Rabbit Model Of Osteoarthritis Research Articles

Miao medicine Gu Yan Xiao tincture inhibits mTOR to stimulate chondrocyte autophagy in a rabbit model of osteoarthritis

Ethnopharmacological relevanceThe Gu Yan Xiao tincture, a blend of traditional Chinese herbs, is traditionally used for osteoarthritis and related pain. This study investigated its mechanism of action in order to rationalize and validate its therapeutic use. Aim of the studyThis study analyzed, in a rabbit model of knee osteoarthritis, whether and how Gu Yan Xiao tincture exerts therapeutic benefits by modulating chondrocyte autophagy. Materials and methodsThe active constituents within the GYX tincture were identified using liquid chromatography-mass spectrometry. The rabbit model was established by injecting animals with type II collagenase intra-articularly, and the effects of topically applied tincture were examined on osteoarthritis lesions of the knee using histopathology, micro-computed tomography and x-ray imaging. Effects of the tincture were also evaluated on levels of inflammatory cytokines, matrix metalloproteases, and autophagy in chondrocytes. As a positive control, animals were treated with sodium diclofenac. ResultsThe tincture mitigated the reduction in joint space, hyperplasia of the synovium and matrix metalloproteases in serum that occurred after injection of type II collagenase in rabbits. These therapeutic effects were associated with inhibition of mTOR and activation of autophagy in articular chondrocytes. Inhibiting mTOR with rapamycin potentiated the therapeutic effects of the tincture, while inhibiting autophagy with 3-methyladenine antagonized them. ConclusionsGu Yan Xiao tincture mitigates tissue injury in a rabbit model of osteoarthritis, at least in part by inhibiting mTOR and thereby promoting autophagy in chondrocytes. These results rationalize the use of the tincture not only against osteoarthritis but also potentially other diseases involving inhibition of autophagy in bones and joints.

Intra-Articular Injection of Interleukin-8 Neutralizing Monoclonal Antibody Effectively Attenuates Osteoarthritis Progression in Rabbits.

Cytokines are implicated in the pathogenesis of osteoarthritis (OA), and this study aims to assess the therapeutic potential of an IL-8 neutralizing monoclonal antibody (mAb) for OA intervention. The study employed a rabbit model of OA induced by anterior cruciate ligament transection (ACLT) surgery to investigate the effects of an interleukin (IL)-8 neutralizing mAb, with hyaluronic acid (HA) used as a positive control. Primary outcomes assessed in the rabbits included cartilage repair, synovitis, joint effusion, changes in footprints, and lower limb loading conditions. Compared to HA, intra-articular injection of the IL-8 neutralizing mAb demonstrated a more pronounced attenuation of OA progression and enhancement of cartilage repair. We observed a reduction in synovitis and joint effusion, indications of bone marrow edema, as well as improvements in lower limb function. In knees treated with the neutralizing IL-8 mAb, there was a significant decrease in IL-8 levels within the synovial tissues. The IL-8 neutralizing mAb exhibits promising therapeutic potential in the management of OA by attenuating inflammation and facilitating cartilage repair. However, further investigations are warranted to comprehensively elucidate the underlying mechanisms, optimize treatment protocols, and ensure the long-term safety and efficacy of this innovative therapeutic approach.

Effects of Leukocyte-rich platelet-rich plasma and Leukocyte-poor platelet-rich plasma on cartilage in a rabbit osteoarthritis model.

