Prognostic Factors in Intra-articular Platelet-Rich Plasma Treatment for Knee Osteoarthritis: A Comparative Analysis of Responders and Nonresponders.

BACKGROUND: Knee osteoarthritis (KOA) is a chronic joint disease affecting activities of daily living (ADL) and quality of life due to pain and limited range of motion, afflicting a large number of patients worldwide. However, it is difficult to prevent the progression of the disease. Therapeutic strategies for KOA aim to maintain ADL and QOL by alleviating pain or managing locomotive function. Recently, intra-articular injection of platelet-rich plasma (PRP) has been gaining attention. In this study, the clinical results of PRP treatment in our institution were reported and compared between responders and non-responders using patient characteristics and imaging data assessed from plain X-rays and magnetic resonance imaging (MRI). METHODS: Participants in the study were KOA patients with varus deformity assessed as grade 2 or higher in the Kellgren-Lawrence classification who received PRP treatment from January 2022 to November 2023 and were followed up for at least three months. PRP was prepared with 27 mL of blood collected from the patient, and 2.7 mL of PRP was prepared using the PEAK©ï¸ŽPRP System from DePuy Synthes (Raynham, MA). Intra-articular injections of PRP were performed under echo-guided procedures, and responders or non-responders were determined using the Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) criteria evaluated by the Japanese Knee Injury and Osteoarthritis Outcome Score (J-KOOS) at three months after PRP injection. The clinical efficacy of PRP treatment for KOA was assessed in this study, and a dichotomous analysis was performed comparing the responder group and the non-responder group using patient characteristics and assessed data from plain X-ray images and MRI to determine prognostic factors for PRP treatment. RESULTS: The study population included 36 knees with a mean age of 70.6. ± 9.2 years, comprising six knees in men and 30 knees in women. The responder group consisted of 16 knees (44.4%), and the non-responder group consisted of 20 knees (55.6%). J-KOOS subscores at pre-treatment elicited that each subscale in the R group was significantly lower than that in the NR group at pretreatment. A dichotomous analysis for the two groups revealed the distribution of sex and past medical history of hyperlipidemia to be significantly different between the two groups. Multivariable logistic regression analysis showed that the coexistence of hyperlipidemia was the main prognostic factor for the efficacy of PRP therapy. DISCUSSION: In this study, comparisons were conducted between responders and non-responders to estimate prognostic factors for the efficacy of PRP therapy. Surprisingly, responders to the treatment tended to show lower J-KOOS scores and to have hyperlipidemia. A literature review revealed conflicting reports on prognostic factors for PRP therapy in KOA, highlighting the need for further research.

Suppressive Activity of Boiogito, a Japanese Traditional Kampo Medicine, on Periostin Secretion in Human Fibroblast-Like Synoviocytes In Vitro.

Background Knee osteoarthritis (KOA) is a prevalent degenerative disease that affects the knee joints, particularly among individuals aged over 40 years. It leads to pain, stiffness, and reduced quality of life; affects approximately 300 million individuals worldwide; and is increasing, particularly in developed nations. Although treatments for KOA range from conservative measures to surgical interventions, such as total knee arthroplasty (TKA), the financial burden of TKA in many countries underscores the urgent need for effective conservative therapies. The pathophysiology of KOA involves articular cartilage degeneration, increased subchondral bone turnover, synovitis, and periarticular soft tissue contracture. Abnormal bone turnover, intensified by factors, such as weight gain and knee injury, precedes cartilage degeneration. Synovitis, characterized by inflammation in the synovial tissue, plays a crucial role in perpetuating the disease by triggering a cascade of catabolic and proinflammatory mediators, including cytokines, such as interleukin (IL)-1 beta, tumor necrosis factor-alpha, and IL-13. Periostin, an extracellular matrix protein, is implicated in KOA progression, with its levels increasing with disease severity. Materials & methods In this study, the preventive effect of boiogito (BOT), a traditional herbal medicine, on periostin secretion in human fibroblast-like synoviocytes (hFLS) stimulated by IL-13 was investigated. Synoviocyte Growth Medium and recombinant human IL-13 were used for cell culture and stimulation. BOT was dissolved in phosphate-buffered saline and applied to cell cultures. Periostin secretion and mRNA expression were measured using enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction, respectively. Cell viability was assessed using an MTT assay, and signal transducer and activator of transcription factor 6 (STAT6) phosphorylation was examined using Western blotting. Results IL-13 stimulation of hFLS significantly increased periostin secretion, with levels rising above 20 ng/mL after 72 h of stimulation. Pretreatment with BOT dose-dependently suppressed periostin secretion, with doses of 1,000 µg/mL significantly reducing periostin levels. Furthermore, BOT inhibited periostin mRNA expression and STAT6 phosphorylation in IL-13-stimulated hFLS, suggesting its potential in modulating IL-13-mediated inflammatory pathways in KOA. Conclusion This study demonstrated the preventive effect of BOT on periostin secretion in IL-13-stimulated hFLS, highlighting its potential as a therapeutic agent for KOA. By inhibiting periostin production and downstream signaling pathways, BOT may offer a promising conservative treatment option for KOA, addressing the inflammatory cascade implicated in disease progression. Further research is warranted to elucidate the specific herbal components responsible for the therapeutic effects of BOT and to validate its efficacy in clinical settings.

