Osteoarthritis Pathology Research Articles

Simvastatin retards cartilage degradation and subchondral bone deterioration induced by a high-fat diet in mice

ABSTRACT To evaluate the effects of simvastatin on the degeneration of cartilage and subchondral bone in a mice model of osteoarthritis (OA) induced by obesity. Thirty male 3-month-old C57BL/6J mice were randomized into three groups: mice with normal diet + vehicle (distilled water) (Control), mice with High-fat diet + vehicle (HFD), mice with HFD + Simvastatin (HFD+S). HFD+S group were treated with simvastatin (10 mg/kg/day) for 12 weeks. The pathology of OA was assessed by histomorphology analyses, immunohistochemistry, micro-computed tomography, and enzyme-linked immunosorbent assay. Histomorphological analysis revealed that OA was significantly exacerbated by the HFD-induced obesity and markedly alleviated by the simvastatin intervention. In details, simvastatin ameliorated the abnormal metabolic status and cartilage lesions, significantly increased aggrecan and collagen-II expression and decreased the expression of MMP-13 and leptin in cartilage. Furthermore, the results of micro-CT analysis revealed that the HFD+S group exhibited higher BMD, BV/TV, and Tb.N values but a lower Tb.Sp value than that of the HFD group. Serum glucose, leptin, and IL-1β concentrations were significantly correlated with the OARSI score. Histomorphological analysis revealed that OA was significantly exacerbated by the HFD-induced obesity and markedly alleviated by the simvastatin intervention. In details, simvastatin ameliorated the abnormal metabolic status and cartilage lesions, significantly increased aggrecan and collagen-II expression and decreased the expression of MMP-13 and leptin in cartilage. Furthermore, the results of micro-CT analysis revealed that the HFD+S group exhibited higher BMD, BV/TV, and Tb.N values but a lower Tb.Sp value than that of the HFD group. Serum glucose, leptin, and IL-1β concentrations were significantly correlated with the OARSI score. The HFD-induced obesity aggravates articular degeneration and deterioration in subchondral bone, which could be improved by the intervention of simvastatin, suggesting that simvastatin may be a potential candidate for amelioration of the progression of obesity induced-OA.

Bone Remodeling in Osteoarthritis-Biological and Radiological Aspects.

Among available papers published on the given subject over the last century, various terms have been used as synonyms for one, now generally accepted-osteoarthritis, in some countries called "wear and tear" or "overload arthritis". The opsolent terms-hypertrophic arthritis, degenerative arthritis, arthritis deformans and osteoarthrosis-sought to highlight the dominant clinical signs of this ubiquitous, polymorph disease of the whole osteochondral unit, which by incidence and prevalence represents one of the leading chronic conditions that cause long-term pain and incapacity for work. Numerous in vitro and in vivo research resulted in broadened acknowledgments about osteoarthritis pathophysiology and pathology on both histological and cellular levels. However, the cause of osteoarthritis is still unknown and is currently the subject of a hypothesis. In this paper, we provide a review of recent findings on biological phenomena taking place in bone tissue during osteoarthritis to the extent useful for clinical practice. Choosing a proper radiological approach is a conditio sine qua non to the early diagnosis of this entity.

Metabolic reprogramming of glycolysis favors cartilage progenitor cells rejuvenation

Osteoarthritis (OA), the leading cause of disability in the elderly, still lacks effective treatment due to the unelucidated mechanisms of pathogenesis and progression. In cartilage, although the solo cell type of chondrocytes is resident, cartilage progenitor cells (CPCs) are identified. Chondrocytes in cartilage mainly utilize glycolysis because of the low oxygen tension. Until now, whether the metabolic pathway changes are associated with OA initiation or progression, as well as the biology of CPCs, remains fully clarified. By reviewing relevant literature from previous functional studies, we further mined recently published mouse and human chondrocytes single-cell RNA-sequencing datasets to explore gene expression profiles shift in OA initiation or during OA progression, regarding metabolism. In this review, we demonstrated that chondrocytes’ metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) in OA initiation or during OA progression. Genes that related to OXPHOS, electron transport, mitochondrial translation, and mitochondrial respiratory chain complex assembly were upregulated in chondrocytes of injured cartilage or during OA progression. In addition, compared to OXPHOS, glycolysis facilitates CPC expansion and chondrogenic potential. The collated information suggests a potential therapeutic for OA through metabolic reprogramming of glycolysis to interrupt OA pathology and favor CPCs rejuvenation to restore healthy cartilage.

