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Aims: Abnormal lipid metabolism is involved in the development of osteoarthritis (OA). Growth differentiation factor 11 (GDF11) is crucial in inhibiting the differentiation of bone marrow mesenchymal stem cells into adipocytes. However, whether GDF11 participates in the abnormal adipogenesis of chondrocytes in OA cartilage is still unclear. Methods: Six-week-old female mice were subjected to unilateral anterior crossbite (UAC) to induce OA in the temporomandibular joint (TMJ). Histochemical staining, immunohistochemical staining (IHC), and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. Primary condylar chondrocytes of rats were stimulated with fluid flow shear stress (FFSS) and collected for oil red staining, immunofluorescence staining, qRT-PCR, and immunoprecipitation analysis. Results: Abnormal adipogenesis, characterized by increased expression of CCAAT/enhancer-binding protein α (CEBPα), fatty acid binding protein 4 (FABP4), Perilipin1, Adiponectin (AdipoQ), and peroxisome proliferator-activated receptor γ (PPARγ), was enhanced in the degenerative cartilage of TMJ OA in UAC mice, accompanied by decreased expression of GDF11. After FFSS stimulation, there were fat droplets in the cytoplasm of cultured cells with increased expression of PPARγ, CEBPα, FABP4, Perilipin1, and AdipoQ and decreased expression of GDF11. Exogenous GDF11 inhibited increased lipid droplets and expression of AdipoQ, CEBPα, and FABP4 induced by FFSS stimulation. GDF11 did not affect the change in PPARγ expression under FFSS, but promoted its post-translational modification by small ubiquitin-related modifier (SUMOylation). Local injection of GDF11 alleviated TMJ OA-related cartilage degeneration and abnormal adipogenesis in UAC mice. Conclusion: Abnormal adipogenesis of chondrocytes and decreased GDF11 expression were observed in degenerative cartilage of TMJ OA. GDF11 supplementation effectively inhibits the adipogenesis of chondrocytes and thus alleviates TMJ condylar cartilage degeneration. GDF11 may inhibit the abnormal adipogenesis of chondrocytes by affecting the SUMOylation of PPARγ. Cite this article: Bone Joint Res 2022;11(7):453–464.

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Osteoarthritis (OA) is the most common joint disease primarily characterized by cartilage degeneration. Milk-derived extracellular vesicles (mEVs) were reported to inhibit catabolic and inflammatory processes in the cartilage of OA patients. However, the current therapies target the advanced symptoms of OA, and it is significant to develop a novel strategy to inhibit the processes driving OA pathology. In this study, we investigated the therapeutic potential of mEVs in alleviating OA in vivo. The results revealed that mEVs ameliorated cartilage degeneration by increasing hyaline cartilage thickness, decreasing histological Osteoarthritis Research Society International (OARSI) scores, enhancing matrix synthesis, and reducing the expression of cartilage destructive enzymes in the destabilization of medial meniscus (DMM) mice. In addition, the disturbed gut microbiota in DMM mice was partially improved upon treatment with mEVs. It was observed that the pro-inflammatory bacteria (Proteobacteria) were reduced and the potential beneficial bacteria (Firmicutes, Ruminococcaceae, Akkermansiaceae) were increased. mEVs could alleviate the progression of OA by restoring matrix homeostasis and reshaping the gut microbiota. These findings suggested that mEVs might be a potential therapeutic dietary supplement for the treatment of OA. [ABSTRACT FROM AUTHOR]

Background: T1ρ mapping has been proposed for the detection of early cartilage degeneration associated with chronic ankle instability (CAI). However, there are limited data surrounding the influence of ankle loading on T1ρ relaxation. Purpose: To evaluate T1ρ relaxation times of talar cartilage, as an indicator of early degenerative changes, associated with CAI and to investigate the influence of acute axial in situ loading on T1ρ values in CAI patients and healthy controls. Study Type: Prospective. Subjects: A total of 9 patients (age = 21.8 ± 2.5 years, male/female = 2/7) with chronic ankle instability and 18 healthy control subjects (age = 22.8 ± 3.6 years, male/female = 5/13). Field Strength: 3 T. Sequence: 3D gradient echo fast low‐angle shot (FLASH) sequence augmented with a variable spin‐lock preparation period. Assessment: Ankle T1ρ mapping was performed without and with axial loading of 500 N. The talar cartilage was segmented in five coronal slices covering the central talocrural joint. Median talar T1ρ values were separately calculated for the medial and lateral facets. Statistical Tests: Mann–Whitney U and Wilcoxon signed‐rank tests, significance level: P < 0.05. Results: For the combined cohorts, the statistical analysis yielded significantly lower T1ρ values with loading compared to the no‐load measurement for both the lateral (no load: [51.0 ± 4.0] msec, load: [49.5 ± 5.4] msec) as well as the medial compartment (no load: [50.0 ± 5.4] msec, load: [47.8 ± 6.8] msec). In the unloaded scans, the CAI patients showed significantly increased talar T1ρ values ([53.0 ± 7.4] mse) compared to the healthy control subjects ([48.8 ± 4.1] msec) in the medial compartment. Data Conclusion: Increased talar T1ρ relaxation times in CAI patients compared to healthy controls suggest that T1ρ relaxation is a sensitive biomarker for CAI‐induced early‐stage cartilage degeneration. However, the load‐induced T1ρ change did not prove to be a viable marker for the altered biomechanical properties of the hyaline talar cartilage. Level of Evidence: 2 Level of Efficacy: Stage 2. [ABSTRACT FROM AUTHOR]

Objective: To describe the protocol of a multi-vendor, multi-site quantitative MRI study for knee post-traumatic osteoarthritis (PTOA), and to present preliminary results of cartilage degeneration using MR T1ρ and T2 imaging 10 years after anterior cruciate ligament reconstruction (ACLR).Design: This study involves three sites and two MR platforms. The patients are from a nested cohort (termed as Onsite cohort) within the Multicenter Orthopaedic Outcomes Network (MOON) cohort 10 years after ACLR. Phantoms and controls were scanned for evaluating reproducibility. Cartilage was automatically segmented, and T1ρ and T2 were compared between operated, contralateral, and control knees.Results: Sixty-eight ACL-reconstructed patients and 20 healthy controls were included. In phantoms, the intra-site coefficients of variation (CVs) of repeated scans ranged 1.8-2.1% for T1ρ and 1.3-1.7% for T2. The inter-site CVs ranged 1.6-2.1% for T1ρ and 1.1-1.4% for T2. In human subjects, the intra-site scan/rescan CVs ranged 2.2-3.5% for T1ρ and 2.6-4.9% for T2 for the six major compartments. In patients, operated knees showed significantly higher T1ρ and T2 values mainly in medial femoral condyle, medial tibia and trochlear cartilage compared with contralateral knees, and showed significantly higer T1ρ and T2 values in all six compartments compared to healthy control knees. The patient contralateral knees showed higher T1ρ and T2 values mainly in the lateral femoral condyle, lateral tibia, trochlear, and patellar cartilage compared to healthy control knees.Conclusion: A platform and workflow with rigorous quality control has been established for a multi-vendor multi-site quantitative MRI study in evaluating PTOA 10 years after ACLR. Our preliminary report suggests significant cartilage matrix changes in both operated and contralateral knees compared with healthy control knees. [ABSTRACT FROM AUTHOR]

Cartilage metabolism dysregulation is a crucial driver in knee osteoarthritis (KOA). Modulating the homeostasis can mitigate the cartilage degeneration in KOA. Curcumenol, derived from traditional Chinese medicine Curcuma Longa L. , has demonstrated potential in enhancing chondrocyte proliferation and reducing apoptosis. However, the specific mechanism of Curcumenol in treating KOA remains unclear. This study aimed to demonstrate the molecular mechanism of Curcumenol in treating KOA based on the transcriptomics and metabolomics, and both in vivo and in vitro experimental validations. In this study, a destabilization medial meniscus (DMM)-induced KOA mouse model was established. And the mice were intraperitoneally injected with Curcumenol at 4 and 8 mg/kg concentrations. The effects of Curcumenol on KOA cartilage and subchondral was evaluated using micro-CT, histopathology, and immunohistochemistry (IHC). In vitro, OA chondrocytes were induced with 10 μg/mL lipopolysaccharide (LPS) and treated with Curcumenol to evaluate the proliferation, apoptosis, and extracellular matrix (ECM) metabolism through CCK8 assay, flow cytometry, and chondrocyte staining. Furthermore, transcriptomics and metabolomics were utilized to identify differentially expressed genes (DEGs) and metabolites. Finally, integrating multi-omics analysis, virtual molecular docking (VMD), and molecular dynamics simulation (MDS), IHC, immunofluorescence (IF), PCR, and Western blot (WB) validation were conducted to elucidate the mechanism by which Curcumenol ameliorates KOA cartilage degeneration. Curcumenol ameliorated cartilage destruction and subchondral bone loss in KOA mice, promoted cartilage repair, upregulated the expression of COL2 while downregulated MMP3, and improved ECM synthesis metabolism. Additionally, Curcumenol also alleviated the damage of LPS on the proliferation activity and suppressed apoptosis, promoted ECM synthesis. Transcriptomic analysis combined with weighted gene co-expression network analysis (WGCNA) identified a significant downregulation of 19 key genes in KOA. Metabolomic profiling showed that Curcumenol downregulates the expression of d-Alanyl-d-alanine, 17a-Estradiol, Glutathione, and Succinic acid, while upregulating Sterculic acid and Azelaic acid. The integrated multi-omics analysis suggested that Curcumenol targeted KDM6B to regulate downstream protein H3K27me3 expression, which inhibited methylation at the histone H3K27, consequently reducing Succinic acid levels and improving KOA cartilage metabolism homeostasis. Finally, both in vivo and in vitro findings indicated that Curcumenol upregulated KDM6B, suppressed H3K27me3 expression, and stimulated collagen II expression and ECM synthesis, thus maintaining cartilage metabolism homeostasis and alleviating KOA cartilage degeneration. Curcumenol promotes cartilage repair and ameliorates cartilage degeneration in KOA by upregulating KDM6B expression, thereby reducing H3K27 methylation and downregulating Succinic Acid, restoring metabolic stability and ECM synthesis. [ABSTRACT FROM AUTHOR]