Duration of the preemptive analgesic effects of low- and high-frequency transcutaneous electrical nerve stimulation in rats with acute inflammatory pain.

Transcutaneous electrical nerve stimulation (TENS) activates various pathways to induce antinociceptive effects, based on the frequencies used. This study evaluates the preemptive analgesic effects and their duration of low- (LT: 4 Hz) and high-frequency TENS (HT: 100 Hz) using a rat model of acute inflammatory pain. Acute inflammation was induced by injecting 1% formalin into the hind paws of rats. LT or HT was applied for 30 min before formalin injection. Pain-related behaviors, such as licking, flinching, and lifting, were recorded for 60 min postinjection. Immunohistochemistry was used to assess the number of phosphorylated extracellular signal-regulated kinase (pERK)- and c-fos-positive cells in the spinal cord. Naloxone, a µ-opioid receptors (MORs) antagonist, and naltrindole, a δ-opioid receptors (DORs) antagonist, were administered before TENS application. Pain behavior duration and pERK- and c-fos-positive cell expression were then measured. LT and HT pretreatment significantly reduced both pain behaviors and the number of pERK- and c-fos-positive cells postformalin injection. Naloxone and naltrindole partially reversed the effects of LT and HT, respectively. Notably, HT's analgesic effect lasted up to 120 min whereas that of LT persisted for 90 min. LT and HT effectively exerted their preemptive analgesic effects on acute inflammatory pain by inhibiting pERK and c-fos expression in the spinal cord. HT presented a longer-lasting effect compared to LT. MOR and DOR activation may contribute to LT and HT's analgesic mechanisms, respectively.

The Preventive Effects of Platelet-Rich Plasma Against Knee Osteoarthritis Progression in Rats.

BACKGROUND: In recent years, the intra-articular administration of platelet-rich plasma (PRP), a novel therapeutic strategy for knee osteoarthritis (KOA), has gained attention. However, the efficacy of PRP in inhibiting degenerative joint changes remains unclear. The current study aimed to evaluate the therapeutic effect of the intra-articular administration of PRP in rats with induced KOA. MATERIALS AND METHODS: PRP was prepared from the whole blood of nine-week-old male Wistar rats via centrifugation at 25°C, 200 × g, for seven minutes. KOA was induced in the right knees of the rats via destabilization of the medial meniscus (DMM) surgery. The animals were divided into the control, sham, DMM, and DMM + PRP groups (n = 5 each). The rats in the DMM + PRP group received 50 µL of intra-articular PRP in the right knee joint four weeks after surgery. The rotarod test was conducted to assess locomotive function. Eight weeks after DMM surgery, the degree of medial meniscus extrusion was measured via computed tomography (CT) images on the right knee. Then, a histological analysis of the harvested knees was conducted. KOA progression was assessed using the Osteoarthritis Research Society International (OARSI) score. The number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in the subchondral bone was counted via histological analysis. RESULTS: The degree of medial meniscus extrusion did not significantly differ between the DMM and DMM + PRP groups. Similarly, there were no significant differences in the walking time based on the rotarod test between the DMM and DMM + PRP groups. However, the DMM group had a significantly higher OARSI score than the DMM + PRP group. The number of TRAP-positive osteoclasts in the subchondral bone of the DMM group increased over time, peaking four weeks after surgery. The DMM + PRP group had a higher number of TRAP-positive osteoclasts in the subchondral bone than the control group. However, there was no significant difference between the number of TRAP-positive osteoclasts between the DMM group and the control and sham groups. CONCLUSION: The intra-articular administration of PRP may inhibit KOA progression in a rat model, especially in the articular cartilage degradation and osteophyte formation. The results can provide further evidence about the efficacy of PRP against KOA progression and can contribute to the current practice of healthcare professionals based on accurate knowledge.

