Saponin Esculeoside A and Aglycon Esculeogenin A from Ripe Tomatoes Inhibit Dendritic Cell Function by Attenuation of Toll-like Receptor 4 Signaling.

Dendritic cells (DCs) can initiate immune response through the presenting antigens to naïve T lymphocytes. Esculeoside A (EsA), a spirosolane glycoside, is reported as a major component in the ripe fruit of tomato. Little is known about the effect of tomato saponin on mice bone marrow-derived DCs. This study revealed that EsA and its aglycon, esculeogenin A (Esg-A), attenuated the phenotypic and functional maturation of murine DCs stimulated by lipopolysaccharide (LPS). We found that EsA/Esg-A down-regulated the expression of major histocompatibility complex type II molecules and costimulatory molecule CD86 after LPS stimulation. It was also determined that EsA-/Esg-A-treated DCs were poor stimulators of allogeneic T-cell proliferation and exhibited impaired interleukin-12 and TNF-α production. Additionally, EsA/Esg-A was able to inhibit TLR4-related and p-NFκB signaling pathways. This study shows new insights into the immunopharmacology of EsA/Esg-A, and represents a novel approach to controlling DCs for therapeutic application.

Enhancing Cartilage Metabolism in Rats through a Novel Thermal Stimulation Technique with Photosensitizers.

Although the moderate thermal stimulation of articular cartilage exerts chondroprotective effects, it is difficult to effectively heat deep articular cartilage with conventional methods. Photosensitizers increase the ambient temperature using near-infrared (NIR) radiation, which has high tissue permeability. We hypothesized that the intra-articular administration of photosensitizers and NIR irradiation would exert a greater heating effect on articular cartilage. We aimed to evaluate the heating effect of this method on cultured chondrocytes and rat knee cartilage. In vitro, we irradiated a photosensitizer-containing medium with NIR and measured changes in the medium temperature, cytotoxicity, and gene expression of heat shock protein (HSP) 70 and aggrecan (ACAN). In vivo, the knee joints of rats treated with photosensitizers were irradiated with NIR, and changes in intra-articular temperature and gene expression were measured, alongside histological analysis. The results showed that the medium and intra-articular temperature were raised to approximately 40 °C with no apparent disruption to articular cartilage or the immunohistochemically enhanced staining of HSP70 in chondrocytes. The gene expression of HSP70 and ACAN was increased in both cultured and articular cartilage. In summary, this method can safely heat joints and enhance cartilage metabolism by inducing HSP70 expression in articular cartilage. It presents a new hyperthermia therapy with effective cartilage protection.

Hypoxia with or without Treadmill Exercises Affects Slow-Twitch Muscle Atrophy and Joint Destruction in a Rat Model of Rheumatoid Arthritis.

The effects of treadmill running under hypoxic conditions on joints and muscles of collagen-induced arthritis (CIA) rats were investigated. CIA rats were divided into normoxia no-exercise, hypoxia no-exercise (Hypo-no), and hypoxia exercise (Hypo-ex) groups. Changes were examined on days 2 and 44 of hypoxia with or without treadmill exercises. In the early stage of hypoxia, the expression of hypoxia-inducible factor (HIF)-1α increased in the Hypo-no and Hypo-ex groups. The expression of the egl-9 family hypoxia-inducible factor 1 (EGLN1) and vascular endothelial growth factor (VEGF) in the Hypo-ex group also increased. Under sustained hypoxia, the Hypo-no and Hypo-ex groups did not show increased expression of HIF-1α or VEGF, but p70S6K levels were elevated. Histologically, joint destruction was alleviated in the Hypo-no group, the loss of muscle weight in slow-twitch muscles was prevented, and muscle fibrosis was suppressed. In the Hypo-ex group, the preventive effect of a reduction in the slow-twitch muscle cross-sectional area was enhanced. Thus, chronic hypoxia in an animal model of rheumatoid arthritis controlled arthritis and joint destruction and prevented slow-twitch muscle atrophy and fibrosis. The combination of hypoxia with treadmill running further enhanced the preventive effects on slow-twitch muscle atrophy.