Chondrocyte degeneration and extracellular matrix component loss are the primary causes of osteoarthritis (OA). OA can be treated by inhibiting chondrocyte degeneration and increasing extracellular matrix component secretion. Osteopontin (OPN), a multifunctional protein, has gained immense attention with regard to its involvement in OA. This study aimed to explore the therapeutic value and mechanism of action of OPN in OA treatment. Results of the histomorphological analysis revealed a worn-off OA cartilage tissue surface, cartilage matrix layer deterioration, and calcium salt deposition. Compared to that in normal chondrocytes, in OA chondrocytes, the OPN, CD44, and PI3K protein and mRNA expression was upregulated. Further, siOPN, rhOPN, and rhOPN plus LS-C179404 interfered with OA chondrocytes. As verified in mice, OPN directly inhibited the expression level of PI3K in OA chondrocytes by binding with CD44. Morphological analysis of the knee joints demonstrated that OPN effectively inhibited OA progression via the OPN/CD44/PI3K signal axis. In conclusion, OPN activates intracellular PI3K signaling molecules by binding to CD44 on the cell surface to cause downstream cascading effects, thereby delaying chondrocyte degeneration and reducing cartilage matrix component loss; therefore, OPN is a potential therapeutic agent for OA.

Introduction: Trochlear dysplasia is a commonly encountered lower extremity deformity in humans. However, the molecular mechanism of cartilage degeneration in trochlear dysplasia is unclear thus far. Objectives: The PI3K/AKT signaling pathway is known to be important for regulating the pathophysiology of cartilage degeneration. The aim of this study was to investigate the relationship of the PI3K/AKT signaling pathway with trochlear dysplasia cartilage degeneration. Methods: In total, 120 female Sprague-Dawley rats (4 weeks of age) were randomly separated into control and experimental groups. Distal femurs were isolated from the experimental group at 4, 8, and 12 weeks after surgery; they were isolated from the control group at the same time points. Micro-computed tomography and histological examination were performed to investigate trochlear anatomy and changes in trochlear cartilage. Subsequently, expression patterns of PI3K/AKT, TGFβ1, and ADAMTS-4 in cartilage were investigated by immunohistochemistry and quantitative polymerase chain reaction. Results: In the experimental group, the trochlear dysplasia model was successfully established at 8 weeks after surgery. Moreover, cartilage degeneration was observed beginning at 8 weeks after surgery, with higher protein and mRNA expression levels of PI3K/AKT, TGFβ1, and ADAMTS-4, relative to the control group. Conclusion: Patellar instability might lead to trochlear dysplasia in growing rats. Moreover, trochlear dysplasia may cause patellofemoral osteoarthritis; cartilage degeneration in trochlear dysplasia might be associated with activation of the PI3K/AKT signaling pathway. These results provide insights regarding the high incidence of osteoarthritis in patients with trochlear dysplasia. However, more research is needed to clarify the underlying mechanisms.

Osteoarthritis (OA) causes joint pain, stiffness, and dysfunction in middle-aged and older adults; however, its pathogenesis remains unclear. Circular RNAs (circRNAs) are differentially expressed in patients with OA and participate in a multigene, multitarget regulatory network. CircRNAs are involved in the development of OA through inflammatory responses, including proliferation, apoptosis, autophagy, differentiation, oxidative stress, and mechanical stress. Most circRNAs are used as intracellular miRNA sponges in chondrocytes, endplate chondrocytes, mesenchymal stem cells, synoviocytes, and macrophages to promote the progression of OA. However, a small portion of circRNAs participates in the pathogenesis of OA by intracellular mechanisms, such as protein binding, methylation, or intercellular exosome pathways. In this sense, circRNAs might serve as potential novel biomarkers and therapeutic targets for OA.

Background: Osteoarthritis (OA) is a common joint disorder worldwide which causes great health and economic burden. However, there remains an unmet goal to develop an effective therapeutic method to prevent or delay OA. Chondrocytes, as the major cells involved in OA progression, may serve as a promising therapeutic target. Results: A kind of carbon dots (CDs) with excellent biocompatibility was fabricated from folic acid via hydrothermal method and could effectively attenuate osteoarthritis. It was demonstrated that CDs treatment could rescue IL1β-induced proinflammatory responses, oxidative stress, cartilage degeneration and extracellular matrix degradation. Moreover, CDs reprogrammed lipopolysaccharide (LPS)-induced macrophage inflammation and polarization. Conditioned medium (CM) from CDs-treated macrophages could attenuate IL1β-induced chondrocyte injury. Also, CM from CDs-treated chondrocytes had immunoregulatory functions on macrophages. Mechanistically, CDs inhibited the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in IL1β-stimulated chondrocytes. In vivo, anterior cruciate ligament transection (ACLT) mice model was adopted and it was indicated that intra-articular injection of CDs effectively delays OA pathogenesis. Conclusions: Taken together, these findings indicated CDs could mediate OA via promoting cartilage repair and immunomodulating macrophages within local microenvironment, which may provide evidences for utilizing CDs as a novel nanomaterial for OA treatment. [ABSTRACT FROM AUTHOR]

Dampened peripheral clocks have been linked to osteoarthritis (OA), yet it is unclear whether drugging the clock can ameliorate OA. Given that RORs and REV‐ERBs mediate respectively, positive and negative transcriptional feedback of the master clock gene BMAL1, we investigate whether RORs agonist Nobiletin (NOB) and SR1078, and REV‐ERBs antagonist SR8278 can enhance BMAL1 expression and attenuate cartilage degeneration. NOB and SR8278 promoted BMAL1 expression and elicited mitigating effects against IL‐1β‐induced degeneration of cartilage explants, as evidenced by increased cellular density and collagen synthesis along with alleviated catabolism and collagen denaturation. Despite promoted BMAL1 expression, SR1078 concomitantly suppressed chondrocyte anabolism and catabolism. Consistent with these findings, NOB and SR8278 treatment, but not SR1078, effectively attenuated structural destruction of articular cartilage in surgery‐induced OA mouse models. Notably, the beneficial effects of NOB and SR8278 were evidently observed in IL‐1β‐induced degeneration of human cartilage explants and immortalized human chondrocytes. Moreover, BMAL1 knockdown assays indicated that NOB and SR8278 enhanced clock function and concordantly rendered protection against altered anabolism and catabolism in a BMAL1‐dependent regime. Collectively, our study suggests that targeting RORs and REV‐ERBs to promote the dampened peripheral clocks could be a route taken to apply chronotherapy within the context of OA. [ABSTRACT FROM AUTHOR]