Multifactorial Comparative Analysis of Platelet-Rich Plasma and Serum Prepared Using a Commercially Available Centrifugation Kit.

Background Platelet-rich plasma (PRP) is an autologous product prepared by centrifuging whole blood. PRP is reported to have high tissue repair potential and anti-inflammatory properties. Recently, PRP has become a potential treatment option for osteoarthritis, contributing to pain relief and locomotive improvement. However, the underlying therapeutic mechanisms and key biochemical factors in PRP remain unclear. This study aimed to estimate the major factors for tissue repair involved in PRP treatment by comparing between serum and PRP prepared from the same patients using the Luminex assay. Methodology Blood samples were collected from nine healthy volunteers, and serum and PRP were prepared. PRP was prepared using a PEAK©ï¸Ž PRP SYSTEM kit of DePuy Synthes Mitek Sports Medicine (Raynham, Massachusetts, USA), which is a commercially available PRP preparation kit. The white blood cell count, hemoglobin level, and platelet count were automatically measured for both whole blood and PRP in the hospital's clinical laboratory using the XE-5000™ Automated Hematology System (Sysmex, Kobe, Japan). Comparative analysis of biological factors was then performed using the Luminex assay on serum and PRP. Results PRP was found to have significantly higher white blood cell and platelet counts and lower hemoglobin levels than whole blood. Furthermore, PRP contained significantly higher levels of various factors, including interleukin (IL)-1ra, IL-10, IL-13, C-C motif chemokine ligand (CCL)-2, CCL3, CCL4, CCL8, CCL13, CCL21, C-X-C motif chemokine ligand (CXCL)-10, matrix metalloproteinase (MMP)-3, MMP-9, cluster of differentiation (CD) 40 ligand, vascular endothelial growth factor (VEGF), VEGF-C, platelet-derived growth factor (PDGF)-AB, PDGF-BB, and bone morphogenic protein (BMP)-2. Additionally, IL-1ra and IL-4 showed significant correlations with white blood cell counts in PRP, whereas VEGF had a significant correlation with platelet counts. Conclusions PRP contains various factors in higher quantities than serum. Specifically, the notable increase in the anti-inflammatory cytokine IL-1ra is suggested to play a key role as a major therapeutic mechanism of PRP.

Yokukansan Inhibits the Development of Morphine Tolerance by Regulating Presynaptic Proteins in DRG Neurons.

Opioids, such as morphine, are used in clinical settings for the management of acute and chronic pain. However, long-term use of morphine leads to antinociceptive tolerance and hypersensitivity. The cellular and molecular mechanisms of morphine tolerance seem to be quite complex, with suggestions including internalization of the µ-opioid receptor (MOR), neuroinflammation with activation of microglia and astrocytes, and changes in synaptic function in the central nervous system. Yokukansan (YKS), a traditional Kampo medicine consisting of seven herbs, has been used to treat emotional instability, neurosis, and insomnia. Interestingly, recent studies have begun to reveal the inhibitory effect of YKS on the development of morphine tolerance. In the present study, we determined the effect of YKS on morphine tolerance formation and its mechanisms in a rat model, focusing on the synapses between primary sensory neurons and spinal dorsal horn secondary neurons. We found that morphine tolerance formation was significantly inhibited by YKS (0.3 or 1.0 g/kg/day) preadministration for 7 days. Repeated administration of morphine (10 mg/kg/day) increased the expression of presynaptic proteins, including synaptotagmin I, in the spinal cord, which was suppressed by YKS. Furthermore, these changes in presynaptic protein expression were more pronounced at isolectin B4 (IB4)-positive excitatory synapses around the lamina II of the dorsal horn. These results suggest that YKS suppresses the development of morphine tolerance by inhibiting the enhancement of presynaptic function of dorsal root ganglia neurons projecting to spinal dorsal horn neurons caused by continuous morphine administration.