Cartilage degeneration of patellofemoral joint occurs in open wedge high tibial osteotomy, rather than in hybrid closed wedge high tibial osteotomy, during the early postoperative period: A qualitative analysis using MRI T2 mapping.

PURPOSE: After high tibial osteotomy, the patella may change position and osteoarthritis of the patellofemoral joint (PFJ) may occur. It was hypothesized that the course of PFJ degeneration would differ between open wedge high tibial osteotomy (OWHTO) and hybrid closed wedge high tibial osteotomy (hybrid HTO). Accordingly, this study aimed to evaluate the qualitative changes in PFJ articular cartilage, during the early postoperative period after OWHTO and hybrid HTO. METHODS: This was a retrospective observational study of 75 knees that underwent OWHTO (N = 37) or hybrid HTO (N = 38) for medial knee osteoarthritis. OWHTO and hybrid HTO were indicated for corrections of less than 10° and more than 10°, respectively. MRI of all knees was performed before and 6 months after surgery to evaluate patellar cartilage in sagittal images for T2 mapping. Three regions of interest (medial, middle, and lateral facets) were defined in the articular cartilage, and T2 values were measured. Patellar tilting angle, lateral shift ratio, and patellar height were compared before and after surgery. RESULTS: There was no significant change in arthroscopic findings of PFJ articular cartilage between the OWHTO and hybrid HTO groups. In the OWHTO group, the mean T2 value of medial and middle facets increased significantly (lateral, 43.0 ± 3.9 to 43.7 ± 3.5; middle, 44.2 ± 3.9 to 46.2 ± 3.8; medial 41.0 ± 4.3 to 42.4 ± 4.0). Conversely, no significant change was observed in the hybrid HTO group (lateral, 41.1 ± 4.0 to 42.3 ± 4.0; middle, 43.6 ± 4.2 to 44.5 ± 4.3; medial, 40.7 ± 4.1 to 41.5 ± 4.5). Patellar height decreased and increased in the OWHTO and hybrid HTO groups, respectively, and patellar tilt decreased in the OWHTO group. Lateral shift ratio decreased significantly in both groups. CONCLUSIONS: OWHTO with a small correction angle may result in qualitative changes in PFJ articular cartilage from an early stage, while hybrid HTO with a relatively large correction angle is unlikely to affect PFJ articular cartilage.

Analysis of the relationship between the morphology of the proximal tibiofibular joint and lateral hinge fracture in open wedge high tibial osteotomy.

BACKGROUND: One of the complications of open wedge high tibial osteotomy is lateral hinge fracture, which causes delayed bone healing. In this study, we focused on the morphology of the proximal tibiofibular joint to clarify the influence of this morphology on the occurrence of lateral hinge fracture in open wedge high tibial osteotomy. METHODS: The proximal tibiofibular joint of 58 knees in 55 patients who underwent open wedge high tibial osteotomy was classified as either horizontal or oblique, depending on the morphology of the fibular head. Lateral hinge fracture of Takeuchi classification type II or III was defined as unstable lateral hinge fracture. We analyzed whether patient background and bone morphological factors, including the morphology of the proximal tibiofibular joint, were associated with the occurrence of unstable lateral hinge fracture. RESULTS: The horizontal and oblique types were found in 34 and 24 knees, respectively. There was no difference in the percentage of hinge points within the safe zone between the horizontal and oblique types; however, there was a significant difference in the unstable lateral hinge fracture incidence between the two groups. Unstable lateral hinge fracture occurred in seven knees, mostly in patients with an oblique proximal tibiofibular joint. The factors associated with the occurrence of unstable lateral hinge fracture were analyzed using logistic regression analysis; the fibular head of the oblique type was a significant factor. CONCLUSION: Open wedge high tibial osteotomy for oblique-type proximal tibiofibular joints may be more likely to cause unstable lateral hinge fracture than the horizontal type.