Elucidating individual differences in chronic pain and whole person health with allostatic load biomarkers

Chronic pain is a stressor that affects whole person functioning. Persistent and prolonged activation of the body's stress systems without adequate recovery can result in measurable physiological and neurobiological dysregulation recognized as allostatic load. We and others have shown chronic pain is associated with measures of allostatic load including clinical biomarker composites, telomere length, and brain structures. Less is known regarding how different measures of allostatic load align. The purpose of the study was to evaluate relationships among two measures of allostatic load: a clinical composite and pain-related brain structures, pain, function, and socioenvironmental measures. Participants were non-Hispanic black and non-Hispanic white community-dwelling adults between 45 and 85 years old with knee pain. Data were from a brain MRI, questionnaires specific to pain, physical and psychosocial function, and a blood draw. Individuals with all measures for the clinical composite were included in the analysis (n = 175). Indicating higher allostatic load, higher levels of the clinical composite were associated with thinner insula cortices with trends for thinner inferior temporal lobes and dorsolateral prefrontal cortices (DLPFC). Higher allostatic load as measured by the clinical composite was associated with greater knee osteoarthritis pathology, pain disability, and lower physical function. Lower allostatic load as indicated by thicker insula cortices was associated with higher income and education, and greater physical functioning. Thicker insula and DLPFC were associated with a lower chronic pain stage. Multiple linear regression models with pain and socioenvironmental measures as the predictors were significant for the clinical composite, insular, and inferior temporal lobes. We replicate our previously reported bilateral temporal lobe group difference pattern and show that individuals with high chronic pain stage and greater socioenvironmental risk have a higher allostatic load as measured by the clinical composite compared to those individuals with high chronic pain stage and greater socioenvironmental buffers. Although brain structure differences are shown in individuals with chronic pain, brain MRIs are not yet clinically applicable. Our findings suggest that a clinical composite measure of allostatic load may help identify individuals with chronic pain who have biological vulnerabilities which increase the risk for poor health outcomes.

Disease-modifying interactions between chronic kidney disease and osteoarthritis: a new comorbid mouse model

ObjectiveThe prevalence of comorbid chronic kidney disease (CKD) and osteoarthritis (OA) is increasing globally. While sharing common risk factors, the mechanism and consequences of concurrent CKD-OA are unclear. The aims...

Nrf2 participates in progression of osteoarthritis through modulating redox balance

Osteoarthritis (OA) is one of the most common degenerative joint diseases associated with aging, obesity and joint trauma, and is always associated with pain, joint deformity and dysfunction. Recent studies have shown that OA is closely related to oxidative stress, which serves as a major cause of chronic inflammation in cartilage, leading to irreversible structural changes in the joint. As a transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the antioxidant system, which regulates the expression of cytoprotective genes to facilitate the elimination of reactive oxygen species (ROS). In this review, we have summarized the dramatic function of oxidative stress in OA pathology, established a complex regulatory network of Nrf2 in OA progression, and aimed to provide new insights into the treatment of OA.