Kampo Formulae for the Treatment of Neuropathic Pain ∼ Especially the Mechanism of Action of Yokukansan ∼.

Kampo medicine has been practiced as traditional medicine (TM) in Japan. Kampo medicine uses Kampo formulae that are composed of multiple crude drugs to make Kampo formulae. In Japan, Kampo formulae are commonly used instead of or combined with Western medicines. If drug therapy that follows the guidelines for neuropathic pain does not work or cannot be taken due to side effects, various Kampo formulae are considered as the next line of treatment. Since Kampo formulae are composed of two or more kinds of natural crude drugs, and their extracts contain many ingredients with pharmacological effects, one Kampo formula usually has multiple effects. Therefore, when selecting a formula, we consider symptoms other than pain. This review outlines the Kampo formulae that are frequently used for pain treatment and their crude drugs and the basic usage of each component. In recent years, Yokukansan (YKS) has become one of the most used Kampo formulae for pain treatment with an increasing body of baseline research available. We outline the known and possible mechanisms by which YKS exerts its pharmacologic benefits as an example of Kampo formulae's potency and holistic healing properties.

Influences of Lavender Essential Oil Inhalation on Stress Responses during Short-Duration Sleep Cycles: A Pilot Study.

Lavender essential oil (LEO) was reported to improve sleep quality. We investigated the influence of aromatherapy by testing the effects of LEO on stress responses during a short-duration sleep in a single-blind, randomized, crossover trial. The subjects were twelve healthy adults who were nonsmokers without any known disease and who were not prescribed medications, and nine of these completed the study. After the subjects had fallen asleep, they were sprayed with LEO using an aroma diffuser. Before and after 90 min of sleep, α-amylase, chromogranin A (CgA), and cortisol levels in saliva were measured as objective stress indicators, and the Japanese version of the UWIST Mood Adjective Checklist was used as a subjective indicator. A comparison of changes before and after sleep, with and without LEO, revealed that the cortisol level did not significantly change; however, α-amylase (p < 0.05) and CgA (p < 0.01) levels significantly decreased after LEO inhalation. A mood test indicated no change in mood before and after sleep, with or without LEO. Since α-amylase and CgA reflect the sympathetic nervous system response, these results indicate that LEO aromatherapy during a short-duration sleep cycle suppresses the stress response, especially that of the sympathetic nervous system.

Analgesic Effect of Combined Therapy with the Japanese Herbal Medicine "Yokukansan" and Electroacupuncture in Rats with Acute Inflammatory Pain.

Background: Japanese herbal medicine, called Kampo medicine, and acupuncture are mainly used in Japanese traditional medicine. In this experiment, the analgesic effect of Yokukansan (YKS) alone and a combination of YKS and electroacupuncture (EA) on inflammatory pain induced by formalin injection were examined. Methods: Animals were divided into four groups: a control group, formalin injection group (formalin), YKS-treated formalin group (YKS), and YKS- and EA-treated formalin group (YKS + EA). The duration of pain-related behaviors and extracellular signal-regulated protein kinase (ERK) activation in the spinal cord after formalin injection in the right hind paw were determined. Results: The duration of pain-related behaviors was dramatically prolonged in the late phase (10-60 min) in the formalin group. The YKS treatment tended to reduce (p = 0.08), whereas YKS + EA significantly suppressed the pain-related behaviors (p < 0.01). Immunohistochemical and Western blot analyses revealed that the number of phosphorylated ERK1/2 (pERK1/2)-positive cells and the pERK expression level, which were increased by formalin injection, were significantly inhibited by YKS (p < 0.05) and YKS + EA (p < 0.01). Conclusions: The YKS + EA combination therapy elicited an analgesic effect on formalin-induced acute inflammatory pain.

