be attributed to malalignment. Materials and Methods. The picture archiving system was searched to identify all 1160 long leg x ray films available at a major metropolitan trauma center over a 12-year period. Images were screened for inclusion and exclusion criteria, namely patients >10 years after traumatic long bone fracture without contralateral injury or arthroplasty to give 39 cases. Alignment was measured according to established surgical standards on long leg films by 3 independent reviewers, and arthritis scores Osteoarthritis Research Society International (OARSI) and Kellegren-Lawrence (KL) were recorded independently for each compartment of both knees. Malalignment was defined conservatively as mechanical axis deviation outside of 0–20 mm medial from centre of the knee, to give 27 patients. Comparison of mean compartmental arthritis score was performed for patients with varus and valgus malalignment, using Analysis of Variance and linear regression. Results. In knees with varus malalignment there was a greater mean arthritis score in the medial compartment compared to the contralateral knee, with OARSI scores 5.69 vs 3.86 (0.32, 3.35 95% CI; p<0.05) and KL 2.92 vs 1.92 (0.38, 1.62; p<0.005). There was a similar trend in valgus knees for the lateral compartment OARSI 2.98 vs 1.84 (CI −0.16, 2.42; p=0.1) and KL 1.76 vs 1.31 (CI −0.12, 1.01; p=0.17), but the evidence was not conclusive. OARSI arthritis score was significantly associated with absolute MAD (0.7/10mm MAD, p<0.0005) and Time (0.6/decade, p=0.01) in a linear regression model. Conclusions. Malalignment in the coronal plane is correlated with worsened arthritis scores in the medial compartment for varus deformity and may similarly result in worsened lateral compartment arthritis in valgus knees. These findings support the mechanical hypothesis that arthritis may be related to altered stress distribution at the knee, larger studies may provide further conclusive evidence