Early pain in females is linked to late pathological features in murine experimental osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease and a major cause of chronic pain in adults. The prevalence of OA is higher in female patients, who tend to have worse OA outcomes, partially due to pain. The association between joint pain and OA pathology is often inconclusive. Preclinical research studies have largely overlooked sex as a potential determinant in joint pain during OA. This study aimed to investigate the role of sex in joint pain in the collagenase-induced OA (CiOA) model and its link with joint pathology. Multiple aspects of pain were evaluated during identically executed experiments of CiOA in male and female C57BL/6J mice. Cartilage damage, osteophyte formation, synovial thickness, and cellularity were assessed by histology on day 56. The association between pain and pathology was investigated, disaggregated by sex. Differences in pain behavior between sexes were found in the majority of the evaluated pain methods. Females displayed lower weight bearing ability in the affected leg compared to males during the early phase of the disease, however, the pathology at the end stage was comparable between sexes. In the second cohort, males displayed increased mechanical sensitivity in the affected joint compared to females but also showed more cartilage damage at the end stage of the model. Within this cohort, gait analysis showed varied results. Males used the affected paw less often and displayed dynamic weight-bearing compensation in the early phase of the model. These differences were not observed in females. Other evaluated parameters displayed comparable gait behavior between males and females. A detailed analysis of individual mice revealed that seven out of 10 pain measurements highly correlated with OA histopathology in females (Pearson r range: 0.642-0.934), whereas in males this measurement was only two (Pearson r range: 0.645-0.748). Our data show that sex is a determinant in the link between pain-related behavior with OA features. Therefore, to accurately interpret pain data it is crucial to segregate data analysis by sex to draw the correct mechanistic conclusion.

LncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes.

In view of the association between long noncoding RNA OIP5-AS1 and osteoarthritis (OA) pathology, the corresponding potential mechanism is worthy of exploration. Primary chondrocytes were identified by morphological observation and immunohistochemical staining of collagen II. The association between OIP5-AS1 and miR-338-3p was analyzed by StarBase and dual-luciferase reporter assay. After the expression of OIP5-AS1 or miR-338-3p in interleukin (IL)-1β-stimulated primary chondrocytes and CHON-001 cells was manipulated, cell viability, proliferation, apoptosis rate, apoptosis-related protein (cleaved caspase-9, Bax) expressions, extracellular matrix (ECM) (matrix metalloproteinase (MMP)-3, MMP-13, aggrecan, and collagen II), PI3K/AKT pathway, and mRNA expressions of inflammatory factors (IL-6 and IL-8), OIP5-AS1, and miR-338-3p were determined by cell counting kit-8, EdU, flow cytometry, Western blot, and quantitative reverse transcription-polymerase chain reaction. As a result, the expression of OIP5-AS1 was downregulated in IL-1β-activated chondrocytes, while miR-338-3p was overexpressed. OIP5-AS1 overexpression reversed the effects of IL-1β on viability, proliferation, apoptosis, ECM degradation, and inflammation in chondrocytes. However, OIP5-AS1 knockdown exhibited opposite effects. Interestingly, the effects of OIP5-AS1 overexpression were partially offset by miR-338-3p overexpression. Furthermore, OIP5-AS1 overexpression blocked the PI3K/AKT pathway by modulating miR-338-3p expression. In sum, OIP5-AS1 promotes viability and proliferation, and inhibits apoptosis and ECM degradation in IL-1β-activated chondrocytes by targeting miR-338-3p through blocking the PI3K/AKT pathway, indicating an attractive strategy for OA treatment.

Transient receptor potential ankyrin 1 in the knee is involved in osteoarthritis pain

Transient receptor potential families play important roles in the pathology of osteoarthritis (OA) of the knee. While transient receptor potential ankyrin 1 (TRPA1) is also an essential component of the pathogenesis of various arthritic conditions, its association with pain is controversial. Thus, we researched whether TRPA1 is involved in knee OA pain by in vivo patch–clamp recordings and evaluated the behavioral responses using CatWalk gait analysis and pressure application measurement (PAM). Injection of the Trpa1 agonist, allyl isothiocyanate (AITC), into the knee joint significantly increased spontaneous excitatory synaptic current (sEPSC) frequency in the substantia gelatinosa of rats with knee OA, while injection of the Trpa1 antagonist, HC-030031, significantly decreased the sEPSC. Meanwhile, AITC did not affect the sEPSC in sham rats. In the CatWalk and PAM behavioral tests, AITC significantly decreased pain thresholds, but no difference between HC-030031 and saline injections was observed. Our results indicate that Trpa1 mediates knee OA-induced pain. We demonstrated that Trpa1 is activated in the knee joints of rats with OA, and Trpa1 activity enhanced the pain caused by knee OA.

JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy.

Interruption of iron homeostasis is correlated with cell ferroptosis and degenerative diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been reported as a vital mechanism to control cellular iron levels, but its impact on osteoarthritis (OA) pathology and the underline mechanism are unknown. Herein we aimed to investigate the role and regulatory mechanism of NCOA4 in chondrocyte ferroptosis and OA pathogenesis. We demonstrated that NCOA4 was highly expressed in cartilage of patients with OA, aged mice, post-traumatic OA mice, and inflammatory chondrocytes. Importantly, Ncoa4 knockdown inhibited IL-1β-induced chondrocyte ferroptosis and extracellular matrix degradation. Contrarily, overexpression of NCOA4 promoted chondrocyte ferroptosis and the delivery of Ncoa4 adeno-associated virus 9 into knee joint of mice aggravated post-traumatic OA. Mechanistic study revealed that NCOA4 was upregulated in a JNK-JUN signaling-dependent manner in which JUN could directly bind to the promoter of Ncoa4 and initial the transcription of Ncoa4. NCOA4 could interact with ferritin and increase autophagic degradation of ferritin and iron levels, which caused chondrocyte ferroptosis and extracellular matrix degradation. In addition, inhibition of JNK-JUN-NCOA4 axis by SP600125, a specific inhibitor of JNK, attenuated development of post-traumatic OA. This work highlights the role of JNK-JUN-NCOA4 axis and ferritinophagy in chondrocyte ferroptosis and OA pathogenesis, suggesting this axis as a potential target for OA treatment.

Therapeutic effect of C-type natriuretic peptide on persistent pain in a rat knee arthritis model.

Intra-articular injection of C-type natriuretic peptide (CNP) at the acute inflammatory stage suppressed fibrotic changes in the infrapatellar fat pad (IFP), articular cartilage degeneration, and persistent pain in a monoiodoacetic acid (MIA)-induced rat knee arthritis model. In this study, we administered CNP during the inflammation subsiding period to evaluate CNP effectiveness in knees with osteoarthritis (OA) pathology. 20male Wistar rats were randomly divided into two groups. The rats received an intra-articular injection of MIA solution in the right knee to induce inflammation-induced joint degeneration. One group subsequently received an intra-articular CNP injection for six consecutive days from day 8, whereas another group received vehicle solution. Pain avoidance behavior tests and histological analyses were conducted to examine the therapeutic effects of CNP. The incapacitance test indicated that the percent weight on the ipsilateral limb decreased after MIA injection by day 4 and continued to decrease until the end of the experiment in the vehicle group, suggesting persistent pain in the knee. Intra-articular injection of CNP reversed the weight-bearing ratio on day 19. Histological evaluation showed that the CNP group had more residual fat tissue in the IFP and fewer calcitonin gene-related peptide-positive nerve endings compared to the vehicle group. CNP could not reverse articular cartilage degeneration. Intra-articular injection of CNP after the IFP fibrosis onset had no significant effect on OA severity and extent. Nevertheless, CNP might be utilized therapeutically for OA treatment since it can alleviate persistent knee pain and inhibit structural changes in residual fat tissue.

Does Order of Operation Matter in Patients Who Have Concomitant Hip and Spine Pathology?

