Catalpol promotes articular cartilage repair by enhancing the recruitment of endogenous mesenchymal stem cells.

Articular cartilage defect is challenged by insufficient regenerative ability of cartilage. Catalpol (CA), the primary active component of Rehmanniae Radix, could exert protective effects against various diseases. However, the impact of CA on the treatment of articular cartilage injuries is still unclear. In this study, full-thickness articular cartilage defect was induced in a mouse model via surgery. The animals were intraperitoneally injected with CA for 4 or 8 weeks. According to the results of macroscopic observation, micro-computed tomography CT (µCT), histological and immunohistochemistry staining, CA treatment could promote mouse cartilage repair, resulting in cartilage regeneration, bone structure improvement and matrix anabolism. Specifically, an increase in the expression of CD90, the marker of mesenchymal stem cells (MSCs), in the cartilage was observed. In addition, we evaluated the migratory and chondrogenic effects of CA on MSCs. Different concentration of CA was added to C3H10 T1/2 cells. The results showed that CA enhanced cell migration and chondrogenesis without affecting proliferation. Collectively, our findings indicate that CA may be effective for the treatment of cartilage defects via stimulation of endogenous MSCs.

Epimedium-Curculigo herb pair enhances bone repair with infected bone defects and regulates osteoblasts through LncRNA MALAT1/miR-34a-5p/SMAD2 axis.

Infected bone defects (IBDs) are the common condition in the clinical practice of orthopaedics. Although surgery and anti-infective medicine are the firstly chosen treatments, in many cases, patients experience a prolonged bone union process after anti-infective treatment. Epimedium-Curculigo herb pair (ECP) has been proved to be effective for bone repair. However, the mechanisms of ECP in IBDs are insufficiency. In this study, Effect of ECP in IBDs was verified by micro-CT and histological examination. Qualitative and quantitative analysis of the main components in ECP containing medicated serum (ECP-CS) were performed. The network pharmacological approaches were then applied to predict potential pathways for ECP associated with bone repair. In addition, the mechanism of ECP regulating LncRNA MALAT1/miRNA-34a-5p/SMAD2 signalling axis was evaluated by molecular biology experiments. In vivo experiments indicated that ECP could significantly promote bone repair. The results of the chemical components analysis and the pathway identification revealed that TGF-ß signalling pathway was related to ECP. The results of in vitro experiments indicated that ECP-CS could reverse the damage caused by LPS through inhibiting the expressions of LncRNA MALAT1 and SMAD2, and improving the expressions of miR-34a-5p, ALP, RUNX2 and Collagen type І in osteoblasts significantly. This research showed that ECP could regulate the TGF-ß/SMADs signalling pathway to promote bone repair. Meanwhile, ECP could alleviate LPS-induced bone loss by modulating the signalling axis of LncRNA MALAT1/miRNA-34a-5p/ SMAD2 in IBDs.

α-Solanine attenuates chondrocyte pyroptosis to improve osteoarthritis via suppressing NF-κB pathway.

α-Solanine has been shown to exhibit anti-inflammatory and anti-tumour properties; however, its efficacy in treating osteoarthritis (OA) remains ambiguous. The study aimed to evaluate the therapeutic effects of α-solanine on OA development in a mouse OA model. The OA mice were subjected to varying concentrations of α-solanine, and various assessments were implemented to assess OA progression. We found that α-solanine significantly reduced osteophyte formation, subchondral sclerosis and OARSI score. And it decreased proteoglycan loss and calcification in articular cartilage. Specifically, α-solanine inhibited extracellular matrix degradation by downregulating collagen 10, matrix metalloproteinase 3 and 13, and upregulating collagen 2. Importantly, α-solanine reversed chondrocyte pyroptosis phenotype in articular cartilage of OA mice by inhibiting the elevated expressions of Caspase-1, Gsdmd and IL-1ß, while also mitigating aberrant angiogenesis and sensory innervation in subchondral bone. Mechanistically, α-solanine notably hindered the early stages of OA progression by reducing I-κB phosphorylation and nuclear translocation of p65, thereby inactivating NF-κB signalling. Our findings demonstrate the capability of α-solanine to disrupt chondrocyte pyroptosis and sensory innervation, thereby improving osteoarthritic pathological progress by inhibiting NF-κB signalling. These results suggest that α-solanine could serve as a promising therapeutic agent for OA treatment.