Osteoarthritis is a prevalent chronic disease. One of its primary pathological processes involves the degeneration of articular cartilage. Platelet-rich plasma (PRP) contains cytokines and growth factors that can stimulate the repair and regeneration of articular cartilage tissues. PRP may also slow the progression of osteoarthritis. The purpose of this experiment is to compare the efficacy of Leukocyte poor (LP) - PRP and Leukocyte rich (LR) - PRP in treating rabbit osteoarthritis and to investigate their mechanisms of action. Analyzing the impact of leukocytes on PRP therapeutic effectiveness will provide a valuable clinical reference for the choice of which PRP is better for the treatment of osteoarthritis. A rabbit osteoarthritis model was established by injecting papain into the knee joint cavity, and LP-PRP and LR-PRP were prepared through different centrifugation methods for injection into the knee joint cavity. Eight weeks after injection, rabbit knee cartilage specimens were observed for gross changes, HE staining, senna O-solid green staining, and immunohistochemistry of type II collagen and were quantitatively compared using Pelletier's score, Mankin's pathology score, and ImageJ image processing software. Injection of papain into the knee joint cavity successfully established a rabbit model of osteoarthritis. All three evaluation indexes differed significantly from those of the blank group (P<0.05). LP-PRP and LR-PRP exhibited therapeutic effects when compared with the model group. The two PRP groups had similar gross tissue appearance and pathology (P>0.05). The LR-PRP group had higher collagen type-II expression (P < 0.05) than the LP-PRP group. Both LP-PRP and LR-PRP proved therapeutic for the rabbit papain osteoarthritis model. The difference in leukocyte content between the two groups did not yield different cartilage morphology or other factors by 8 weeks posttreatment. LR-PRP displayed the ability to release more factors relevant to the metabolism of type II collagen than LP-PRP, enabling the preservation of into cartilage collagen content of type II collagen and delaying osteoarthritis progression.

Human Adipose-derived Stem Cells Upregulate IGF-1 and Alleviate Osteoarthritis in a Two-stage Rabbit Osteoarthritis Model.

In recent years, it has been known that mesenchymal stem cells (MSCs) have the potential to treat osteoarthritis (OA). This study aimed to investigate the effects of intraarticular injection of human adipose-derived stem cells (hADSCs) in a new double-damage rabbit osteoarthritis model. The OA model was established surgically first by medial collateral ligament and anterior insertional ligament transection and medical meniscectomy, then by articular cartilage full-thickness defect. At six weeks following surgery, hADSCs were labeled with Enhanced Green Fluorescence Protein expressing lentivirus FG12 and injected into the knee joints. All rabbits were sacrificed at 4- and 8 weeks post-surgery. Assessments were carried out by macroscopic examination, immunohistochemistry staining, magnetic resonance imaging, qRT-PCR and ELISA analysis. At 4- and 8 weeks, hADSCs injection showed less cartilage loss, few fissures and few cracks, decreased volume of joint effusion and cartilage defect measured with MRI. Furthermore, ELISA and qRT-PCR methods showed that hADSCs treatment increased the level of IGF-1. Our data suggest that hADSC transplantation promotes articular cartilage healing in the double-damage rabbit osteoarthritis model, IGF-1 may play an essential role in the hADSC-based cartilage repair process. Transplantation of hADSCs may be suitable for clinical application in the treatment of osteoarthritis.

Retracted] Acetylsalicylic acid combined with diclofenac inhibits cartilage degradation in rabbit models of osteoarthritis.

[This retracts the article DOI: 10.3892/etm.2016.3560.].

Total Glucosides of Peony Alleviate Joint Destruction in Rabbits With Osteoarthritis

Objective Although many painkillers can be used to relieve the symptoms of osteoarthritis (OA), these drugs do not address joint bone degeneration and muscle wasting, highlighting the need for alternative treatments. This study evaluated the ability of various plant extracts to inhibit joint destruction, focusing on the total glucosides of peony (TGP) obtained from the normal Chinese medication white peony. Methods A rabbit OA model was established by anterior cruciate ligament resection (ACLT) and TGP treatment was initiated for 3 months. The morphologies of the skeletal muscle fibers, articular cartilage, and subchondral bone of the knee joint were histologically observed via X-ray and micro-computed tomography scan. Results TGP significantly reduced the histopathological changes associated with skeletal muscle atrophy and inflammation, and alleviated cartilage degeneration. In addition, TGP treatment significantly improved the bone density and microstructure of subchondral bone in rabbit knee joints compared with the model group. Conclusion The results suggested that TGP treatment may alleviate the progression of osteoarthritis and reduce the destruction of joint cartilage and bone in ACLT.