BackgroundIn patients, who have coexisting lumbar spine and degenerative hip disease, there remains uncertainty regarding whether hip or spine surgery should be performed first. We hypothesized that undergoing total hip arthroplasty (THA) would protect against subsequent lumbar spine surgery (LSS) in patients who have ‘hip-spine syndrome.’ MethodsA retrospective cohort study was performed from 2013 to 2021 on patients who had radiographically–confirmed hip osteoarthritis and degenerative lumbar spine pathology, evaluated separately in spine and arthroplasty clinics prior to surgical intervention. Included patients ultimately underwent THA and/or LSS. The primary outcome was survivorship free of LSS or THA after the other was initially performed. ResultsOf 256 patients, 206 (80.5%) underwent THA first. Only 14 of 206 (6.8%) who underwent THA required subsequent LSS, while 31 of 50 (62%) who underwent LSS required subsequent THA, (P < .001). At 5 years, there was 93.9% survivorship-free of LSS in the THA first group, compared to 44.7% survivorship-free of subsequent THA in the LSS group. Multivariate analyses showed that patients who had THA first had lower odds of undergoing subsequent surgery (odds ratio [OR]: 0.61, CI: 0.52-0.70, P < .001) compared to those who underwent LSS first. Additionally, those who have higher initial Kellgren-Lawrence grade hip osteoarthritis had lower odds (OR: 0.94, CI: 0.89-0.99, P = .04), and those who have progressive neurologic deficits (OR: 2.64, CI: 1.89-3.7, P < .001) and neurogenic claudication (OR: 1.15, CI: 1.06-1.24, P = .001) had increased odds of undergoing subsequent LSS. ConclusionPatients with ‘hip-spine syndrome’ may receive more initial benefit from undergoing THA, potentially reducing the subsequent need for LSS. The exceptions were those patients who had lower-severity hip osteoarthritis and symptoms of major spinal stenosis.

Inhibition of Leukotriene A4 Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis.

Chronic inflammation plays an important role in the osteoarthritis (OA) pathology but how this influence OA disease progression is unclear. Leukotriene B4 (LTB4) is a potent proinflammatory lipid mediator generated from arachidonic acid through the sequential activities of 5-lipoxygenase, 5-lipoxygenase-activating protein, Leukotriene A4 hydrolase (LTA4H) and its downstream product LTB4. The aim of this study is to investigate the involvement and the potential therapeutic target of the LTB4 pathway in OA disease progression. Both clinical human cartilage samples (n = 7) and mice experimental OA models (n = 6) were used. The levels of LTA4H 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 LTA4H pathway was associated with cartilage degeneration and synovitis inflammation in OA mice models and human articular chondrocytes. We found that both LTA4H and LTB4 receptor (BLT1) were highly expressed in human and mice OA cartilage. Inhibition of LTA4H suppressed cartilage degeneration and synovitis in OA mice model. Furthermore, inhibition of LTA4H promoted cartilage regeneration by upregulating chondrogenic genes expression such as aggrecan (ACAN), collagen 2A1 (COL2A1), and SRY-Box transcription factor 9 (SOX9). Our results indicate that the LTA4H pathway is a crucial regulator of OA pathogenesis and suggest that LTA4H could be a therapeutic target in combat OA.

Analysis of the regulatory role of miR-34a-5p/PLCD3 in the progression of osteoarthritis