Objective: Osteoarthritis (OA) causes gradual cellular alterations, structural anomalies and joint dysfunction. Progressive decline of chondrocyte function plays a vital role on OA pathogenesis. Although protein phosphorylation controls cartilage metabolism, its regulation mechanism in OA remains unclear. Thus, proteomic methods were used to investigate phosphorylation changes in preserved and OA articular cartilage samples, and to explore the intervention targets of phosphorylated kinase.Methods: Preserved (control) and lesioned (OA) cartilage samples from OA cases were assessed by phosphoproteomics. Immobilized metal affinity chromatography was performed for phosphopeptide enrichment. Quantitated phosphosites were comparatively assessed in the cartilage sample pair. Kinase-substrate enrichment analyses were carried out for identifying OA-related kinases. BRAF expression in cartilage tissues was assessed by immunohistochemical staining. The effects of BRAF inhibitor on cartilage degeneration were examined in mouse chondrocytes and OA mouse model.Results: High-sensitivity mass spectrometry-based proteomics revealed 7,471 peptides and 4,375 phosphorylated peptides differing between preserved and lesioned cartilage samples, which represented the significant alteration of kinase hubs and transduction pathways. Phosphoproteomics identified BRAF may be involved in developing OA. BRAF regulated the downstream ERK signaling pathway. In addition, BRAF was upregulated in human OA cartilage as shown by immunohistochemistry. Remarkably, BRAF inhibition alleviated cartilage degradation in a mouse model of OA through its downstream of ERK pathway activation.Conclusions: Jointly, these findings provide an overview of phosphoproteomic alterations occurring during cartilage degeneration, identifying the BRAF-ERK1/2 Axis signaling as a potential signaling pathway involved in OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is driven by chronic low-grade inflammation and subsequent cartilage degradation. OA is the most prevalent degenerative joint disease worldwide, and its treatment remains a challenge. The aim of this study was to explore the potential effects and mechanism underlying the anti-OA properties of ginkgolide C (GC). Protective effects of GC on hydrogen peroxide (H2O2)-treated rat chondrocytes were evaluated using ELISA, qPCR, western blot analysis, flow cytometry, ROS detection and immunofluorescence in vitro. Ameliorating effects of GC on cartilage degeneration in rats were evaluated through behavioral assays, microcomputed tomography, histopathological analysis, western blot analysis and ELISA in vivo. In vitro, GC treatment inhibited the release of pro-apoptotic factors induced by H2O2 and promoted the release of the anti-apoptotic proteins. In addition, GC decreased the expression of matrix metalloproteinase (MMP3 and MMP13), thrombospondin motifs 4 (ADAMTS4), and inflammatory mediators inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and SOX9 thereby inhibiting extracellular matrix (ECM) degradation. Mechanistically, GC exerts its anti-apoptotic and anti-inflammatory effects by upregulating the oxidative stress signaling Nrf2/HO-1 pathway and preventing p65 from binding to DNA. Similarly, In a rat model with post-traumatic OA (PTOA) induced by anterior cruciate ligament transection (ACLT), GC inhibited joint pain, cartilage destruction, and abnormal bone remodeling of subchondral bone. GC inhibited H2O2-induced chondrocyte apoptosis through Nrf2/HO-1 and NF-κB axis, exerted anti-inflammatory effects, and inhibited cartilage degeneration in rat OA. Our findings advanced the concept that GC may contribute to cartilage metabolism through anti-inflammatory and anti-apoptotic effects, and the identified GC is a potential therapeutic agent for the treatment of OA. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression of mTOR in TMJOA condylar cartilage of SD rats. Methods The model of TMJOA in SD rats was established by unilateral mastication，and the corresponding shamoperation group was established. TMJOA model was established by unilateral mastication.The right condyle was taken 2, 4 and 8 weeks after modeling. HE staining and safranine o-solid green staining were used for pathological examination； The expressions of Sox9 and mTOR were detected by immunohistochemical staining. Results　Hematoxylin-eosin (HE) staining and saffron o-green staining showed that the condylar cartilage of the control group had clear structure，smooth and intact surface，and the proteoglycans were evenly distributed. In the experimental group (TMD group)，obvious degenerative changes of condylar cartilage were observed over time (P < 0.05)，and the lesions were the highest in 4 W. Immunohistochemical staining showed that the expression level of Sox9 in the condylar cartilage of the experimental group decreased successively at 2 W (P < 0.01)，4 W (P < 0.05) and 8 W (P < 0.05)，and were lower than that of the control group. The expression level of mTOR decreased at 2 W (P < 0.05) and 4 W (P < 0.001)，but increased relatively at 8 W (P < 0.05) . Conclusion　With the progress of inflammation，mTOR in TMJOA condylar cartilage of SD rats shows a trend of early down-regulation and late upregulation, which plays a key role in transforming protective autophagy into destructive apoptosis. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (KOA) is mainly based on the degeneration of articular cartilage, which is aggravated by local load changes and adverse biomechanical structure changes, followed by articular cartilage deformation, bone hyperplasia and necrosis, secondary inflammatory stimulation, and immunological factors lead to chronic joint disease with aggravated articular dysfunction. Acupuncture is effective in the treatment of KOA, but its mechanism is not clear. The paper summarizes the relevant literature research on acupuncture and moxibustion in the treatment of KOA, and finds that the main mechanism is related to inhibiting chondrocyte apoptosis, adjusting biomechanics, regulating molecular biological response, improving local microcirculation, anti-inflammatory, and analgesic. The purpose of the paper is to provide ideas for clinical diagnosis and treatment and to further develop and popularize acupuncture treatment of KOA. [ABSTRACT FROM AUTHOR]

Background: The development of osteoarthritis after anterior cruciate ligament (ACL) reconstruction (ACLR) is an important issue. However, the appropriate rehabilitation protocol to prevent cartilage degeneration due to postoperative osteoarthritis is unclear. Purpose: To examine the effects of joint immobilization and treadmill exercise on articular cartilage after ACLR. Study Design: Controlled laboratory study. Methods: A total of 55 rats received unilateral knee ACL transection and reconstruction surgery using tail tendon autografts. After surgery, rats were reared without intervention, with joint immobilization, or with daily treadmill exercise (12 m/minute, 60 minutes/day, 6 days/week). Treadmill exercise was initiated at 3 or 14 days postoperatively. After 2 weeks of immobilization, the fixation device was removed from some of the immobilized rats, and the knee was allowed to move freely for 2 weeks. Untreated, age-matched rats (n = 8) were used as controls. At 2 or 4 weeks after starting the experiment, cartilage degeneration in the medial tibial plateau was histologically assessed using a modified Mankin score, cartilage thickness, chondrocyte density, and immunohistochemistry for cyclooxygenase-2 (COX-2) in the anterior, middle, and posterior regions. Results: After ACLR, cartilage degeneration in the anterior region characterized by increased Mankin score, accompanied with increased COX-2 expression, was detected. Joint immobilization after ACLR facilitated cartilage degeneration, which is detected by histological changes such as reductions in cartilage thickness, chondrocyte density, and high Mankin scores. Enhanced COX-2 expression in all degenerated cartilage regions was also detected. It was found that 2 weeks of remobilization could not restore cartilage degeneration induced by 2 weeks of immobilization after ACLR. Treadmill exercise after ACLR did not affect most articular cartilage parameters, regardless of the timing of exercise. Conclusion: Our results indicated that (1) immobilization after ACLR accelerates cartilage degeneration, even when applied only for 2 weeks, and (2) mild exercise during early phases after ACLR does not facilitate cartilage degeneration. Clinical Relevance: To reduce cartilage degeneration, periods of joint immobilization after ACLR should be minimized. Mild exercise during the early phases after ACLR will not negatively affect articular cartilage. [ABSTRACT FROM AUTHOR]

Specific knee kinematic alterations have been theorized to correlate with the progression of cartilage degeneration, and therefore, post-traumatic osteoarthritis in patients with anterior cruciate ligament reconstruction (ACLR). However, how specific knee kinematic alterations contribute to knee joint cartilage degenerations remains to be unclear. To solve this problem, we hypothesized that there are specific cartilage-degenerating kinematic gait patterns that could be supported by the specific areas of cartilage lesions in ACLR knees. Thirty patients with unilateral ACLR knees and 30 healthy controls were recruited for the study. The kinematic differences between the ACLR knees and the healthy control knees during the stance phase were calculated to identify the kinematic patterns. Cartilage lesion distribution characteristics were acquired for patients with ACLR knees to validate the kinematic patterns using magnetic resonance images. Two kinematic patterns were modeled, i.e., sagittal (increased flexion angle and posterior tibial translation) and coronal (increased lateral tibial translation and abduction angle) kinematic patterns. For the sagittal pattern, the cartilage lesion distributions showed that there were more cartilage lesions (CLs) in the superoposterior regions than the posterior regions in the femoral condyles (p = 0.001), and more CLs in the posterior regions than the middle regions in the tibial plateau (p < 0.001). For the coronal pattern, the cartilage lesion distributions showed that there were more CLs in the lateral compartments near the tibial spine than the medial compartments near the tibial spine (tibial sides, p = 0.005 and femoral sides, p = 0.290). To conclude, the cartilage degeneration distribution evidence largely supports that the two kinematic patterns may contribute to cartilage degeneration in ACLR knees. These findings may provide a potential strategy of delaying early cartilage degeneration in ACLR knees by using motion (kinematic) pattern modification or training. However, investigations should be conducted on the actual effects of this potential strategy. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic degenerative disease caused by aging, obesity, trauma, heredity and other factors, which is a difficult disease faced by orthopedic doctors in clinic, and brings a heavy burden to patients and families. Resveratrol is a natural compound with anti-inflammatory and antioxidant effects. It can affect cartilage aging, cartilage matrix metabolism, and cartilage injury in participate in the process of OA, which might be related to NF-KB, TLR4 and ERK signaling pathway. This paper reviews the research progress of resveratrol in the process of OA and its possible mechanism, so as to facilitate relevant research. [ABSTRACT FROM AUTHOR]

The primary objective of this study is to report the initial efficacy data observed with the use of cryopreserved human umbilical tissue allografts for supplementation in patients with symptomatic degeneration of load-bearing articular cartilage in the knee joint. Our primary endpoints were pain, stiffness, and functional recovery scores. In this ongoing study, 55 participants (age 56–93 years) received a single Wharton's jelly tissue allograft application. The study dose consisted of 150 mg of Wharton's jelly allograft suspended in approximately 2 mL of sterile sodium chloride 0.9% solution (normal saline). Each study knee application was performed under ultrasound guidance in a physician's office. The research methodology consisted of Numeric Pain Rating Scale (NPRS) scores and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subsection scores including pain, stiffness, and physical function. Study enrollment consisted of 55 patients followed for a post-application duration of 90 days. No adverse events or adverse reactions were reported. The results demonstrated statistically significant improvements of NPRS and WOMAC in initial versus 90-day examination. The data represent Wharton's jelly tissue allograft applications are safe, non-surgical, and efficacious for patients with symptomatic osteoarthritis of the knee. [ABSTRACT FROM AUTHOR]