Donor-Matched Peripheral Blood–Derived Mesenchymal Stem Cells Combined With Platelet-Rich Plasma Synergistically Ameliorate Surgery-Induced Osteoarthritis in Rabbits: An In Vitro and In Vivo Study

Background: Osteoarthritis (OA) is a common disease that causes joint pain and disability. Stem cell therapy is emerging as a promising treatment for OA. Purpose: To evaluate the ability of peripheral blood–derived mesenchymal stem cells (PBMSCs) combined with donor-matched platelet-rich plasma (PRP) to treat OA in a rabbit model. Study Design: Controlled laboratory study. Methods: PBMSCs and donor-matched PRP were isolated and prepared from the same rabbit. PBMSCs were treated with serum-free medium, fetal bovine serum, and PRP; a series of PBMSC behaviors, including proliferation, migration, and adhesion, were compared among groups. The ability of PBMSCs or PRP alone and PBMSCs+PRP to protect chondrocytes against proinflammatory cytokine (interleukin 1β [IL-1β]) treatment was compared by analyzing reactive oxygen species (ROS)–scavenging ability and apoptosis. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate the expression of extracellular matrix (ECM) metabolism genes and proteins, and Western blotting was used to explore the potential mechanism of the corresponding signaling pathway. In vivo, the effect of PBMSCs+PRP on cartilage and inflammation of the synovium was observed in a surgery-induced OA rabbit model via gross observation, histological and immunohistochemical staining, and enzyme-linked immunosorbent assay. Results: Proliferation, migration, and adhesion ability were enhanced in PBMSCs treated with PRP. Moreover, compared with either PBMSCs or PRP alone, PBMSCs+PRP enhanced ROS-scavenging ability and inhibited apoptosis in IL-1β–treated chondrocytes. PBMSCs+PRP also reversed the IL-1β–induced degradation of collagen type 2 and aggrecan and increased expression of matrix metalloproteinase 13, and this effect was related to increased expression of ECM synthesis and decreased expression of degradation and inflammatory genes and proteins. Mechanistically, PBMSCs+PRP reduced the phosphorylation of inhibitor of nuclear factor-κBα (IκBα), which further inhibited the phosphorylation of downstream nuclear factor–κB (NF-κB) in the NF-κB signaling pathway. In vivo, compared with PBMSCs or PRP alone, intra-articular (IA) injection of PBMSCs+PRP enhanced cartilage regeneration and attenuated synovial inflammation in OA-induced rabbits. Conclusion: These results demonstrate that PRP could enhance biological activities, including viability, migration, and adhesion, in PBMSCs. PBMSCs+PRP could rescue ECM degeneration by inhibiting inflammatory signaling in IL-1β–treated OA chondrocytes. In addition, IA injection of PBMSCs+PRP effectively attenuated OA progression in a surgery-induced OA rabbit model. Clinical Relevance: PBMSCs+PRP may provide a promising treatment for knee OA, and this study can advance the related basic research.

Chondroprotective Effects of Chondrogenic Differentiated Adipose-Derived Mesenchymal Stem Cells Sheet on Degenerated Articular Cartilage in an Experimental Rabbit Model.

Adipose-derived stem cells (ADSCs) have been studied for many years as a therapeutic option for osteoarthritis (OA); however, their efficacy remains insufficient. Since platelet-rich plasma (PRP) induces chondrogenic differentiation in ADSCs and the formation of a sheet structure by ascorbic acid can increase the number of viable cells, we hypothesized that the injection of chondrogenic cell sheets combined with the effects of PRP and ascorbic acid may hinder the progression of OA. The effects of induction of differentiation by PRP and formation of sheet structure by ascorbic acid on changes in chondrocyte markers (collagen II, aggrecan, Sox9) in ADSCs were evaluated. Changes in mucopolysaccharide and VEGF-A secretion from cells injected intra-articularly in a rabbit OA model were also evaluated. ADSCs treated by PRP strongly chondrocyte markers, including type II collagen, Sox9, and aggrecan, and their gene expression was maintained even after sheet-like structure formation induced by ascorbic acid. In this rabbit OA model study, the inhibition of OA progression by intra-articular injection was improved by inducing chondrocyte differentiation with PRP and sheet structure formation with ascorbic acid in ADSCs.