Osteoarthritis is a heterogeneous disease with a complex etiology. However, there is no effective treatment strategy at present. The purpose of this study was to explore the miRNA‒mRNA regulatory network and molecular mechanism that regulate the progression of osteoarthritis. In this article, we downloaded datasets (GSE55457, GSE82107, GSE143514 and GSE55235) from Gene Expression Omnibus (GEO) to screen differentially expressed mRNAs in osteoarthritis. Then, through weighted gene coexpression network (WGCNA), functional enrichment, protein‒protein interaction (PPI) network, miRNA‒mRNA coexpression network, ROC curve, and immune infiltration analyses and qPCR, the mRNA PLCD3, which was highly expressed in osteoarthritis and had clinical predictive value, was screened. We found that PLCD3 directly targets miR-34a-5p through DIANA and dual-luciferase experiments. The expression levels of PLCD3 and miR-34a-5p were negatively correlated. In addition, CCK-8 and wound healing assays showed that the miR-34a-5p mimic inhibited hFLS-OA cell proliferation and promoted hFLS-OA cell migration. PLCD3 overexpression showed the opposite trend. Western blotting further found that overexpression of miR-34a-5p reduced the protein expression levels of p-PI3K and p-AKT, while overexpression of PLCD3 showed the opposite trend. In addition, combined with the effect of the PI3K/AKT pathway inhibitor BIO (IC50 = 5.95μM), the results showed that overexpression of miR-34a-5p increased the inhibitory effects of BIO on p-PI3K and p-AKT protein expression, while overexpression of PLCD3 significantly reversed these inhibitory effects. Overall, the miR-34a-5p/PLCD3 axis may mediate the PI3K/AKT pathway in regulating cartilage homeostasis in synovial osteoarthritis. These data indicate that miR-34a-5p/PLCD3 may be a new prognostic factor in the pathology of synovial osteoarthritis.

Targeting Synovial Lymphatic Function as a Novel Therapeutic Intervention for Age-Related Osteoarthritis in Mice.

The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, are crucial for lymphangiogenesis. However, their involvement in age-related osteoarthritis (OA) is unknown. This study was undertaken to determine whether the SLS and the VEGF-C/VEGFR-3 pathway contribute to the development and progression of age-related OA, using a murine model of naturally occurring joint disease. SLS function was assessed in the knees of young (3-month-old) and aged (19-24-month-old) male and female C57BL/6J mice via a newly established in vivo IVIS-dextran imaging approach, which, in addition to histology, was used to assess the effects of VEGF-C treatment on SLS function and OA pathology in aged mice. RNA-sequencing of synovial tissue was performed to explore molecular mechanisms of the disease in the mouse knee joints. Results showed that aged mice had impaired SLS function, including decreases in joint clearance (mean T1/2 of signal intensity clearance, 2.8 hours in aged mice versus 0.5 hours in young mice; P < 0.0001), synovial influx (mean ± SD 1.7 ± 0.8% in aged mice versus 4.1 ± 1.9% in young mice; P=0.0004), and lymph node draining capacity (mean ± SD epifluorescence total radiant intensity ([photons/second]/[μW/cm2 ]) 1.4 ± 0.8 in aged mice versus 3.7 ± 1.2 in young mice; P < 0.0001). RNA-sequencing of the synovial tissue showed that Vegf-c and Vegfr3 signaling genes were decreased in the synovium of aged mice. VEGF-C treatment resulted in improvements in SLS function in aged mice, including increased percentage of signal intensity joint clearance (mean ± SD 63 ± 9% in VEGF-C-treated aged mice versus 52 ± 15% in vehicle-treated aged mice; P=0.012), increased total articular cartilage cross-sectional area (mean ± SD 0.38 ± 0.07 mm2 in VEGF-C-treated aged mice versus 0.26 ± 0.07 mm2 in vehicle-treated aged mice; P < 0.0001), and decreased percentage of matrix metallopeptidase 13-positive staining area within total synovial area in 22-month-old VEGF-C-treated mice versus 22-month-old vehicle-treated mice (mean ± SD decrease 7 ± 2% versus 4 ± 1%; P=0.0004). SLS function is reduced in the knee joints of aged mice due to decreased VEGF-C/VEGFR-3 signaling. VEGF-C treatment attenuates OA joint damage and improves synovial lymphatic drainage in aged mice. The SLS and VEGF-C/VEGFR-3 signaling represent novel physiopathologic mechanisms that could potentially be used as therapeutic targets for age-related OA.

A Review of Recent Innovations in Cartilage Regeneration Strategies for the Treatment of Primary Osteoarthritis of the Knee: Intra-articular Injections.