Inhibition of Angiogenic Factor Productions by Quercetin In Vitro and In Vivo.

Background: Angiogenesis is well known to be an important event in the tissue remodeling observed in allergic diseases. Although there is much evidence that quercetin, one of the most abundant dietary flavonoids, exerts anti-allergic effects in both human and experimental animal models of allergic diseases, the action of quercetin on angiogenesis has not been defined. Therefore, in this study, we first examined the action of quercetin on the secretion of angiogenic factors from murine mast cells in vitro. We also examined the action of quercetin on angiogenic factor secretion in the murine allergic rhinitis model in vivo. Methods: Mast cells (1 × 105 cells/mL) sensitized with ovalbumin (OVA)-specific murine IgE were stimulated with 10.0 ng/mL OVA in the presence or the absence of quercetin for 24 h. The concentrations of angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-α, IL-6 and IL-8 in the supernatants were examined by ELISA. BALB/c male mice immunized with OVA were challenged intranasally with OVA every other day, starting seven days after the final immunization. These mice were then orally administered quercetin once a day for five days, starting seven days after the final immunization. Clinical symptoms were assessed by counting the number of sneezes and nasal rubbing behaviors during the 10 min period just after OVA nasal provocation. The angiogenic factor concentrations in the nasal lavage fluids obtained 6 h after nasal antigenic provocation were examined by ELISA. Results: Quercetin significantly inhibited the production of angiogenetic factors induced by IgE-dependent mechanisms at 5.0 µM or more. Oral administration of 25.0 mg/kg quercetin into the mice also suppressed the appearance of angiogenetic factors in nasal lavage fluids, along with the attenuation of nasal symptoms. Conclusions: These results strongly suggest that the inhibitory action of quercetin on angiogenic factor secretion may be implicated in the therapeutic action of quercetin on allergic diseases, especially allergic rhinitis.

Kamikihito, a traditional Japanese Kampo medicine, increases the secretion of oxytocin in rats with acute stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Kamikihito (KKT) is a Kampo medicine that is prescribed in Japan for the treatment of anemia, insomnia and mental anxiety in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: This study aimed to evaluate the possible antistress effect of KKT in rats with acute stress and the contribution of oxytocin to the process. MATERIALS AND METHODS: Acute immobilization stress (AIS; for 90 min) was used to assess the effect of KKT on acute stress. Male Wistar rats were orally treated with KKT. Parameters of stress were evaluated, and concentrations of oxytocin in plasma and cerebrospinal fluid (CSF) were measured. RESULTS: AIS-induced defecation and fecal weight were significantly decreased because of treatment with KKT. The plasma levels of stress-related hormones following AIS were investigated. The pre-administration of KKT significantly increased adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels following AIS. Conversely, there was no significant change in the plasma oxytocin level. Microdialysis and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were used to monitor the oxytocin secretion in CSF. Oxytocin level increased during AIS following the treatment of KKT. At 30 min after AIS, the level remained higher than before AIS. Furthermore, using an open field test, the locomotion (exploratory behavior) immediately after AIS was examined. The total traveled distance decreased after AIS; however, the decrease was significantly inhibited by the treatment of KKT. However, the effect of KKT was obstructed by the pre-administration of the oxytocin receptor antagonist. CONCLUSIONS: These results suggest that KKT has antistress activity and increased oxytocin secretion may be a mechanism underlying this phenomenon.

Analgesic effect of voluntary exercise in a rat model of persistent pain via suppression of microglial activation in the spinal cord.

In this study, we employed a rodent model for persistent allodynia and hyperalgesia to determine whether voluntary exercise could exert analgesic effects on these pain symptoms. Rats were subcutaneously injected with formalin into the plantar surface of the right hind paw to induce mechanical allodynia and hyperalgesia. We assessed the analgesic effects of a voluntary wheel running (VWR) using the von Frey test and investigated microglial proliferation in the dorsal horn of the spinal cord. We also determined the effect of formalin and VWR on the protein expression levels of brain-derived neurotrophic factor (BDNF), its receptor TrkB, and K+-Cl- cotransporter 2 (KCC2), which play a key role in inducing allodynia and hyperalgesia. Rats with access to the running wheels showed beneficial effects on persistent formalin-induced mechanical allodynia and hyperalgesia. The effects of VWR were elicited through the suppression of formalin-induced microglial proliferation, TrkB up-regulation, and KCC2 down-regulation in the spinal cord. BDNF, however, might not contribute to the beneficial effects of VWR. Our results show an analgesic effect of voluntary physical exercise in a rodent model with persistent pain, possibly through the regulation of microglial proliferation and TrkB and KCC2 expression in the spinal cord.