Background: Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) is an advanced imaging technique that is purported to quantify cartilage damage in acute and chronic joint disease and predict periacetabular osteotomy (PAO) outcomes. There is a paucity of literature relating dGEMRIC values to arthroscopic findings before PAO and postoperative outcomes after PAO. Purpose: To assess the utility and validity of dGEMRIC as a preoperative and prognostic assessment tool of cartilage status and integrity as it relates to intraoperative findings and midterm postoperative outcomes after PAO. Study Design: Case series; Level of evidence, 4. Methods: We analyzed a cohort of 58 patients (70 hips) with a median age of 30.1 years (range, 15-50) with hip dysplasia who underwent hip arthroscopy, followed by a PAO with preoperative dGEMRIC. The primary outcome measures were intraoperative assessment and correlation with cartilage damage (presence of cartilage flap, Outerbridge grade of the acetabulum and femoral head). Secondary outcome measures were postoperative patient-reported outcome (PRO) scores, including the International Hip Outcome Tool and Non-arthritic Hip Score. Correlation analyses were performed to determine the relationship between dGEMRIC values and (1) PROs and (2) intraoperative assessment of cartilage damage. Results: There were significant negative linear relationships between dGEMRIC values and the primary outcome measures: presence of a cartilage flap (coronal, P =.004; sagittal, P <.001), Outerbridge grade of acetabular articular cartilage lesion (coronal, P =.002; sagittal, P =.003), and Outerbridge grade of femoral head articular cartilage lesion (coronal, P =.001; sagittal, P <.001). Despite significant overall improvement in all patients, there was no significant correlation between preoperative dGEMRIC values and improvement in PROs from presurgery to latest postoperative follow-up (median, 2.2 years; range, 1.0-5.0 years). Conclusion: Although dGEMRIC values (sagittal and coronal) were significant predictors of the intraoperative presence of cartilage flaps and overall cartilage integrity, they were not associated with midterm outcomes after PAO. [ABSTRACT FROM AUTHOR]

Yu Jin,&ast; Zhenxia Li,&ast; Yanran Wu, Hairui Li, Zhen Liu, Lu Liu, Ningjuan Ouyang, Ting Zhou, Bing Fang, Lunguo Xia Department of Orthodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lunguo Xia; Bing FangDepartment of Orthodontics, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 500 Quxi Road, Shanghai, 200011, People’s Republic of ChinaTel +86 21 23271699Email xialunguo@hotmail.com; fangbing@sjtu.edu.cnPurpose: Osteoarthritis (OA) is a common disease for human beings, characterized by severe inflammation, cartilage degradation, and subchondral bone destruction. However, current therapies are limited to relieving pain or joint replacement and no effective treatment methods have been discovered to improve degenerative changes. Currently, a variety of evidences have indicated that aberrant mechanical stimuli is closely associated with articular joint pathogenesis, while the detailed underlying mechanism remains unelucidated. In the present study, we determined to investigate the impact of excessive high fluid shear stress (FSS) on primary chondrocytes and the underlying epigenetic mechanisms.Materials and Methods: Phalloidin staining and EdU staining were used to evaluate cell morphology and viability. The mRNA level and protein level of genes were determined by qPCR, Western blot assay, and immunofluorescence staining. Mechanistic investigation was performed through RNA-sequencing and CUT&Tag sequencing. In vivo, we adopted unilateral anterior crossbites (UAC) mice model to investigate the expression of H3K4me3 and ZBTB20 in aberrant force-related cartilage pathogenesis.Results: The results demonstrated that FSS greatly disrupts cell morphology and significantly decreased chondrocyte viability. Aberrant FSS induces remarkable inflammatory mediators production, leading to cartilage degeneration and degradation. In depth mechanistic study showed that FSS results in more than 10-fold upregulation of H3K4me3, and the modulatory effect of H3K4me3 on cartilage was obtained by directly targeting ZBTB20. Furthermore, Wnt signaling was strongly activated in high FSS-induced OA pathogenesis, and the negative impact of ZBTB20 on chondrocytes was also achieved through activating Wnt signaling pathway. Moreover, pharmacological inhibition of H3K4me3 activation by MM-102 or treatment with Wnt pathway inhibitor LF3 could effectively alleviate the destructive effect of FSS on chondrocytes. In vivo UAC mice model validated the dysregulation of H3K4me3 and ZBTB20 in aberrant force-induced cartilage pathogenesis.Conclusion: Through the combination of in vitro FSS model and in vivo UAC model, KMT2B-H3K4me3-ZBTB20 axis was first identified in aberrant FSS-induced cartilage pathogenesis, which may provide evidences for epigenetic-based therapy in the future.Keywords: osteoarthritis, fluid shear stress, H3K4me3, epigenetic, cartilage degeneration

Osteoarthritis (OA) is a principal cause of aches and disability worldwide. It is characterized by the inflammation of the bone leading to degeneration and loss of cartilage function. Factors, including diet, age, and obesity, impact and/or lead to osteoarthritis. In the past few years, OA has received considerable scholarly attention owing to its increasing prevalence, resulting in a cumbersome burden. At present, most of the interventions only relieve short-term symptoms, and some treatments and drugs can aggravate the disease in the long run. There is a pressing need to address the safety problems due to osteoarthritis. A disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats (ADAMTS) metalloproteinase is a kind of secretory zinc endopeptidase, comprising 19 kinds of zinc endopeptidases. ADAMTS has been implicated in several human diseases, including OA. For example, aggrecanases, ADAMTS-4 and ADAMTS-5, participate in the cleavage of aggrecan in the extracellular matrix (ECM); ADAMTS-7 and ADAMTS-12 participate in the fission of Cartilage Oligomeric Matrix Protein (COMP) into COMP lyase, and ADAMTS-2, ADAMTS-3, and ADAMTS-14 promote the formation of collagen fibers. In this article, we principally review the role of ADAMTS metalloproteinases in osteoarthritis. From three different dimensions, we explain how ADAMTS participates in all the following aspects of osteoarthritis: ECM, cartilage degeneration, and synovial inflammation. Thus, ADAMTS may be a potential therapeutic target in osteoarthritis, and this article may render a theoretical basis for the study of new therapeutic methods for osteoarthritis. [ABSTRACT FROM AUTHOR]

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Arthropathy or joint disease leads to significant pain and disability irrespective of etiology. Clinical and experimental evidence point to the presence of considerable links between arthropathy and iron overload. Previous work has suggested that iron accumulation in the joints is often associated with increased oxidative stress, disrupted matrix metabolism, and cartilage degeneration. However, key issues regarding the role of iron overload in the pathogenesis of arthropathy remain ambiguous. For example, significant gaps in our knowledge of the primary cellular targets of iron overload‐induced damage and the exact molecular mechanism through which disrupted iron homeostasis leads to joint damage still exist. The exact signaling pathway that links iron metabolism and cellular damage in arthropathy also remains largely unmapped. In this review, we focus on the relationship between iron overload and arthropathy with special emphasis on the adversarial relationship between iron that accumulates in the joints over time and cartilage homeostasis. A better understanding of the mechanisms and pathways underlying iron‐induced cartilage degeneration may help in defining new prognostic markers and therapeutic targets in arthropathy. [ABSTRACT FROM AUTHOR]

Objective: The association between the spatially distributed level of active TGFβ1 in human subchondral bone, and the characteristic structural and cellular parameters of human knee OA, was assessed.Design: Paired subchondral bone samples from 35 OA arthroplasty patients, (15 men and 20 women, aged 69 ± 9 years) were obtained from beneath macroscopically present (CA+) or denuded cartilage (CA-) to determine the concentration of active TGFβ1 (ELISA) and its relationship to bone quality (synchrotron micro-CT), cellularity, and vascularization (histology).Results: Bone samples beneath (CA-) regions had significantly increased concentrations of active TGFβ1 protein (mean difference: 26.4; 95% CI: [3.2, 49.7]), when compared to bone in CA + regions. Trabecular Bone below (CA-) regions had increased bone volume (median difference: 4.3; 96.49% CI: [-1.7, 17.8]), increased trabecular number (1.5 [0.006, 2.6], decreased trabecular separation (-0.05 [-0.1,-0.005]), and increased bone mineral density (394.5 [65.7, 723.3]) comparing to (CA+) regions. Further, (CA-) bone regions showed increased osteocyte density (0.012 [0.006, 0.018]), with larger osteocyte lacunae (39.8 [7.8, 71.7]) that were less spherical (-0.02 [-0.04, -0.003]), and increased bone matrix vascularity (12.4 [0.3, 24.5]) compared to (CA+). In addition, increased levels of active TGFβ1 related to increased bone volume (0.04 [-0.11, 0.9]), while increased OARSI grade associated with lacunar volume (-44.1 [-71.1, -17.2]), and orientation (2.7 [0.8, 4.6]).Conclusion: Increased concentration of active TGFβ1 in the subchondral bone of human knee OA associates spatially with impaired bone quality and disease severity, suggesting that TGFβ1 is a potential therapeutic target to prevent or reduce human OA disease progression. [ABSTRACT FROM AUTHOR]