Inflammation-Mediated Aberrant Glucose Metabolism in Subchondral Bone Induces Osteoarthritis.

Osteoarthritis (OA) is an entire joint disease with pathological alteration in both articular cartilage and subchondral bone. It has been recognized recently the association between metabolic syndrome and OA, particularly glucose metabolism in regulation of articular cartilage homeostasis and joint integrity. Whereas the role of glucose metabolism in subchondral bone sclerosis remains largely unknown during pathogenesis of OA. Consistent with common OA features, we observed subchondral bone sclerosis and abnormal bone remodeling in human OA joints and murine OA joints as reflected by hyperactive bone resorption and overall bone formation which was measured via dynamic histomorphometry. Osx-CreER;tdTomato mice also displayed the similar overall bone formation under injury-induced OA condition. Immunohistochemistry further revealed increased IL-1ß expression in human and murine OA subchondral bone. Given the inflammatory environment in joints under OA condition, we treated MC3T3-E1 cell, a pre-osteoblast cell line, with IL-1ß in this study and demonstrated that IL-1ß treatment could stimulate the cell osteogenic differentiation and meanwhile upregulate glycolysis and oxidative phosphorylation in cell cultures. More importantly, intraperitoneal injection of 2-deoxy-D-glucose (2-DG) and oligomycin (OGM), respectively, suppressed the subchondral bone glycolysis and oxidative phosphorylation in mice. Consequently, 2-DG and OGM treatment attenuated abnormal osteoblast differentiation and protected against aberrant bone formation in subchondral bone and articular cartilage degradation in wildtype mice following with joint injury. Collectively, these data strongly suggest glycolysis and oxidative may serve as important therapeutic targets for OA treatment.

Multiple intra-articular injections of autologous stromal vascular fractions for the treatment of multicompartmental osteoarthritis in both the tibiofemoral and patellofemoral joint: a single-blind randomized controlled study.

BACKGROUND: Multicompartmental osteoarthritis (MOA) in both tibiofemoral and patellofemoral joints is a more commonly occurring, but neglected, clinical condition, and we examined the short-term safety and efficacy of autologous stromal vascular fractions (SVFs) for MOA using a single-blind, prospective, randomized, placebo-controlled trial. METHODS: Seventy MOA patients were recruited and randomly assigned to the SVF group and hyaluronic acid (HA) group (control group). The scores of visual analog scale, the Western Ontario and McMaster University Osteoarthritis Index, and the Samsung Medical Center patellofemoral scoring system were assessed and compared between the two groups 3, 6 and 12 months after treatment. RESULTS: The SVF group had significantly better visual analog scale scores than the HA group at 6 and 12 months after treatment and had better Western Ontario and McMaster University Osteoarthritis Index scores than the HA group only at 6 months after treatment. For Samsung Medical Center patellofemoral scoring system of the patellofemoral joint, the SVF group had significantly better scores than the control group at all postoperative time points. The proportion of patients whose visual analog scale and Western Ontario and McMaster University Osteoarthritis Index scores were above the minimal clinically important improvement was higher in the SVF group than in the HA group in the majority of assessments. The improvement of bone marrow by SVF treatment was significantly better than that of the HA group as observed by pre- and postoperative Magnetic resonance imaging (MRI). CONCLUSIONS: Multiple intra-articular injection of autologous SVF reduces pain and improves function in the short term in patients with early or midstage MOA. However, there was heterogeneity in the improvement of overall knee and isolated patellofemoral joint after treatment.

Crohn's disease in hemophilic arthropathy patient: a case report.

Crohn's disease (CD) is an inflammatory bowel disease affecting the digestive tract, the incidence of which is on the rise worldwide. The most common clinical manifestation of hemophilia is arthropathy secondary to recurrent joint effusions and chronic synovitis. This article reports on a rare 25-year-old male patient with both hemophilic arthropathy and Crohn's disease who was at risk for pathogenic gastrointestinal bleeding. After undergoing endoscopic pathologic testing and genetic testing, a multidisciplinary expert work-up of a treatment and nutritional plan was performed. The patient improved clinically and adhered to conservative treatment. This case report is the first report of this rare co-morbidity, demonstrating the highly pathogenic mutation locus and summarizing the clinical experience of early diagnosis and treatment.