Analysis of Hemodynamic Changes After Medial Patellofemoral Ligament Reconstruction.

The resumption of blood flow is an important factor in the remodeling process of the graft. The purpose of this study is to evaluate hemodynamic changes after medial patellofemoral ligament (MPFL) reconstruction using magnetic resonance angiography (MRA) as the evaluation of graft remodeling. Eleven knees that underwent anatomical MPFL reconstruction with the semitendinosus tendon were studied. We evaluated the blood flow around the bone tunnel wall in the arterial phase using MRA approximate 3 months and 1 year after surgery. Clinical and radiological evaluations were also analyzed. MRA showed an inflow vessel into the bone tunnel wall from the medial superior genicular artery on the femoral side, and from the articular branch of the descending genicular artery and the medial superior genicular artery on the patellar side. This contrast effect was decreased at 12 months after surgery in all cases. The clinical scores improved from baseline one year postoperatively. We revealed the blood flow to the bone tunnel wall after anatomical MPFL reconstruction is detected by MRA. The blood flow started within 2 or 3 months postoperatively and was sustained for 12 months. This study supported remodeling of the graft continues 3 months after surgery when the conformity of the patellofemoral joint stabilizes.

Treadmill running prevents atrophy differently in fast- versus slow-twitch muscles in a rat model of rheumatoid arthritis.

To investigate the effects of treadmill running on two different types of skeletal muscle, we established a rat model of collagen-induced arthritis (CIA). The skeletal muscles studied were the extensor digitorum longus (EDL), which is rich in fast-twitch muscle fibers, and the soleus, which is rich in slow-twitch muscle fibers. The histological and transcriptional changes in these muscles at 14 and 44 days after immunosensitization were compared between rats that were forced to exercise (CIA ex group) and free-reared CIA rats (CIA no group). Change in protein expression was examined on day 14 after a single bout of treadmill running. Treadmill running had different effects on the relative muscle weight and total and fiber cross-sectional areas in each muscle type. In the soleus, it prevented muscle atrophy. Transcriptional analysis revealed increased eukaryotic translation initiation factor 4E (Eif4e) expression on day 14 and increased Atrogin-1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression on day 44 in the soleus in the CIA ex group, suggesting an interaction between muscle type and exercise. A single bout of treadmill running increased the level of Eif4e and p70S6K and decreased that of Atrogin-1 in the soleus on day 14. Treadmill running prevented muscle atrophy in the soleus in a rat model of rheumatoid arthritis via activation of mitochondrial function, as evidenced by increased PGC-1α expression.

Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α.

Hypoxia inducible factor (HIF)-1α has been implicated in the pathogenesis of rheumatoid arthritis (RA). HIF-1α, which is expressed in hypoxia, is reversely suppressed in sustained hypoxia. Here, we investigated the inhibitory effect of hypoxia on arthritis by controlling HIF-1α. Rheumatoid fibroblast-like synoviocyte MH7A cells were cultured in a hypoxic incubator for up to 72 h to evaluate the expression of HIF-1. Furthermore, collagen-induced arthritis (CIA) model rats were maintained under 12% hypoxia in a hypoxic chamber for 28 days to evaluate the effect on arthritis. In MH7A cells, HIF-1α protein level increased at 3 h, peaked at 6 h, and subsequently decreased in a time-dependent manner. The transcription of pro-inflammatory cytokines increased at 1 h; however, they decreased after 3 h (p < 0.05). Deferoxamine-mediated activation of HIF-1α abolished the inhibitory effect of sustained hypoxia on pro-inflammatory cytokines. In the rat CIA model, the onset of joint swelling was delayed and arthritis was suppressed in the hypoxia group compared with the normoxia group (p < 0.05). Histologically, joint destruction was suppressed primarily in the cartilage. Thus, sustained hypoxia may represent a new safe, and potent therapeutic approach for high-risk patients with RA by suppressing HIF-1α expression.

Clinical outcomes after medial patellofemoral ligament reconstruction: an analysis of changes in the patellofemoral joint alignment.