Meckel's cartilage, a cartilage rod present in the mandible during developmental stages, shows a unique developmental fate: while the anterior and posterior portions undergo ossification, the middle part degenerates. Previously, it was shown that a stiff environment promoted cartilage degeneration in the middle region, while a soft environment enhanced the mineralization in the anterior region of Meckel's cartilage. This study aims to elucidate the spatio‐temporal changes in the mechanosensing properties of Meckel's cartilage during its early developmental stages and clarify the mechanotransduction‐related mechanisms involved in its degeneration. The results show that the expression of Hippo pathway effector yes‐associated protein (YAP) is only detectable in the Meckel's cartilage onward embryonic day (E)14.5, indicating that mechanosensing is dependent on the tissue developmental stage. Consistently, microenvironmental stiffness‐induced cartilage degeneration can only be induced in cartilages onward E14.5, but not in those at earlier developmental stages. Expressions of integrin‐β1 and cartilage matrix‐degrading enzymes, matrix metalloproteinase 1 (MMP‐1) and MMP‐13, are significantly enhanced in the degeneration area. Moreover, verteporfin (YAP inhibitor) and integrin‐β1 antibody block the substrate stiffness‐induced degeneration by suppressing the expressions of MMP‐1 and MMP‐13. These data provide new insights into the interplay between biochemical and mechanical cues determining the fate of Meckel's cartilage. [ABSTRACT FROM AUTHOR]

In this exploratory study, gait analysis and quantitative MRI (QMRI) were used to assess biomechanical differences in patients that present with cyclops lesions at 12 months after ACL-reconstruction (ACLR). Thirty ACLR patients without and 10 ACLR patients with cyclops lesions underwent 3T MR T1ρ mapping of the reconstructed knee joint prior to ACLR and at 12 months after ACLR, as well as a gait assessment during a fixed walking speed at 12 months after ACLR. Both external sagittal and frontal plane knee joint moments and joint moment impulses were calculated and assessed throughout the stance phase of gait. ACLR patients with cyclops lesions demonstrated a significantly greater (34% larger, p = 0.03) first peak knee flexion moment (KFM) and KFM impulse (42% larger, p = 0.05), compared to those without cyclops lesions, which may suggest an increased load during the loading response phase of gait. There were no differences (p > 0.05) in knee extension or adduction joint moments or moment impulses. ACLR patients with cyclops lesions demonstrated a significantly increased change in T1ρ (ΔT1ρ  = 4.7 ms, p = 0.03), over 12 months, within the central medial tibia. The results of the study suggest that ACLR patients with cyclops lesions demonstrate altered sagittal plane loading patterns which may be related to an increased rate of medial tibiofemoral cartilage degeneration at 12 months after ACLR. The first peak external KFM may be an important target for intervention programs in ACLR patients with cyclops lesions in order to possibly slow the onset or progression of medial tibiofemoral cartilage degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2275-2281, 2017.

In this multi-center study, voxel-based relaxometry (VBR), a novel technique to automatically quantify localized cartilage change, was used to investigate T1ρ and T2 relaxation times of patients with anterior cruciate ligament (ACL) tears at the time of injury and 6 months after reconstructive surgery. Sixty-four ACL-injured patients from three sites underwent bilateral 3T MR T1ρ and T2 mapping; 56 patients returned 6 months after surgery. Cross-sectional and longitudinal VBR comparisons of relaxation times were calculated. Noyes Score (NS) clinical grades of cartilage lesions were noted at both times and correlated with relaxation times. Lastly, patients were divided into two groups based on baseline NS grades in the injured knee. T1ρ times of each group were assessed with VBR and compared. Results illustrate the feasibility of VBR for efficiently analyzing data from patients at different sites. Significant relaxation time elevations at baseline were observed in the injured knee compared to the uninjured, particularly in the posterolateral tibia (pLT). Longitudinally, a decrease was observed in the pLT and patella, while an increase was noted in the trochlea. Stratifying patients by baseline lesion presence revealed T1ρ increased more 6 months after surgery in patients with lesions. Such findings propose that the presence of cartilage lesions at baseline are associated with the longitudinal progression of T1ρ and T2 after ACL injury, and may contribute to early cartilage degeneration. Furthermore, the speed and localized specificity of automatic VBR analysis may translate well for clinical application, as seen in this multicenter study. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:688-698, 2017.

This study looked to investigate a new quantitative metric, R2  - R1ρ (1/T2  - 1/T1ρ ), using magnetic resonance (MR) images and voxel-based relaxometry (VBR) for detecting early cartilage degeneration and explore the association with patient-reported outcomes measures (PROMs) in patients 6 months after ACL reconstruction. Sixty-four patients from three sites were bilaterally scanned on a 3T MR with a combined T1ρ /T2 protocol to calculate R1ρ (1/T1ρ ) and R2 (1/T2 ) values at baseline and 6 months after reconstructive surgery. Non-rigid registration was applied to align images onto a template, allowing VBR to determine VBR rate differences and explore cross-sectional and longitudinal differences between injured and uninjured knees, generating Statistical Parametric Maps (SPMs). Baseline R2  - R1ρ differences were further correlated with change in PROMs from the Knee Injury and Osteoarthritis Outcome Score (KOOS) from baseline to 6 months. Cross-sectional results demonstrated low relaxation rate differences in the injured patella (baseline: 21%, p = 0.01; 6-months: 18%, p = 0.02), lateral tibia (baseline: 25%, p = 0.01; 6-months: 24%, p = 0.01), and weight-bearing regions of the tibia and femur. The uninjured patella showed significant longitudinal changes (17%, p = 0.02). R2  - R1ρ differences showed significant correlations with KOOS PROMs, particularly in the lateral tibia, patella, and trochlea. R2  - R1ρ difference VBR analyses provide new and highly sensitive parameters for assessing early cartilage degeneration in patients after ACL injury by integrating findings from both T1ρ and T2 , commonly used relaxation time parameters, into a single metric. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:718-729, 2017.

• The morphological images obtained by 3D MIXTURE have a contrast comparable to that of standard 2D TSE and have equivalent diagnostic performance. • The T2 map obtained by 3D MIXTURE is equivalent to the conventional multi-echo spin-echo (MESE) technique and shows no systematic bias. • The T2 map obtained by 3D MIXTURE correlates well with the location of the lesion on morphological images, allowing quantitative evaluation of the knee cartilage (T2 values of the lesion are consistent with those reported in the literature). Quantitative MRI techniques such as T2 mapping are useful in comprehensive evaluation of various pathologies of the knee joint yet require separate scans to conventional morphological measurements and long acquisition times. The recently introduced 3D MIXTURE (Multi-Interleaved X-prepared Turbo-Spin Echo with Intuitive Relaxometry) technique can obtain simultaneous morphologic and quantitative information of the knee joint. To compare MIXTURE with conventional methods and to identify differences in morphological and quantitative information. Phantom studies were conducted, and in vivo human scans were performed (20 patients) presented with knee arthralgia. MIXTURE is based on 3D TSE without and with T2 preparation modules in an interleaved manner for both morphology with PDW and fat suppressed T2W imaging as well as quantitative T2 mapping within one single scan. Image quality and lesion depiction were visually assessed and compared between MIXTURE and conventional 2D TSE by two experienced radiologists. Contrast-to-noise ratio was used to assess the adjacent tissue contrast in a quantitative way for both obtained PDW and fat suppressed T2W images. Quantitative T2 values were measured in phantom and from in vivo knee cartilage. The overall diagnostic confidence and contrast-to-noise ratio were deemed comparable between MIXTURE and 2D TSE. While the chosen T2 preparation modules for MIXTURE rendered consistent T2 values comparing to the current standard, measured cartilage T2 values ranged from 26.1 to 50.7 ms, with significant difference between the lesion and normal areas (p < 0.05). MIXTURE can help to provide high-resolution information for both anatomical and pathological assessment. [ABSTRACT FROM AUTHOR]