The pathology of primary osteoarthritis (OA) begins with structural cartilage damage, which initiates a self-propagating inflammatory pathway that further exacerbates cartilage deterioration. Current standard of care for knee primary OA involves treating the inflammatory symptoms to manage pain, which includes intra-articular (IA) injections of cortisone, an anti-inflammatory steroid, followed by a series of joint-cushioning hyaluronic acid gel injections. However, these injections do not delay the progression of primary OA. More focus on the underlying cellular pathology of OA has prompted researchers to develop treatments targeting the biochemical mechanisms of cartilage degradation. Researchers have yet to develop a United States Food and Drug Administration (FDA)-approved injection that has been demonstrated to significantly regenerate damaged articular cartilage. This paper reviews the current research on experimental injections aimed at achieving cellular restoration of the hyaline cartilage tissue of the knee joint. Narrative review. The authors conducted a narrative literature review examining studies on primary OA pathogenesis and a systematic review of non-FDA-approved IA injections for the treatment of primary OA of the knee, described as "disease-modifying osteoarthritis drugs" in phase 1, 2, and 3 clinical trials. New treatment approaches for primary OA investigate the potential of genetic therapies to restore native cartilage. It is clear that the most promising IA injections that could improve treatment of primary OA are bioengineered advanced-delivery steroid-hydrogel preparations, ex vivo expanded allogeneic stem cell injections, genetically engineered chondrocyte injections, recombinant fibroblast growth factor therapy, injections of selective proteinase inhibitors, senolytic therapy via injections, injectable antioxidant therapies, injections of Wnt pathway inhibitors, injections of nuclear factor-kappa β inhibitors, injections of modified human angiopoietin-like-3, various potential viral vector-based genetic therapy approaches, and RNA genetic technology administered via injections.

Bulk RNA-seq analyses of mandibular condylar cartilage in a post-traumatic TMJ osteoarthritis rabbit model.

The temporomandibular joint (TMJ) is anatomically comprised of the mandibular condylar cartilage (CC) lined with fibrocartilaginous superficial zone and is crucial for eating and dental occlusion. TMJ osteoarthritis (OA) leads to pain, joint dysfunction and permanent loss of cartilage tissue. However, there are no drugs clinically available that ameliorate OA and little is known about global profiles of genes that contribute to TMJ OA. Furthermore, animal models that recapitulate the complexity of signalling pathways contributing to OA pathogenesis are crucial for designing novel biologics that thwart OA progression. We have previously developed a New Zealand white rabbit TMJ injury model that demonstrates CC degeneration. Here, we performed genome-wide profiling to identify new signalling pathways critical for cellular functions during OA pathology. Temporomandibular joint OA was surgically induced in New Zealand white rabbits. Three months following injury, we performed global gene expression profiling of the TMJ condyle. RNA samples from TMJ condyles were subjected to sequencing. After raw RNA-seq data were mapped to relevant genomes, differential expression was analysed with DESeq2. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted. Our study revealed multiple pathways altered during TMJ OA induction including the Wnt, Notch and PI3K-Akt signalling pathways. We demonstrate an animal model that recapitulates the complexity of the cues and signals underlying TMJ OA pathogenesis, which is essential for developing and testing novel pharmacologic agents to treat OA.

Intensive cholesterol-lowering treatment reduces synovial inflammation during early collagenase-induced osteoarthritis, but not pathology at end-stage disease in female dyslipidemic E3L.CETP mice