HUCMSCS-DERIVED EXOSOMES SUPPRESS OSTEOARTHRITIS IN RABBITS THROUGH INHIBITING CCL2

Osteoarthritis (OA), the most prevalent chronic joint disease, represents a relevant social and economic burden worldwide. Human umbilical cord mesenchymal stem cells (HUCMSCs) have been used for injection into the joint cavity to treat OA. The aim of this article is to clarify whether Huc-MSCs derived exosomes could inhibit the progression of OA and the mechanism in this process.A rabbit OA model was established by the transection of the anterior cruciate ligament. The effects of HUCMSCs or exosomes derived from HUCMSCs on repairing articular cartilage of knee osteoarthritis was examined by micro-CT. Immunohistochemical experiments were used to confirm the expression of relevant inflammatory molecules in OA. In vitro experiments, Transwell assay was used to assess the migration of macrophages induced by TNF-a.Results showed that a large number of macrophages migrated in arthcular cavity in OA model in vivo, while local injection of HUCMSCs and exosomes did repair the articular cartilage. Immunohistochemical results suggested that the expression of CCL2 and CD68 in the OA rabbit model increased significantly, but was significantly reduced by HUCMSCs or exosomes. Transwell assay showed that both HUCMSCs and exosomes can effectively inhibit the migration of macrophage.In conclusion, the exosomes derived by HUCMSCs might might rescue cartilage defects in rabbit through its anti-inflammatory effects through inhibiting CCL2.

MicroRNA-146a-5p alleviates the pathogenesis of osteoarthritis by inhibiting SDF-1/CXCR4-induced chondrocyte autophagy.

SDF-1/CXCR4 signaling promotes osteoarthritis (OA) development. CXCR4 is a potential target of miR-146a-5p. This study investigated the therapeutic role and the underlying mechanism of miR-146a-5p in OA. Human primary chondrocytes C28/I2 were stimulated with SDF-1. Cell viability and LDH release were examined. Chondrocyte autophagy was assessed using Western blot analysis, ptfLC3 transfection, and transmission electron microscopy. MiR-146a-5p mimics were transfected into C28/I2 cells to investigate the role of miR-146a-5p in SDF-1/CXCR4-induced autophagy of chondrocytes. An SDF-1-induced rabbit OA model was established to investigate the therapeutic role of miR-146a-5p in OA. Histological staining was performed to observe the morphology of osteochondral tissue. SDF-1/CXCR4 signaling promoted autophagy in C28/I2 cells, as demonstrated by increased LC3-II protein expression and autophagic flux induced by SDF-1. SDF-1 treatment significantly inhibited cell proliferation while promoting necrosis and autophagosome formation in C28/I2 cells. In the presence of SDF-1, miR-146a-5p overexpression in C28/I2 cells suppressed CXCR4 mRNA expression, LC3-II and Beclin-1 protein expression, LDH release, and autophagic flux. In addition, SDF-1 increased the autophagy of chondrocytes in rabbits and promoted the development of OA. Compared with the negative control, miR-146a-5p significantly reduced the morphological abnormalities of the rabbit cartilage that were induced by SDF-1, as well as the number of LC3-II-positive cells, protein expression of LC3-II and Beclin 1, and mRNA expression of CXCR4 in osteochondral tissue. These effects were reversed by the autophagy agonist rapamycin. SDF-1/CXCR4 promotes OA development by enhancing chondrocyte autophagy. MicroRNA-146a-5p may alleviate OA by suppressing CXCR4 mRNA expression and SDF-1/CXCR4-induced chondrocyte autophagy.