BACKGROUND: The main pathological change of osteoarthritis is cartilage degeneration. The current means of treatment of osteoarthritis is very limited. With the development of interdisciplinary science in recent years, tissue engineering brings new hope for the repair and reconstruction of cartilage degeneration. Nerve growth factor plays an important role in the physiological and pathological processes of multiple systems and organs in the body. In recent years, it has been found that nerve growth factor is closely related to the occurrence and development of osteoarthritis. OBJECTIVE: To explore the research progress of nerve growth factor in osteoarthritis in recent years from the aspects of nerve growth factor’s effects on cartilage, subchondral bone, synovium, and pain. It was envisaged that nerve growth factor could be used as a bioactive factor or cytokine in tissue engineering to repair bone and cartilage, providing new thoughts and ideas for the treatment of osteoarthritis. METHODS: In PubMed, Web of Science, CNKI, and WanFang databases, search terms used were “nerve growth factor, TrkA, osteoarthritis, chondrocyte, cartilage degeneration, subchondral bone, synovium, pain” in English and Chinese. Basic and clinical studies on the mechanisms of nerve growth factor in osteoarthritis were searched from January 1, 2010 to July 1, 2021. RESULTS AND CONCLUSION: Nerve growth factor promoted the differentiation of stem cells, maintained the phenotype of chondrocytes, and promoted the expression of chondrocytes to maintain the characteristics of cartilage. Nerve growth factor promoted osteogenic expression in a variety of ways, inducing or aggravating the occurrence and development of osteoarthritis, but some studies suggest that subchondral bone repair is beneficial to cartilage repair. Synovium promoted nerve growth factor expression and participated in the pain of osteoarthritis. Synovium also indirectly promoted the expression of cartilage degradation protein under the stimulation of inflammatory factors. Nerve growth factor is the main signal factor causing pain. The use of nerve growth factor antibody has a good and definite effect on the pain of osteoarthritis, but its use is limited by serious side effects, and the mechanism of its occurrence is explored. It may still become the most potential analgesic drugs in the future. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have shown that the stromal cell-derived factor 1/C-X-C chemokine receptor type 4 signaling pathway plays an important role in the occurrence and development of osteoarthritis. OBJECTIVE: To explore the effect of C-X-C chemokine receptor type 4 antagonist on the degeneration of articular cartilage in vivo. METHODS: Ninety-six 6-month-old male Hartley guinea pigs were randomly divided into four groups, namely, TN14003 treatment, T140 treatment, AMD3100 treatment group, and blank control group (n=24 per group). Except for the blank control group without any treatment, in the rest three groups, Alzet micropumps were directly implanted and fixed under the skin of the back of the guinea pigs, followed by daily injection of TN14003, T140, and AMD3100 drugs at a concentration of 180 mg/L, respectively. After 12 weeks of interventions, the articular cartilage of the knee joint was taken out from guinea pigs for hematoxylin-eosin staining, Safranin-fast green staining, and modified Mankin histological scoring. Immunohistochemical staining was used to detect the expression levels of interleukin-1 and tumor necrosis factor-α. RESULTS AND CONCLUSION: Hematoxylin-eosin staining and Safranin-fast green staining showed that the degree of cartilage degeneration in the TN14003 treatment group was significantly delayed, with the highest Mankin score, followed by T140 treatment group, AMD3100 group and blank control group in turn. There were significant differences in the Mankin scores between the experimental groups (P < 0.05). The results of immunohistochemical staining analysis showed that the positive expression of interleukin-1 and tumor necrosis factor-α in each experimental group was lower than that of the blank control group, among which the expression was lowest in the TN14003 treatment group (P < 0.05). To conclude, these three kinds of C-X-C chemokine receptor type 4 antagonists can all block the stromal cell-derived factor 1/C-X-C chemokine receptor type 4 signaling pathway in vivo, reduce the expression levels of interleukin-1 and tumor necrosis factor-α, and delay cartilage degeneration, among which TN14003 has the best effects. [ABSTRACT FROM AUTHOR]

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage‐associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain‐like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra‐articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria‐derived activator of caspases (SMAC) mimetics and carbobenzoxy‐valyl‐alanyl‐aspartyl‐[O‐methyl]‐ fluoromethylketone (z‐VAD‐fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα‐SDC4‐TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

The uppermost superficial zone of articular cartilage is the first line of defense against the initiation of osteoarthritis (OA). We previously used Col2‐Cre to demonstrate that epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, plays an essential role in maintaining superficial chondrocytes during articular cartilage development. Here, we showed that EGFR activity in the articular cartilage decreased as mice age. In mouse and human OA samples, EGFR activity was initially reduced at the superficial layer and then resurged in cell clusters within the middle and deep zone in late OA. To investigate the role of EGFR signaling in postnatal and adult cartilage, we constructed an inducible mouse model with cartilage‐specific EGFR inactivation (Aggrecan‐CreER EgfrWa5/flox, Egfr iCKO). EdU incorporation revealed that postnatal Egfr iCKO mice contained fewer slow‐cycling cells than controls. EGFR deficiency induced at 3 months of age reduced cartilage thickness and diminished superficial chondrocytes, in parallel to alterations in lubricin production, cell proliferation, and survival. Furthermore, male Egfr iCKO mice developed much more severe OA phenotypes, including cartilage erosion, subchondral bone plate thickening, cartilage degeneration at the lateral site, and mechanical allodynia, after receiving destabilization of the medial meniscus (DMM) surgery. Similar OA phenotypes were also observed in female iCKO mice. Moreover, tamoxifen injections of iCKO mice at 1 month post‐surgery accelerated OA development 2 months later. In summary, our data demonstrated that chondrogenic EGFR signaling maintains postnatal slow‐cycling cells and plays a critical role in adult cartilage homeostasis and OA progression. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

To develop a semi‐automatic framework for quantitative analysis of biochemical properties and thickness of femur cartilage using magnetic resonance (MR) images and evaluate its potential for femur cartilage classification into asymptomatic (AS), early osteoarthritis (OA), and advanced OA groups. In this study, knee joint MRI data (fat suppressed‐proton density‐weighted and multi‐echo T2‐weighted images) of eight AS‐volunteers (data acquired twice) and 34 OA patients including 20 early OA (16 Grade‐I and 4 Grade‐II), 14 advanced‐OA (Grade‐III) were acquired at 3.0T MR scanner. Modified Outerbridge classification criteria was performed for the clinical evaluation of data by an experienced radiologist. Cartilage segmentation, T2‐mapping, 2D‐WearMap generation, and subregion analysis were performed semi‐automatically using in‐house developed algorithms. The intraclass correlation coefficient (ICC) and coefficient of variation (CV) were computed for testing the reproducibility of T2 values. One‐way analysis of variance with Tukey–Kramer post hoc test was performed for evaluating the differences among the groups. The performance of individual T2 and thickness, as well as their combination using logistic regression, were evaluated with receiver operating characteristics (ROC) curve analysis. The interscan agreement based on the ICC index was 0.95 and the CV was 2.45 ± 1.33%. T2 mean of values greater than 75th percentile showed sensitivity and specificity of 94.1% and 81.3% (AUC = 0.93, cut‐off value = 47.9 ms) in differentiating AS volunteers versus OA group, while sensitivity and specificity of 90.0% and 81.3% (AUC = 0.90, cut‐off value = 47.9 ms) in differentiating AS volunteers versus early OA groups, respectively. In the differentiation of early OA versus advanced‐OA group, ROC results of combination (T2 and thickness) showed the highest sensitivity and specificity of 85.7%, and 70.0% (AUC = 0.79, cut‐off value = 0.39) compared with individual T2 and thickness features, respectively. A computer‐aided quantitative evaluation of femur cartilage degeneration showed promising results and can be used to assist clinicians in diagnosing OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a whole‐joint disease characterized by synovial inflammation and cartilage degeneration. However, the relationship between synovial inflammation and cartilage degeneration remains unclear. The modified Hulth's method was adopted to establish a knee OA (KOA) rabbit model. Synovial tissue was collected after 8 weeks, and synovial tissue‐derived extracellular vesicles (ST‐EVs) were extracted by filtration combined with size exclusion chromatography (SECF), followed by identification through transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA) and Western blot (WB). The collagenase digestion method was used to extract normal rabbit chondrocytes, which were then treated with the SF‐EVs to observe the effect and mechanism of SF‐EVs on chondrocytes. The morphology, particle size and labelled protein marker detection confirmed that SECF successfully extract ST‐EVs. The ST‐EVs in the KOA state significantly inhibited chondrocyte proliferation and promoted chondrocytes apoptosis. Moreover, the ST‐EVs also promoted the expression of pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α and COX‐2) and cartilage degradation‐related enzymes (MMP13, MMP9 and ADAMTS5) in the chondrocytes. Mechanistically, the ST‐EVs significantly promoted the activation of NF‐κB signalling pathway in chondrocytes. Inhibition the activation of the NF‐κB signalling pathway significantly rescued the expression of inflammatory cytokines and cartilage degradation‐related enzymes in the ST‐EVs–induced chondrocytes. In conclusion, the ST‐EVs promote chondrocytes inflammation and degradation by activating the NF‐κB signalling pathway, providing novel insights into the occurrence and development of OA. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease in aged people. Progressive cartilage degradation is the hallmark of KOA, but its deeper mechanism remains unclear. Substantial evidence indicates the importance of the synovium for joint homeostasis. The present study aimed to determine whether the synovium regulates cartilage metabolism through chondrogenesis-related microRNAs (miRNAs) in the KOA microenvironment. Clinical sample testing and in vitro cell experiments screened out miR-455 and miR-210 as effective miRNAs. The levels of both were significantly reduced in KOA cartilage but increased in KOA synovial fluid compared with controls. We further revealed that transforming growth factor β1 (TGF-β1) can significantly upregulate miR-455 and miR-210 expression in synoviocytes. The upregulated miRNAs can be secreted into the extracellular environment and prevent cartilage degeneration. Through bioinformatics and in vitro experiments, we found that Runx1 can bind to the promoter regions of miR-455 and miR-210 and enhance their transcription in TGF-β1-treated synoviocytes. Collectively, our findings demonstrate a protective effect of the synovium against cartilage degeneration mediated by chondrogenesis-related miRNAs, which suggests that Runx1 is a potential target for KOA therapy.