Regulatory Role of Orexin in the Antistress Effect of "Press Tack Needle" Acupuncture Treatment.

The aim of this research was to investigate the antistress effect of press tack needle (PTN) acupuncture treatment using rats with social isolation stress (SIS). Rats were divided into non-stress group (Grouped+sham), stress group (SIS+sham), and PTN-treated SIS group (SIS+PTN). Rats in the SIS+PTN and SIS+sham groups were housed alone for eight days. For the SIS+PTN group, a PTN (length, 0.3 or 1.2 mm) was fixed on the GV20 acupoint on day 7. We measured stress behavior based on the time the rats showed aggressive behavior and the levels of plasma corticosterone and orexin A on day 8. In addition, the orexin-1 receptor or orexin-2 receptor antagonist was administered to rats that were exposed to SIS. The duration of aggressive behavior was significantly prolonged in the SIS+sham group, and the prolonged duration was inhibited in the SIS+PTN (1.2 mm) group. The levels of plasma corticosterone and orexin A were significantly increased in the SIS+sham group; however, these increases were inhibited in the SIS+PTN group. The aggressive behavior was significantly reduced after the orexin-2 receptor antagonist was administered. These findings suggest that PTN treatment at GV20 may have an antistress effect, and the control of orexin is a mechanism underlying this phenomenon.

Senso-Immunologic Prospects for Complex Regional Pain Syndrome Treatment.

Complex regional pain syndrome (CRPS) is a chronic pain syndrome that occurs in tissue injuries as the result of surgery, trauma, or ischemia. The clinical features of this severely painful condition include redness and swelling of the affected skin. Intriguingly, it was recently suggested that transient receptor potential ankyrin 1 (TRPA1) is involved in chronic post-ischemia pain, a CRPS model. TRPA1 is a non-selective cation channel expressed in calcitonin gene-related peptide (CGRP)-positive primary nociceptors that becomes highly activated in ischemic conditions, leading to the generation of pain. In this review, we summarize the history of TRPA1 and its involvement in pain sensation, inflammation, and CRPS. Furthermore, bone atrophy is also thought to be a characteristic clinical sign of CRPS. The altered bone microstructure of CRPS patients is thought to be caused by aggravated bone resorption via enhanced osteoclast differentiation and activation. Although TRPA1 could be a target for pain treatment in CRPS patients, we also discuss the paradoxical situation in this review. Nociceptor activation decreases the risk of bone destruction via CGRP secretion from free nerve endings. Thus, TRPA1 inhibition could cause severe bone atrophy. However, the suitable therapeutic strategy is controversial because the pathologic mechanisms of bone atrophy in CRPS are unclear. Therefore, we propose focusing on the remission of abnormal bone turnover observed in CRPS using a recently developed concept: senso-immunology.

Analgesic Efficacy of a Combination of Fentanyl and a Japanese Herbal Medicine "Yokukansan" in Rats with Acute Inflammatory Pain.

Background: Fentanyl can induce acute opioid tolerance and postoperative hyperalgesia when administered at a single high dose; thus, this study examined the analgesic efficacy of a combination of fentanyl and Yokukansan (YKS). Methods: Rats were divided into control, formalin-injected (FOR), YKS-treated+FOR (YKS), fentanyl-treated+FOR (FEN), and YKS+FEN+FOR (YKS+FEN) groups. Acute pain was induced via subcutaneous injection of formalin into the paw. The time engaged in pain-related behavior was measured. Results: In the early (0-10 min) and intermediate (10-20 min) phases, pain-related behavior in the YKS+FEN group was significantly inhibited compared with the FOR group. In the late phase (20-60 min), pain-related behavior in the FEN group was the longest and significantly increased compared with the YKS group. We explored the influence on the extracellular signal-regulated kinase (ERK) pathway in the spinal cord, and YKS suppressed the phosphorylated ERK expression, which may be related to the analgesic effect of YKS in the late phase. Conclusions: These findings suggest that YKS could reduce the use of fentanyl and combined use of YKS and fentanyl is considered clinically useful.