Micro-computed Tomography-Based Collagen Orientation and Anisotropy Analysis of Rabbit Articular Cartilage

The collagen network is the highly organized backbone of articular cartilage providing tissue tensile stiffness and restricting proteoglycan bleaching out of the tissue. Osteoarthritis (OA) diminishes proper collagen network adaptation. Our aim was to provide quantitative three-dimensional (3D) information of the cartilage collagen network adaptation in early osteoarthritis using high resolution micro-computed tomography (µCT)-imaging. Osteochondral samples from the femoral condyles were collected from healthy (N = 8, both legs) and experimental OA rabbit model with anterior cruciate ligament transection (N = 14, single leg). Samples were processed for cartilage µCT-imaging and histological evaluation with polarized light microscopy (PLM). Structure tensor analysis was used to analyse the collagen fibre orientation and anisotropy of the µCT-images, and PLM was used as a validation for structural changes. Depth-wise comparison of collagen fibre orientation acquired with µCT-imaging and PLM correlated well, but the values obtained with PLM were systematically greater than those measured with µCT-imaging. Structure tensor analysis allowed for 3D quantification of collagen network anisotropy. Finally, µCT-imaging revealed only minor differences between the control and experimental groups.

Adipose stem cell transplantation using adhesive protein-based viscous immiscible liquid for cartilage reconstruction

Articular cartilage (AC) is the smooth tissue that covers the end of bones and absorbs external impacts. AC can be damaged by various types of impacts. Thus, damaged AC can trigger the development of osteoarthritis (OA). With the limited intrinsic healing capacity of AC, cell transplantation has been recognized as a possible means of AC reconstitution. However, transplanted stem cells disappear from the transplantation site rapidly, abrogating the original intent of cell transplantation. In the present work, a viscous immiscible liquid-phase bioadhesive using bioengineered mussel adhesion protein (MAP) was applied for prolonged retention of transplanted stem cells in defective AC and retained stem cells in situ. Through electrostatic interactions with high-molecular-weight hyaluronic acid (HA), MAP was formulated into a viscous immiscible liquid phase complex coacervate (MAP-HA) with self-encapsulation of stem cells. MAP-HA exhibited excellent rheological and adhesive properties without cytotoxicity. Through in vivo rabbit OA model evaluation, we proved that immobilizing transplanted cells and preventing dispersion into the joint cavity by MAP-HA can increase the survival of transplanted cells and enhance their therapeutic effects. Therefore, stem cell-encapsulated biocompatible MAP-HA can be used as a cell-retaining bioadhesive scaffold in effective cartilage regeneration.

Injectable nanofiber microspheres modified with metal phenolic networks for effective osteoarthritis treatment.

Osteoarthritis (OA) is one of the most common chronic musculoskeletal diseases, which accounts for a large proportion of physical disabilities worldwide. Herein, we fabricated injectable gelatin/poly(L-lactide)-based nanofibrous microspheres (MS) via electrospraying technology, which were further modified with tannic acid (TA) named as TMS or metal phenolic networks (MPNs) consisting of TA and strontium ions (Sr2+) and named as TSMS to enhance their bioactivity for OA therapy. The TA-modified microspheres exhibited stable porous structure and anti-oxidative activity. Notably, TSMS showed a sustained release of TA as compared to TMS, which exhibited a burst release of TA. While all types of microspheres exhibited good cytocompatibility, TSMS displayed good anti-inflammatory properties with higher cell viability and cartilage-related extracellular matrix (ECM) secretion. The TSMS microspheres also showed less apoptosis of chondrocytes in the hydrogen peroxide (H2O2)-induced inflammatory environment. The TSMS also inhibited the degradation of cartilage along with the considerable repair outcome in the papain-induced OA rabbit model in vivo as well as suppressed the expression level of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β). Taken together, TSMS may provide a highly desirable therapeutic option for intra-articular treatment of OA. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) is a chronic disease, which is caused by the inflammation of joint. Current treatments for OA achieve pain relief but hardly prevent or slow down the disease progression. Microspheres are at the forefront of drug delivery and tissue engineering applications, which can also be minimal-invasively injected into the joint. Polyphenols and therapeutic ions have been shown to be beneficial for the treatment of diseases related to the joints, including OA. Herein, we prepared gelatin/poly(L-lactide)-based nanofibrous microspheres (MS) via electrospinning incorporated electrospraying technology and functionalized them with the metal phenolic networks (MPNs) consisting of TA and strontium ions (Sr2+), and assessed their potential for OA therapy both in vitro and in vivo.