Inflammatory arthritis is a major cause of disability in the elderly. This condition causes joint pain, loss of function, and deterioration of quality of life, mainly due to osteoarthritis (OA) and rheumatoid arthritis (RA). Currently, available treatment options for inflammatory arthritis include anti-inflammatory medications administered via oral, topical, or intra-articular routes, surgery, and physical rehabilitation. Novel alternative approaches to managing inflammatory arthritis, so far, remain the grand challenge owing to catastrophic financial burden and insignificant therapeutic benefit. In the view of non-targeted systemic cytotoxicity and limited bioavailability of drug therapies, a major concern is to establish stimuli-responsive drug delivery systems using nanomaterials with on-off switching potential for biomedical applications. This review summarizes the advanced applications of triggerable nanomaterials dependent on various internal stimuli (including reduction-oxidation (redox), pH, and enzymes) and external stimuli (including temperature, ultrasound (US), magnetic, photo, voltage, and mechanical friction). The review also explores the progress and challenges with the use of stimuli-responsive nanomaterials to manage inflammatory arthritis based on pathological changes, including cartilage degeneration, synovitis, and subchondral bone destruction. Exposure to appropriate stimuli induced by such histopathological alterations can trigger the release of therapeutic medications, imperative in the joint-targeted treatment of inflammatory arthritis.

The objectives of this study were to evaluate the reliability of cartilage T2 relaxation time measurements and to identify focal changes in T2 relaxation on the affected knee from 6 to 24 months after anatomic anterior cruciate ligament reconstruction (ACLR). Data from 41 patients who received anatomic ACLR were analyzed. A bilateral 3.0-T MRI was acquired 6 and 24 months after ACLR. T2 relaxation time was measured in subregions of the femoral condyle and the tibial plateau. The root-mean-square coefficient of variation (RMS CV ) was calculated to evaluate the reliability of T2 relaxation time in the contralateral knee. Subregion changes in the affected knee T2 relaxation time were identified using the contralateral knee as a reference. The superficial and full thickness layers of the central and inner regions showed good reliability. Conversely, the outer regions on the femoral side and regions in the deep layers showed poor reliability. T2 relaxation time increased in only 3 regions on the affected knee when controlling for changes in the contralateral knee, while changes in T2 relaxation time were identified in 14 regions when not using the contralateral knee as a reference. In conclusion, evaluation of cartilage degeneration by T2 relaxation time after ACLR is most reliable for central and inner cartilage regions. Cartilage degeneration occurs in the central and outer regions of the lateral femoral condyle from 6 to 24 months after anatomic ACLR., (© 2024 The Author(s). Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

PurposeSimultaneous positron emission tomography-magnetic resonance imaging (PET-MRI) is an emerging technology providing both anatomical and functional images without increasing the scan time. Compared to the traditional PET/computed tomography imaging, it also exposes the patient to significantly less radiation and provides better anatomical images as MRI provides superior soft tissue characterization. Using PET-MRI, we aim to study interactions between cartilage composition and bone function simultaneously, in knee osteoarthritis (OA).ProceduresIn this article, bone turnover and remodeling was studied using [18F]-sodium fluoride (NaF) PET data. Quantitative MR-derived T1ρ relaxation times characterized the biochemical cartilage degeneration. Sixteen participants with early signs of OA of the knee received intravenous injections of [18F]-NaF at the onset of PET-MR image acquisition. Regions of interest were identified, and kinetic analysis of dynamic PET data provided the rate of uptake ( Ki) and the normalized uptake (standardized uptake value) of [18F]-NaF in the bone. Morphological MR images and quantitative voxel-based T1ρ maps of cartilage were obtained using an atlas-based registration technique to segment cartilage automatically. Voxel-by-voxel statistical parameter mapping was used to investigate the relationship between bone and cartilage.ResultsIncreases in cartilage T1ρ, indicating degenerative changes, were associated with increased turnover in the adjoining bone but reduced turnover in the nonadjoining compartments. Associations between pain and increased bone uptake were seen in the absence of morphological lesions in cartilage, but the relationship was reversed in the presence of incident cartilage lesions.ConclusionThis study shows significant cartilage and bone interactions in OA of the knee joint using simultaneous [18F]-NaF PET-MR, the first in human study. These observations highlight the complex biomechanical and biochemical interactions in the whole knee joint in OA, which potentially could help assess therapeutic targets in treating OA.

[Display omitted] • Established a new experimental rat model of the developmental trochlear dysplasia; • Using the macroscopic morphological and micro-CT to assess trochlear dysplasia; • Using Histological staining to investigate the cartilage degradation of the model; • Investigated the relationship of the PI3K/AKT signaling pathway with trochlear dysplasia cartilage degeneration; • Using immunohistochemistry and qPCR to investigate the PI3K/AKT and the marker of the cartilage degeneration. Trochlear dysplasia is a commonly encountered lower extremity deformity in humans. However, the molecular mechanism of cartilage degeneration in trochlear dysplasia is unclear thus far. The PI3K/AKT signaling pathway is known to be important for regulating the pathophysiology of cartilage degeneration. The aim of this study was to investigate the relationship of the PI3K/AKT signaling pathway with trochlear dysplasia cartilage degeneration. In total, 120 female Sprague-Dawley rats (4 weeks of age) were randomly separated into control and experimental groups. Distal femurs were isolated from the experimental group at 4, 8, and 12 weeks after surgery; they were isolated from the control group at the same time points. Micro-computed tomography and histological examination were performed to investigate trochlear anatomy and changes in trochlear cartilage. Subsequently, expression patterns of PI3K/AKT, TGFβ1, and ADAMTS-4 in cartilage were investigated by immunohistochemistry and quantitative polymerase chain reaction. In the experimental group, the trochlear dysplasia model was successfully established at 8 weeks after surgery. Moreover, cartilage degeneration was observed beginning at 8 weeks after surgery, with higher protein and mRNA expression levels of PI3K/AKT, TGFβ1, and ADAMTS-4, relative to the control group. Patellar instability might lead to trochlear dysplasia in growing rats. Moreover, trochlear dysplasia may cause patellofemoral osteoarthritis; cartilage degeneration in trochlear dysplasia might be associated with activation of the PI3K/AKT signaling pathway. These results provide insights regarding the high incidence of osteoarthritis in patients with trochlear dysplasia. However, more research is needed to clarify the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Purpose: Degeneration of the cartilage after anterior cruciate ligament reconstruction (ACL-R) is known, and further deterioration can be expected in patients with tunnel malplacement or partial meniscal resection. It was hypothesized that there is a significant increase in cartilage degeneration after failed ACL-R.Material and Methods: Isolated ACL revision surgery was performed in 154 patients at an interval of 46 ± 33 months (5-175 months) between primary and revision surgery. Cartilage status at the medial, lateral femorotibial, and patellofemoral compartments were assessed arthroscopically during primary and revision ACL-R in accordance with the Outerbridge classification. Tunnel placement, roof angle, and tibial slope was measured using anteroposterior and lateral radiographic views.Results: Cartilage degeneration increased significantly in the medial femorotibial compartment, followed by the lateral and patellofemoral compartments. There was a correlation between both cartilage degeneration in the patellofemoral compartment (PFC) (rs = 0.28, p = 0.0012) and medial tibial plateau (Rs = 0.24, p = 0.003) in relation to the position of tibial tunnel in the frontal plane. Worsening of the cartilage status in the medial femorotibial compartment, either femoral or tibial, was correlated with the tibial aperture site in the lateral view (Rs = 0.28, p < 0.001). Cartilage degeneration in the lateral compartment of the knee, on both femoral or tibial side, was inversely correlated with the femoral roof angle (Rs = -0.1985, p = 0.02). Meniscal tears, either at the medial or lateral site or at both, were found in 93 patients (60%) during primary ACL-R and increased to 132 patients (86%) during revision ACL-R.Discussion: Accelerated cartilage degeneration and high prevalence of meniscal lesions are seen in failed ACL-R. Tunnel placement showed significant impact on cartilage degeneration and may partially explain the increased risk of an inferior outcome when revision surgery is required after failed primary ACL-R.Level Of Evidence: Level IV-retrospective cohort study. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) and osteoporosis (OP) are historically considered to be inversely correlated but there may be an overlap between the pathophysiology of the two diseases. This study aimed to investigate the subchondral bone microarchitecture and matrix mineralization, and the association between them in OA and OP in relation to the degree of cartilage degeneration. Fifty‐six osteochondral plugs were collected from 16 OA femoral heads. They were graded on a regional basis according to the stages of cartilage degeneration, as evaluated by a new macroscopic and a modified microscopic grading system. Twenty‐one plugs were collected from seven femoral heads with OP. Plugs were scanned by microcomputed tomography and the microarchitectural and mineral properties were obtained for both subchondral plate and trabecular bone. Microarchitecture and material and apparent densities of subchondral bone in OP were similar to regions with early cartilage degeneration but different from regions with advanced cartilage degradation in OA femoral heads. Subchondral trabecular bone was more mineralized than subchondral plate in both OP and OA, and this compartmental difference varied by severity of cartilage degradation. Furthermore, the relationship among trabecular bone volume fraction, tissue mineral density, and apparent bone density was similar in OP and different stages of OA. Subchondral bone microarchitecture and mineral properties in OP are different from OA in a regionalized manner in relation to stages of cartilage degeneration. Both regional and compartmental differences at structural, material, and cellular levels need to be studied to understand the transition of OA subchondral bone from being osteoporotic to sclerotic. [ABSTRACT FROM AUTHOR]