Modified osteochondral autograft transplantation for steroid-induced osteonecrosis of femoral head in idiopathic thrombocytopenic purpura: a case report and literature.

Osteochondral autograft transplantation (OAT) has been commonly applied in the knee and ankle while the technique has not yet been a popularity in the femoral head. In this article, we present a 28-year-old female patient, who has a history of 1-year-use of glucocorticoid in the treatment of idiopathic thrombocytopenic purpura, with steroid-induced osteonecrosis of the femoral head (SONFH). She underwent surgical hip dislocation, osteochondroplasty, OAT, and internal fixation. Her Harris Hip Score improved from 64 to 82 in 36 months to follow-up. The case is valuable considering that a single, instead of several, 1.5 cm autograft was harvested from the non-bearing part of the same femoral head. This modification dispensed with the need of surgery for harvesting autograft from knee or ankle and reduced the structural vulnerability brought by the multihole donor part of the femoral head.

Intra-articular injection of tranexamic acid in patients with haemophilia arthritis: retrospective controlled study in total knee arthroplasty.

PURPOSE: Total knee arthroplasty is the main method for the treatment of advanced haemophilic knee arthritis. Due to the particularity of hemophilia, the blood management plan is the focus of the perioperative period for haemophilia patients. This study aimed to investigate the clinical effect and safety of intra-articular injection of tranexamic acid in patients with haemophilia. METHODS: This is a retrospective study. According to whether tranexamic acid is used or not, patients are divided into tranexamic acid group (n=30) and non-tranexamic acid group (n=29). Total blood loss, intraoperative blood loss, complete blood count, total amount of coagulation factor VIII (FVIII) usage, coagulation biomarkers, inflammatory biomarkers, knee range of motion, knee joint function, pain status, complication rate, and patient satisfaction were assessed and compared at a mean follow-up of 16 months. RESULTS: Injecting tranexamic acid into the knee joint cavity can effectively reduce the hidden blood loss and total blood loss (P<0.001), and reduce the patient's early postoperative inflammation biomarkers, pain status, and limb swelling. Therefore, the patient can obtain a better range of motion following total knee arthroplasty. In the long run, in terms of joint function and surgical satisfaction, there are no statistically significant differences. In addition, there are no statistically significant differences between the two groups of patients in terms of the total amount of FVIII usage, length of stay, and hospitalization expenses. CONCLUSION: In patients with haemophilia, intra-articular injection of tranexamic acid during total knee arthroplasty can effectively reduce postoperative blood loss, early postoperative inflammation levels, pain and limb swelling, and enable patients to receive higher-quality rehabilitation exercises to get better joint function. Previous studies on TKA in haemophilic patients have already demonstrated the efficacy of intra-articular injections of TXA in reducing postoperative blood loss. Our study confirms this efficacy.

Factors influencing periprosthetic bone mineral density in total knee arthroplasty: a systematic review.

INTRODUCTION: Following total knee arthroplasty (TKA), there is a significant decline in periprosthetic bone mineral density (BMD), potentially resulting in complications such as prosthetic loosening, periprosthetic fracture, and influencing the postoperative recovery. The objective of this study was to summarize the factors influencing periprosthetic BMD in TKA from existing studies. METHODS: A comprehensive systematic search was performed in 4 databases: Pubmed, Embase, Web of Science, and Cochrane Library. The last search was carried out on October 12, 2023. We used the keywords ''total knee arthroplasty'', ''bone mineral density'' and each of them combined with ''tibia'' and ''femur'' to identify all relevant articles reporting about potential impact factors influencing the periprosthetic BMD in patients after TKA. RESULTS: Out of 1391 articles, 22 published from 2001 to 2023 were included in this systematic review. Following eligibility screening, six significant categories affecting periprosthetic BMD were recognized: prosthesis type, design of stem, coating, body weight, cement, and peg distance. CONCLUSION: Mobile-bearing prostheses, modular polyethylene design, short stems, cruciform stems, avoidance of bone cement, higher body mass index, titanium nitride coating, and a smaller medial peg distance could potentially benefit periprosthetic BMD. Comprehensive consideration of diverse factors influencing periprosthetic BMD before surgery and collaboration with post-operative drug therapy are essential. TRIAL REGISTRY: The PROSPERO registration number is CRD42023472030.