Preventive Effect of the Japanese Traditional Herbal Medicine Boiogito on Posttraumatic Osteoarthritis in Rats.

BACKGROUND: Considering the anti-inflammatory properties of the Japanese traditional Kampo medicine Boiogito (BO), we aimed to investigate the therapeutic effect of BO to prevent the development of knee osteoarthritis (KOA) in rats with surgically induced KOA. METHODS: Destabilization of the medial meniscus (DMM) was performed to induce osteoarthritis in the right knees of 12-week-old Wistar rats under general anesthesia. The rats were orally administered 3% BO in standard powder chow for 4 weeks after surgery (controls: n = 6; sham group: n = 6; DMM group: n = 5; DMM + BO group: n = 5). During this period, the rotarod test was performed to monitor locomotive function. After 4 weeks, histological assessment was performed on the right knee. RESULTS: Oral administration of BO improved locomotive function in the rotarod test. Walking time on postoperative days 1, 14, or later was significantly longer in the DMM + BO group than in the DMM group. Histologically, the DMM group showed significant progression of KOA, which, in the DMM + BO group, was strongly suppressed, as assessed by the Osteoarthritis Research Society International score. CONCLUSIONS: Our results showed that oral administration of BO had a clinically preventive effect on early stage posttraumatic KOA.

Influence of Periostin on Synoviocytes in Knee Osteoarthritis.

BACKGROUND: Periostin (POSTN) is a protein that binds to integrins to support adhesion and migration of epithelial cells. Mice lacking this gene exhibit cardiac valve disease as well as skeletal and dental defects. Recent studies indicated that periostin is involved in the pathogenesis and progression of knee osteoarthritis (OA). We investigated the influence of periostin and matrix metalloproteinases (MMPs) on OA synoviocytes. MATERIALS AND METHODS: OA patients were classified according to the Kellgren-Lawrence system and the levels of periostin, interleukin (IL)-4, IL-13 and transforming growth factor-ß (TGFß) in the synovial fluid were measured. MMPs or tissue inhibitor of MMPs (TIMPs) with periostin in cultured cells were measured when periostin was added to OA-associated synovial cells. Dexamethasone, a steroid medication which shows immunosuppressive effects, was used to investigate the influence of the downstream cascade. RESULTS: Periostin and IL-13 levels were up-regulated during the progression of OA. MMP-2 and MMP-3 levels increased in a periostin concentration-dependent manner. Increase in MMP-2 and MMP-3 levels was inhibited by dexamethasone treatment. CONCLUSION: In vivo results herein indicate that IL-13 may induce periostin production in OA. Furthermore, periostin may facilitate MMP production in OA-associated synovial cells.

Influence of IL13 on Periostin Secretion by Synoviocytes in Osteoarthritis.

BACKGROUND: Our previous research provided evidence of periostin increase in parallel with interleukin-13 (IL13) increase in the synovial fluid of patients with osteoarthritis (OA). The reaction cascade from IL13 to periostin, however, remains unidentified. We, therefore, tested the hypothesis that periostin secretion is affected downstream of IL13. MATERIALS AND METHODS: OA synoviocytes were cultured under different concentrations of IL13. Periostin content in culture supernatants and the level of signal transducer and activator of transcription 6 (STAT6) in the cultured cells were measured using enzyme-linked immunosorbent assay (ELISA). Moreover, the influence of dexamethasone and leflunomide on periostin production in relation to the effect of IL13 on the cells was also examined. RESULTS: Periostin content in culture supernatants and the level of STAT6 in cultured cells were significantly increased by IL13. The increase of periostin was significantly inhibited by dexamethasone and leflunomide. CONCLUSION: Periostin may be up-regulated in OA synoviocytes via STAT6 downstream of IL13.