PURPOSE: Medial patellofemoral ligament (MPFL) reconstruction using the hamstring tendon is widely performed to treat recurrent patellar dislocation. MPFL reconstruction includes a post-operative process of necrosis and reperfusion of the hamstring tendon graft. We hypothesise that the patella gradually shifts laterally because of this process, ultimately affecting the patellofemoral joint alignment. This study aimed to analyse the chronological changes in the patellofemoral joint alignment and the outcomes of MPFL reconstruction. METHODS: In this retrospective case-series study, the Knee Society, Lysholm, and Kujala scores were evaluated in 24 consecutive patients (27 knees). To evaluate patellar tracking defects, radiographic indices including the tilting angle, the lateral shift ratio, and the congruence angle were measured before, immediately after, and three, 12, and 36 months after MPFL reconstruction. RESULTS: Post-operative Kujala, Knee Society, and Lysholm scores for the study population significantly improved relative to the pre-operative scores. The tilting and congruence angles at three months after the operation significantly increased relative to those recorded immediately after the operation. The tilting and congruence angles were not significantly different at three, 12, and 36 months after the operation. CONCLUSIONS: The post-operative outcomes of MPFL reconstruction for recurrent patellar dislocation were favourable. Insufficient union between the bone tunnel and tendon graft, along with an elongation of the necrotic tendon graft, may change the alignment of the patellofemoral joint within three months after the operation. Therefore, we believe it is necessary to refrain from knee rotation that places lateral stress on the patella until three months after the operation.

Relationship of alignment in the lower extremity with early degeneration of articular cartilage after resection of the medial meniscus: Quantitative analysis using T2 mapping.

The objective of this study was to examine the relationship between cartilage degeneration early after partial medial meniscectomy and abnormal alignment in the lower extremity.The subjects were 34 patients (37 knees) with medial meniscal tear who underwent arthroscopic partial meniscectomy. MRI was performed before and 6 months after surgery. T2 mapping images in sagittal sections of medial femoral condyle were produced and 10 regions of interest were set at intervals of 10° in the articular cartilage in the femur. Subjects with an increase in T2 of ≥6% at a flexion angle of 30° were assigned to the degeneration group. Patient background, hip-knee-ankle (HKA) angle, and total resection of meniscal segments were compared between this group and the other patients to identify factors involved in degeneration of articular cartilage.T2 values 6 months after surgery in 3 ROIs at flexion angles of 30° to 50° were significantly longer than those before surgery. The preoperative HKA angle was significantly higher in the degeneration group. T2 values in articular cartilage of the femoral condyle increased earlier after meniscectomy with abnormal alignment in the lower extremity.Meniscectomy in cases with abnormal alignment may have a risk of early onset of osteoarthritis.Level of evidence: Level IV.

Treadmill Running in Established Phase Arthritis Inhibits Joint Destruction in Rat Rheumatoid Arthritis Models.

Exercise therapy inhibits joint destruction by suppressing pro-inflammatory cytokines. The efficacy of pharmacotherapy for rheumatoid arthritis differs depending on the phase of the disease, but that of exercise therapy for each phase is unknown. We assessed the differences in the efficacy of treadmill running on rheumatoid arthritis at various phases, using rat rheumatoid arthritis models. Rats with collagen-induced arthritis were used as rheumatoid arthritis models, and the phase after immunization was divided as pre-arthritis and established phases. Histologically, the groups with forced treadmill running in the established phase had significantly inhibited joint destruction compared with the other groups. The group with forced treadmill running in only the established phase had significantly better bone morphometry and reduced expression of connexin 43 and tumor necrosis factor α in the synovial membranes compared with the no treadmill group. Furthermore, few cells were positive for cathepsin K immunostaining in the groups with forced treadmill running in the established phase. Our results suggest that the efficacy of exercise therapy may differ depending on rheumatoid arthritis disease activity. Active exercise during phases of decreased disease activity may effectively inhibit arthritis and joint destruction.