AR/PCC herb pair inhibits osteoblast pyroptosis to alleviate diabetes-related osteoporosis by activating Nrf2/Keap1 pathway.

Osteoporosis is a prevalent complication of diabetes, characterized by systemic metabolic impairment of bone mass and microarchitecture, particularly in the spine. Anemarrhenae Rhizoma/Phellodendri Chinensis Cortex (AR/PCC) herb pair has been extensively employed in Traditional Chinese Medicine to manage diabetes; however, its potential to ameliorate diabetic osteoporosis (DOP) has remained obscure. Herein, we explored the protective efficacy of AR/PCC herb pair against DOP using a streptozotocin (STZ)-induced rat diabetic model. Our data showed that AR/PCC could effectively reduce the elevated fasting blood glucose and reverse the osteoporotic phenotype of diabetic rats, resulting in significant improvements in vertebral trabecular area percentage, trabecular thickness and trabecular number, while reducing trabecular separation. Specifically, AR/PCC herb pair improved impaired osteogenesis, nerve ingrowth and angiogenesis. More importantly, it could mitigate the aberrant activation of osteoblast pyroptosis in the vertebral bodies of diabetic rats by reducing increased expressions of Nlrp3, Asc, Caspase1, Gsdmd and IL-1ß. Mechanistically, AR/PCC activated antioxidant pathway through the upregulation of the antioxidant response protein Nrf2, while concurrently decreasing its negative feedback regulator Keap1. Collectively, our in vivo findings demonstrate that AR/PCC can inhibit osteoblast pyroptosis and alleviate STZ-induced rat DOP, suggesting its potential as a therapeutic agent for mitigating DOP.

Glucocorticoid-induced activation of NOX/ROS/NF-κB signaling in MSCs contributes to the development of GONFH.

BACKGROUND: This study aimed to investigate the pathogenic factors of glucocorticoids (GCs)-induced osteonecrosis of the femoral head (GONFH) and its underlying pathogenesis in vivo and in vitro. METHODS: Radiographical (µCT) scanning, histopathological, immunohistochemical, reactive oxygen species (ROS) and tunel staining were conducted on GONFH patients and rats. ROS, tunel, flow cytometry, alkaline phosphatase, Oil red O staining, reverse transcription­quantitative PCR and western blotting were applied to elucidate the exact pathogenesis mechanism. RESULTS: Clinical and animal studies demonstrated increased levels of ROS, aggravated oxidative stress (OS) microenvironment, augmented apoptosis and imbalance in osteogenic/lipogenic in the GONFH group compared to the control group. The fate of mesenchymal stem cells (MSCs) directed by GCs is a crucial factor in determining GONFH. In vitro studies further revealed that GCs promote excessive ROS production through the expression of NOX family proteins, leading to a deterioration of the OS microenvironment in MSCs, ultimately resulting in apoptosis and imbalance in osteogenic/lipogenic differentiation. Furthermore, our results confirmed that the NOX inhibitor-diphenyleneiodonium chloride and the NF-κB inhibitor-BAY 11-7082 ameliorated apoptosis and osteogenic/lipogenic differentiation imbalance of MSCs induced by an excess of GCs. CONCLUSION: We demonstrated for the first time that the aggravation of the OS microenvironment in MSCs caused by high doses of GCs leading to apoptosis and differentiation imbalance is a crucial factor in the pathogenesis of GONFH, mediated through activating the NOX/ROS/NF-κB signaling pathway.

Detrimental alteration of mesenchymal stem cells by an articular inflammatory microenvironment results in deterioration of osteoarthritis.