Bone marrow stem cells incubated with ellipticine regenerate articular cartilage by attenuating inflammation and cartilage degradation in rabbit model.

Ellipticine (Ellip.) was recently reported to have beneficial effects on the differentiation of adipose-derived stem cells into mature chondrocyte-like cells. On the other hand, no practical results have been derived from the transplantation of bone marrow stem cells (BMSCs) in a rabbit osteoarthritis (OA) model. This study examined whether autologous BMSCs incubated with ellipticine (Ellip.+BMSCs) could regenerate articular cartilage in rabbit OA, a model similar to degenerative arthritis in human beings. A portion of rabbit articular cartilage was surgically removed, and Ellip.+BMSCs were transplanted into the lesion area. After two and four weeks of treatment, the serum levels of proinflammatory cytokines, i.e., tumor necrosis factor α (TNF-α) and prostaglandin E2 (PGE2), were analyzed, while macroscopic and micro-computed tomography (CT) evaluations were conducted to determine the intensity of cartilage degeneration. Furthermore, immuno-blotting was performed to evaluate the mitogen-activated protein kinases, PI3K/Akt, and nuclear factor-κB (NF-κB) signaling in rabbit OA models. Histological staining was used to confirm the change in the pattern of collagen and proteoglycan in the articular cartilage matrix. The transplantation of Ellip.+BMSCs elicited a chondroprotective effect by reducing the inflammatory factors (TNF-α, PGE2) in a time-dependent manner. Macroscopic observations, micro-CT, and histological staining revealed articular cartilage regeneration with the downregulation of matrix-metallo proteinases (MMPs), preventing articular cartilage degradation. Furthermore, histological observations confirmed a significant boost in the production of chondrocytes, collagen, and proteoglycan compared to the control group. Western blotting data revealed the downregulation of the p38, PI3K-Akt, and NF-κB inflammatory pathways to attenuate inflammation. The transplantation of Ellip.+BMSCs normalized the OA condition by boosting the recovery of degenerated articular cartilage and inhibiting the catabolic signaling pathway.

Intra-articular injection of clioquinol ameliorates osteoarthritis in a rabbit model.

Osteoarthritis (OA) is characterized by the degeneration of articular cartilage. Decreased autophagy is tightly associated with chondrocyte death, which contributes to the progression of OA. Thus, pharmacological activation of autophagy may be a promising therapeutic approach for OA. Here, we discovered that clioquinol, an antibiotic, significantly induces autophagy in OA chondrocytes from human tissue and rabbit model. Meanwhile, clioquinol can also augment the expression of extracellular matrix (ECM) components and suppress inflammatory mediators to improve OA microenvironment. Intra-articular injection of clioquinol can greatly prevent or slow down the development of this disease in a trauma-induced rabbit model of osteoarthritis. Such protective effect induced by clioquinol was at least in part explained by decreasing chondrocyte apoptosis and increasing autophagy. This study reveals the therapeutic potential of clioquinol in OA treatment.

Natural product, bilobalide, improves joint health in rabbits with osteoarthritis by anti-matrix degradation and antioxidant activities.