Purpose: To understand if anatomic physeal-sparing ACL reconstruction in the immature host preserves range of motion, permits a return to sports, and avoids limb length discrepancy and accelerated intra-articular degeneration with a cross-sectional radiographic, physical examination and patient-reported outcomes analysis. Methods: A cross-sectional recall study included 38 patients aged 7–15 who underwent all-epiphyseal ACL reconstruction with hamstring allograft performed by a single surgeon at a large academic medical center. All-epiphyseal reconstructions were performed using a modified Anderson physeal-sparing technique, with the femoral tunnel placed using an "inside-out" technique. Assessments consisted of a physical exam, long leg cassette radiographs, KT-1000 measurements, subjective patient metrics, and magnetic resonance imaging. Results: Thirty-eight (56.7%) of 66 eligible patients returned for in-person clinical and radiographic exams. Patients were 11.4 ± 1.8 years at the time of surgery. Five patients were females (13.2%). Mean follow-up was 5.5 ± 2.4 years. ACL re-injuries occurred in four patients (10.5%), all of whom underwent revision reconstructions. Thirty-three of the remaining 34 (97.1%) patients returned to sports following their reconstruction, and 24 (70.6%) returned to their baseline level of competition. Mean limb length discrepancy (LLD) was 0.2 ± 1.4 cm. Nine patients had an LLD of > 1 cm (26.5%), which occurred at an equivalent age as those with < 1 cm LLD (10.8 ± 2.0 vs. 11.7 ± 1.7, n.s.). Pre-operative Marx scores (13.1 ± 3.5) were not significantly different from post-operative values (12.3 ± 5.1, n.s.). Patients who required ACL revisions had significantly lower Marx scores than those with intact primary grafts (8.3 ± 7.1 vs. 13.4 ± 4.5, p = 0.047). Cohort mean International Knee Documentation Committee (IKDC) score was 89.7 ± 12.7. Conclusion: Anatomic all-epiphyseal anatomic ACL reconstruction appears to be useful in patients with significant projected remaining growth, with good return-to-sport outcomes and minimal risk of clinically significant physeal complications. However, given the limited patient recall possible in the present study, further large sample size, high-quality works are necessary to validate our findings. Level of evidence: Level IV. [ABSTRACT FROM AUTHOR]

Abstract Background Joint hemorrhage is caused by trauma, ligament reconstruction surgery, and bleeding disorders such as hemophilia. Recurrence of hemorrhage in the joint space induces hemosiderotic synovitis and oxidative stress, resulting in both articular cartilage degeneration and arthropathy. Joint immobilization is a common treatment option for articular fractures accompanied by joint hemorrhage. Although joint hemorrhage has negative effects on the articular cartilage, there is no consensus on whether a reduction in joint hemorrhage would effectively prevent articular cartilage degeneration. The purpose of this study was to investigate the effect of joint hemorrhage combined with joint immobilization on articular cartilage degeneration in a rat immobilized knee model. Methods The knee joints of adult male rats were immobilized at the flexion using an internal fixator from 3 days to 8 weeks. The rats were randomly divided into the following groups: immobilized blood injection (Im-B) and immobilized-normal saline injection (Im-NS) groups. The cartilage was evaluated in two areas (contact and non-contact areas). The cartilage was used to assess chondrocyte count, Modified Mankin score, and cartilage thickness. The total RNA was extracted from the cartilage in both areas, and the expression of metalloproteinase (MMP)-8, MMP-13, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α was measured by quantitative real-time polymerase chain reaction. Results The number of chondrocytes in the Im-B group significantly decreased in both areas, compared with that in the Im-NS group. Modified Mankin score from 4 to 8 weeks of the Im-B group was significantly higher than that of the Im-NS group only in the contact area. The expression of MMP-8 and MMP-13 from 2 to 4 weeks and TNF-α from 2 to 8 weeks significantly increased in the Im-B group compared with those in the Im-NS group, but there was no significant difference in IL-1β expression. Conclusions The results showed that joint hemorrhage exacerbated immobilization-induced articular cartilage degeneration. Drainage of a joint hemorrhage or avoidance of loading may help prevent cartilage degeneration during joint immobilization with a hemorrhage.

Abstract Purpose The purpose of the study was to determine the effect of cartilage degeneration at the patellofemoral joint on clinical outcomes after open wedge high tibial osteotomy and to investigate the predisposing factors for progressive patellofemoral cartilage degeneration. Methods Seventy-two knees were evaluated on second-look arthroscopy in patients who opted for plate and screw removal at an average of 20.1 months after osteotomy. Cartilage degeneration at the patellofemoral joint was evaluated using the International Cartilage Repair Society grading system, with cases divided into progression and nonprogression groups. Radiographic parameters of the patellofemoral anatomy, knee range of motion, and clinical outcomes were evaluated from the preoperative baseline to the final follow up, on average 50 months after osteotomy. A contracture > 5° was considered a flexion contracture. Results Cartilage degeneration progressed in 31 knees, and preoperative knee flexion contracture was significantly associated with progressive degeneration (P

Osteoarthritis (OA) is the most common joint disease primarily characterized by cartilage degeneration. Milk-derived extracellular vesicles (mEVs) were reported to inhibit catabolic and inflammatory processes in the cartilage of OA patients. However, the current therapies target the advanced symptoms of OA, and it is significant to develop a novel strategy to inhibit the processes driving OA pathology. In this study, we investigated the therapeutic potential of mEVs in alleviating OA in vivo. The results revealed that mEVs ameliorated cartilage degeneration by increasing hyaline cartilage thickness, decreasing histological Osteoarthritis Research Society International (OARSI) scores, enhancing matrix synthesis, and reducing the expression of cartilage destructive enzymes in the destabilization of medial meniscus (DMM) mice. In addition, the disturbed gut microbiota in DMM mice was partially improved upon treatment with mEVs. It was observed that the pro-inflammatory bacteria (Proteobacteria) were reduced and the potential beneficial bacteria (Firmicutes, Ruminococcaceae, Akkermansiaceae) were increased. mEVs could alleviate the progression of OA by restoring matrix homeostasis and reshaping the gut microbiota. These findings suggested that mEVs might be a potential therapeutic dietary supplement for the treatment of OA.

Objective: Chronic inflammation plays an important role in the osteoarthritis (OA) pathology but how this influence OA disease progression is unclear. Leukotriene B4 (LTB 4 ) is a potent proinflammatory lipid mediator generated from arachidonic acid through the sequential activities of 5-lipoxygenase, 5-lipoxygenase-activating protein, Leukotriene A 4 hydrolase (LTA 4 H) and its downstream product LTB 4 . The aim of this study is to investigate the involvement and the potential therapeutic target of the LTB 4 pathway in OA disease progression., Design: Both clinical human cartilage samples ( n = 7) and mice experimental OA models ( n = 6) were used. The levels of LTA 4 H and leukotriene B4 receptor 1 were first examined using immunostaining in human OA/non-OA cartilage and mice experimental OA models. We also determined whether the LTA 4 H pathway was associated with cartilage degeneration and synovitis inflammation in OA mice models and human articular chondrocytes., Results: We found that both LTA 4 H and LTB 4 receptor (BLT1) were highly expressed in human and mice OA cartilage. Inhibition of LTA 4 H suppressed cartilage degeneration and synovitis in OA mice model. Furthermore, inhibition of LTA 4 H promoted cartilage regeneration by upregulating chondrogenic genes expression such as aggrecan ( ACAN ), collagen 2A1 ( COL2A1 ), and SRY-Box transcription factor 9 ( SOX9 )., Conclusions: Our results indicate that the LTA 4 H pathway is a crucial regulator of OA pathogenesis and suggest that LTA 4 H could be a therapeutic target in combat OA., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The aim of this study was to develop an automatic segmentation method for hip abductor muscles and find their fat fraction associations with early stage hip osteoarthritis (OA) cartilage degeneration biomarkers. This Institutional Review Board approved, Health Insurance Portability and Accountability Act compliant prospective study recruited 61 patients with evidence of hip OA or Femoroacetabular Impingement (FAI). Magnetic resonance (MR) images were acquired for cartilage segmentation, T1ρ and T2 relaxation times computation and grading of cartilage lesion scores. A 3D V‐Net (Dice loss, Adam optimizer, learning rate = 1e−4, batch size = 3) was trained to segment the three muscles (gluteus medius, gluteus minimus, and tensor fascia latae). The V‐Net performance was measured using Dice, distance maps between manual and automatic masks, and Bland‐Altman plots of the fat fractions and volumes. Associations between muscle fat fraction and T1ρ, T2 relaxation times values were found using voxel based relaxometry (VBR). A p < 0.05 was considered significant. The V‐Net had a Dice of 0.90, 0.88, and 0.91 (GMed, GMin, and TFL). The VBR results found associations of fat fraction of all three muscles in early stage OA and FAI patients with T1ρ, T2 relaxation times. Using an automatic, validated segmentation model, the associations derived between OA biomarkers and muscle fat fractions provide insight into early changes that occur in OA, and show that hip abductor muscle fat is associated with markers of cartilage degeneration. [ABSTRACT FROM AUTHOR]