BACKGROUND: Articular injection of mesenchymal stem cells (MSCs) has been applied to treat knee osteoarthritis (kOA), but its clinical outcomes are controversial. This study investigated whether an articular inflammatory microenvironment (AIM) impacts MSC-based therapy in a rat model of kOA. METHODS: The biological change of MSCs and the functional change of MSCs on chondrocytes were evaluated under AIM. The key mediator and mechanism for the AIM impact on MSC therapy were explored via gain- and loss-of-function approaches. RESULTS: The results showed that MSCs exerted potent anti-kOA effects in vivo and in vitro, but that this therapy become chondrodestructive if a chronic AIM was present. Mechanistically, the overexpression of MMP13 in the injected MSCs via a MAPKs-AP1 signaling axis was revealed as the underlying mechanism for the detriment outcome. CONCLUSIONS: This study thus clarifies recent clinical findings while also suggesting a means to overcome any detrimental effects of MSC-based therapy while improving its efficacy.

Total hip and knee arthroplasty in HIV- and HCV-positive hemophilia patients: short term follow-up of 14 patients.

BACKGROUND: Haemophilic arthropathy (HA) is a common comorbidity of haemophilia. Some people with haemophilia (PWH) were human immunodeficiency virus (HIV)-positive. Arthroplasty is an effective treatment for end-stage HA. This study was carried out to report the effectiveness and satisfaction following total hip arthroplasty (THA) or total knee arthroplasty (TKA) in PWH with HIV. PATIENTS AND METHODS: All patients with haemophilia and HIV undergoing THA or TKA in our centre from January 2015 to June 2020 were reviewed. All patients were followed for at least twenty-four months. The improvements in postoperative indicators were evaluated at the latest follow-up, including the Visual Analogue Scale (VAS) score, range of motion (ROM), and validated joint scores such as Knee Society Score (KSS; clinical and functional) and Harris Hip Score (HHS). The complications and satisfaction were analysed likewise. Those were utilized to weigh the risks and benefits of the procedure in the population. RESULTS: Fourteen patients (7 hips and 14 knees) were included in the study. The follow-up of the THA cohort was 53.3 months (range, 27-82) and the TKA cohort was 50.1 months (range, 25-85), respectively. The average VAS score was ameliorated from 7.3 to 3.0 and 6.6 to 2.8 in the two groups (P < .001, respectively). Similarly, two cohorts (THA and TKA) showed statistically significant changes in the extension and flexion ROM between the preoperative and the latest follow-up (P < .05, P < .001, respectively). Besides, statistically significant differences between the preoperative and final follow-up values of HHS (from 41.6 to 82.3), clinical KSS (from 34.8 to 72.8), and functional KSS (from 42.9 to 73.2) were observed (P < .001, respectively). Notably, there were 4 complications noted among 21 arthroplasties performed, giving a 19.0% complication rate. Based on the satisfaction score, the majority of patients were optimistic about the arthroplasty. CONCLUSION: Given these findings, THA or TKA of the PWH with HIV is a worthwhile procedure and can be performed by an experienced and collaborative multidisciplinary team in a tertiary centre with a good haemophilia care system.

Antibiotic artificial bone implantation for the treatment of infection after internal fixation of tibial plateau fractures.

OBJECTIVE: To explore the clinical effect of antibiotic artificial bone (Calcium phosphate) in the treatment of infection after internal fixation of tibial plateau fractures. METHODS: We retrospectively reviewed the clinical data of 32 patients with infection after internal fixation of tibial plateau fractures treating from March 2010 to October 2021. There were 18 males and 14 females, aged from 23 to 70 (average 49.66 ± 10.49), 19 cases of the left side and 13 cases of the right side. Among them, 7 cases were open fractures with initial injury and 25 cases were closed fractures. On the basis of thorough debridement and implanting antibiotic artificial bone, the internal fixation of 18 patients were tried to be preserved and the internal fixation of 14 patients were removed completely. In order to provide effective fixation, 14 patients also received external fixation. Postoperative wound healing, infection control, Hospital for Special Surgery knee scores (HSS), related inflammatory indicators and bone healing time were recorded and followed up. RESULTS: Thirty-two patients were followed up for 12 ~ 82 months (average 36.09 ± 19.47 months). The redness, swelling and pain of pin site occurred in 2 patients, which returned to normal after applying antibiotics and continuous dressing change. One patient retained the internal fixation during the first-stage operation. Redness and swelling of incision, subcutaneous undulation occurred after two months. In order to avoid the recurrence of infection, the internal fixation was removed completely and antibiotic artificial bone was filled again. The infection was controlled and fracture healed. Four patients' wounds could not be closed directly due to soft tissue defect and was covered with skin flap. After the first-stage operation, 12 patients received second-stage autologous iliac bone grafting due to residual bone defects and poor healing of the fracture end. The bone healing time was 4 ~ 16 months (average 7.31 ± 2.79 months). Inflammatory indicators including CRP, ESR, and WBC returned to normal levels within 2 ~ 10 weeks (average 4.97 ± 2.58 weeks). The HSS of all patients were 54 ~ 86 points (average 73.06 ± 8.44 points) at the last follow-up. CONCLUSION: Implantation of antibiotic artificial bone, retention or removal of internal fixation according to infection and fracture healing, application of external fixation timely is an effective method to treat infection after internal fixation of tibial plateau fractures, which can control infection effectively and promote functional recovery.