Osteoarthritis (OA) is a common chronic musculoskeletal disease reported in veterinary clinics that severely reduces the quality of life of animals. The natural product, bilobalide, has positive effects on chondroprotection but its exact mechanism of action is unclear. This study aimed to investigate the antioxidant and anti-matrix degradation activities of bilobalide in a rabbit model of OA and its protective effects on joints. We also investigated the possible mechanisms underlying these effects. The rabbit OA model was established by intra-articular injection of 4% papain. Thirty healthy male New Zealand rabbits were randomly divided into control, untreated OA, Cel (100 mg/kg celecoxib intervention as a positive control), BB-L and BB-H (40 mg /kg and 80 mg /kg bilobalide gavage treatment, respectively) groups. Two weeks after surgical induction, bilobalide or celecoxib was administered by gavage daily for 8 weeks. After 8 weeks of bilobalide intervention, cartilage macroscopic observation and histopathological images showed alleviation of cartilage damage after bilobalide treatment, and the Osteoarthritis Research Society International (OARSI) score was significantly lower than that in the OA group. Bilobalide reduced the expression of metalloproteinase 3 (MMP-3) and MMP-13 in cartilage tissue of OA rabbits and reversed the levels of serum C-telopeptides of type II collagen (CTX-II), cartilage oligomeric matrix protein (COMP), interleukin 1(IL-1), and tumor necrosis factor (TNF-α). Bilobalide (80 mg/kg) could improve the biomechanical properties and microstructural changes in subchondral bone in the early stage of OA in rabbits, thereby delaying subchondral bone damage. Mechanistically, bilobalide exerted antioxidant and anti-matrix degradation effects by upregulating the oxidative stress signaling Nrf2/HO-1 pathway and inhibiting cartilage degeneration in rabbit OA. We thus speculate that bilobalide supplements recovery from OA damage.

Psoralen downregulates osteoarthritis chondrocyte inflammation via an estrogen-like effect and attenuates osteoarthritis

Estrogen and its receptor play a positive role in the development of osteoarthritis (OA). Psoralen is a plant-derived estrogen analog. This study aimed to verify whether psoralen inhibits OA through an estrogen-like effect. First, human primary chondrocytes in the late stage of OA were extracted to complete collagen type II immunofluorescence staining and cell proliferation experiments. Subsequently, estrogen, psoralen and estrogen receptor antagonists were co-cultured with OA chondrocytes, and RT-PCR was performed to detect the gene expression. A rabbit OA model was subsequently made by anterior cruciate ligament transection (ACLT). They were set as Sham group, OA group and Psoralen group, respectively. The articular cartilage samples were taken after 5 weeks of treatment, and the effect was observed by gross observation, histological staining, micro-CT scanning of subchondral bone. The results of cellular experiments displayed that the cultured cells were positive for collagen II fluorescence staining and 12 μg/mL psoralen was selected as the optimal concentration. In addition, psoralen had effects similar to estrogen, promoting the expression of estrogen tar-get genes CTSD, PGR and TFF1 and decreasing the expression of the inflammation-related gene TNF- α, IL-1β and IL-6. The effect of psoralen was blocked after the use of an estrogen receptor antagonist. Further animal experiments indicated that the psoralen group showed less destruction of cartilage tissue and decreased OASRI scores compared with the OA group. A subchondral bone CT scan demonstrated that psoralen significantly increased subchondral bone mineral density (BMD), trabecular thickness and trabecular number and decreased trabecular separation. In summary, psoralen inhibits the inflammatory production of chondrocytes, which is related to estrogen-like effect, and can be used to attenuate the progression of OA.

Hybrid composites with magnesium-containing glycosaminoglycans as a chondroconducive matrix for osteoarthritic cartilage repair

The alteration of the extracellular matrix (ECM) homeostasis plays an important role in the development of osteoarthritis (OA). The pathological changes of OA are mainly manifested in the large reduction of components in ECM, like type II collagen and aggrecan, especially hyaluronic acid and chondroitin sulfate and often accompanied by inflammation. Rebuilding ECM and inhibiting inflammation may reverse OA progression. In this work, we developed new magnesium-containing glycosaminoglycans (Mg-GAGs), to create a positive ECM condition for promoting cartilage regeneration and alleviating OA. In vitro results suggested that the introduction of Mg-GAGs contributed to promoting chondrocyte proliferation and facilitated upregulating chondrogenic genes and suppressed inflammation-related factors. Moreover, Mg-GAGs exhibited positive effects on suppressing synovial inflammation, reducing chondrocyte apoptosis and preserving the subchondral bone in the ACLT-induced OA rabbit model. This study provides new insight into ECM-based therapeutic strategy and opens a new avenue for the development of novel OA treatment.