The association between metabolic syndrome (MetS) and osteoarthritis (OA) development has become increasingly recognized. In this context, the exact role of cholesterol and cholesterol-lowering therapies in OA development has remained elusive. Recently, we did not observe beneficial effects of intensive cholesterol-lowering treatments on spontaneous OA development in E3L.CETP mice. We postulated that in the presence of local inflammation caused by a joint lesion, cholesterol-lowering therapies may ameliorate OA pathology. Female ApoE3∗Leiden.CETP mice were fed a cholesterol-supplemented Western type diet. After 3 weeks, half of the mice received intensive cholesterol-lowering treatment consisting of atorvastatin and the anti-PCSK9 antibody alirocumab. Three weeks after the start of the treatment, OA was induced via intra-articular injections of collagenase. Serum levels of cholesterol and triglycerides were monitored throughout the study. Knee joints were analyzed for synovial inflammation, cartilage degeneration, subchondral bone sclerosis and ectopic bone formation using histology. Inflammatory cytokines were determined in serum and synovial washouts. Cholesterol-lowering treatment strongly reduced serum cholesterol and triglyceride levels. Mice receiving cholesterol-lowering treatment showed a significant reduction in synovial inflammation (P=0.008, WTD: 95% CI: 1.4- 2.3; WTD+AA: 95% CI: 0.8- 1.5) and synovial lining thickness (WTD: 95% CI: 3.0-4.6, WTD+AA: 95% CI: 2.1-3.2) during early-stage collagenase-induced OA. Serum levels of S100A8/A9, MCP-1 and KC were significantly reduced after cholesterol-lowering treatment (P=0.0005, 95% CI:-46.0 to-12.0; P=2.8×10-10, 95% CI:-398.3 to-152.1; P=2.1×10-9,-66.8 to-30.4, respectively). However, this reduction did not reduce OA pathology, determined by ectopic bone formation, subchondral bone sclerosis and cartilage damage at end-stage disease. This study shows that intensive cholesterol-lowering treatment reduces joint inflammation after induction of collagenase-induced OA, but this did not reduce end stage pathology in female mice.

Dynamic chromatin accessibility tuning by the long noncoding RNA ELDR accelerates chondrocyte senescence and osteoarthritis

Epigenetic reprogramming plays a critical role in chondrocyte senescence during osteoarthritis (OA) pathology, but the underlying molecular mechanisms remain to be elucidated. Here, using large-scale individual datasets and genetically engineered (Col2a1-CreERT2;Eldrflox/flox and Col2a1-CreERT2;ROSA26-LSL-Eldr+/+ knockin) mouse models, we show that a novel transcript of long noncoding RNA ELDR is essential for the development of chondrocyte senescence. ELDR is highly expressed in chondrocytes and cartilage tissues of OA. Mechanistically, exon 4 of ELDR physically mediates a complex consisting of hnRNPL and KAT6A to regulate histone modifications of the promoter region of IHH, thereby activating hedgehog signaling and promoting chondrocyte senescence. Therapeutically, GapmeR-mediated silencing of ELDR in the OA model substantially attenuates chondrocyte senescence and cartilage degradation. Clinically, ELDR knockdown in cartilage explants from OA-affected individuals decreased the expression of senescence markers and catabolic mediators. Taken together, these findings uncover an lncRNA-dependent epigenetic driver in chondrocyte senescence, highlighting that ELDR could be a promising therapeutic avenue for OA.

The effect of postmenopausal osteoporosis on subchondral bone pathology in a rat model of knee osteoarthritis

This study aimed to investigate the additional effect of ovariectomy-induced osteoporosis (OP) on the pathology of knee osteoarthritis (OA) in a rat meniscectomized model, particularly focusing on subchondral bone changes and pain behaviour. Rats were divided into four groups, sham, OP, OA, OP plus OA, and assessed for histology, osteoclast activity, subchondral bone microstructure, and pain-related behaviour. Rats with OP plus OA had significantly increased calcified cartilage and subchondral bone damage scores, increased densities of subchondral osteoclasts in the weight-bearing area, and more porous subchondral trabecular bone compared with rats with OA. Loss of tidemark integrity was observed most frequently in rats with OP plus OA. The density of subchondral osteoclasts correlated with the calcified cartilage and subchondral bone damage score in rats with OA (OA and OP plus OA). No significant differences in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) expression ratio in subchondral bone and pain-related behavioural tests were observed between rats with OA and rats with OP plus OA. In rats with OA, coexisting OP potentially aggravated OA pathology mainly in calcified cartilage and subchondral trabecular bone by increasing subchondral osteoclast activity.