Mechanism of action of genicular artery embolization in a rabbit model of knee osteoarthritis.

To establish a rabbit osteoarthritis model for genicular artery embolization (GAE) experiments and to investigate the cellular mechanism of action of this novel procedure for interventional radiologists. Rabbit knee osteoarthritis was surgically modeled by anterior cruciate ligament transection and medial partial meniscectomy of the bilateral hindlimbs followed by 10 weeks of incubation. Rabbits exhibiting synovitis on magnetic resonance imaging were randomly divided into two groups: the bilateral GAE group and the control (sham procedure) group. Four weeks later, the rabbits' mobility (moving time, sec/10 min) and the histopathological features of each knee were assessed, and inter-group differences were evaluated using Student's t-test and ordinal/linear logistic models with generalized estimating equations. Osteoarthritis modeling and endovascular procedures were successful in 15 of 20 rabbits (8 and 7 in the GAE and control groups, respectively). There was no significant difference in moving times between the two groups (p = .958). The degree of structural cartilage damage was similar in both groups (p = .780). However, the synovial proliferation (p = .016), synovial hypertrophy (p < .001), and villous hyperplasia of the synovial stroma (p = .002) scores were significantly lower in the GAE group than in the control group. The CD3+ cell density (p = .018) and CD3 + cell-infiltrated area (p = .019) were also significantly lower in the GAE group than in the control group. GAE can limit inflammatory processes in the synovium of osteoarthritis-affected knees. Surgical transection of the anterior cruciate ligament and medial partial meniscectomy of rabbit knees provides a useful animal model for research of genicular artery embolization. Osteoarthritic knees treated by genicular artery embolization showed milder synovial proliferation (p = .016), synovial hypertrophy (p < .001), and villous hyperplasia of the synovial stroma (p = .002) than the untreated knees. Osteoarthritic knees treated by genicular artery embolization presented lower CD3+ cell density (p = .018) and CD3+ cell-infiltrated area (p = .019) in the synovium than the untreated knees.

Knee Cartilage and Subchondral Bone Evaluations by Magnetic Resonance Imaging Correlate with Histological Biomarkers in an Osteoarthritis Rabbit Model.

ObjectiveTo evaluate pathological changes in cartilage and subchondral bone MRI biomarkers in a rabbit model of osteoarthritis (OA) and correlate these with histological variations.DesignTransection of the anterior cruciate ligament was performed on the right knee of eighteen 12-week-old New Zealand white rabbits to induce OA. 3-Tesla MR images were obtained from 18 healthy control knees (left) and 18 knees with OA (right). Imaging biomarkers included volume, thickness, T1 and T2* cartilage parametric maps, and several subchondral bone features: bone volume to total volume ratio, trabecular thickness, trabecular spacing, trabecular number (TbN), 2D and 3D fractal dimensions, and quality of trabecular score (QTS). Microscopic analysis of the lateral femoral condyles was set as the ground truth.ResultsWhen healthy and osteoarthritic knees were compared, significant differences were seen in the T1 and T2* values of the femur and tibia cartilage and in the subchondral bone volume to total volume, TbN, and QTS of both the lateral and medial aspects of the femur and tibia. Histological findings revealed significant osteoarthritic changes between healthy and osteoarthritic knees in stain, structure, chondrocyte density, total score, and subchondral bone biomarker levels. A positive correlation was found between histological staining, structure, chondrocyte density, and total score variables in T1 and T2* cartilage biomarkers. A negative correlation was observed between histological subchondral bone variables and magnetic resonance D2D and QTS biomarkers.ConclusionQuantification of several cartilage and subchondral bone imaging biomarkers in a rabbit model of OA allows the detection of significant changes, which are correlated with histological findings.