Hemophilia A developing cerebral infarction after surgical treatment of giant hemophilic pseudotumor: a case report.

BACKGROUND: Cerebral infarction (CI) is an unusual complication in patients with bleeding disorders. To our knowledge, this is the first case of postoperative internal border-zone infarction (I-BZI) from Hemophilia A. CASE PRESENTATION: We present a case of Hemophilia A developing I-BZI, after surgical treatment of giant hemophilic pseudotumor. A 36-year-old man was introduced from other hospital by Hemophilia with giant hemophilic pseudotumor in his left thigh. Patient and his relatives did not have a history of thrombophilia. After excluding the relevant surgical contraindications, we performed the operation of pseudotumor resection. Prior to surgery, blood tests revealed hemoglobin of 137 g/L. FVIII activity was 1.5%. Activated partial thromboplastin time (APTT) was 71.50 s and D-dimer was 3.33 mg/L FEU. Immediately before surgery, the patient received an intravenous infusion of FVIII products (Xyntha®) at a dose of 3500 IU for his body weight of 80 kg. Post-operative day two (POD2), patient developed vomiting, decreased response, and dysarthria. Hemoglobin was 54 g/L with blood pressure of 110/70 mmHg. Magnetic resonance imaging of the brain showed there were multiple acute cerebral infarctions in bilateral lateral ventricles (internal border zone) and multiple ischemic foci in the white matter areas and basal ganglia of the bilateral cerebral hemispheres. This case suggested that acute severe anemia can be one of the causes of I-BZI. CONCLUSIONS: For the treatment of I-BZI caused by acute anemia from Hemophilia A, volume expansion, red blood cell supplement and continuous improvement of coagulation with suitable dose of factor VIII (FVIII) should be considered to improve prognosis.

Total knee arthroplasty in patients with haemophilic arthropathy is effective and safe according to the outcomes at a mid-term follow-up.

BACKGROUND: Haemophilic arthropathy (HA), a common complication of haemophilia, is secondary to recurrent joint bleeding and increases the prevalence of end-stage osteoarthritis (OA). Total knee arthroplasty (TKA) is a reliable treatment for haemophilia patients. This study was performed to evaluate the mid-term outcomes of TKA for end-stage HA. We hypothesized that the rate of complications of TKA is higher for patients with haemophilia than for patients without haemophilia. METHODS: Patients with HA undergoing TKA from January 2015 to December 2016 in our centre were retrospectively reviewed. All patients were managed by a multidisciplinary team. The improvements in flexion contracture, range of motion (ROM), Knee Society Score (KSS; clinical and functional), Visual Analogue Scale (VAS) score, and satisfaction at final follow-up were analysed to evaluate the effectiveness of TKA in HA. The complications were analysed to evaluate the safety of TKA in HA. RESULTS: Twenty-eight patients (32 knees) were included in the study. The follow-up was 69.1 ± 5.1 months. Significant differences between the preoperative and final follow-up values of flexion contracture (which changed from 21.1 ± 6.5° to 14.3 ± 4.1°, P < 0.001), ROM (from 53.9 ± 15.0° to 70.3 ± 16.3°, P < 0.001), clinical KSS (from 33.5 ± 14.4° to 62.7 ± 9.5°, P < 0.001), functional KSS (from 46.1 ± 15.5° to 62.9 ± 9.7°, P < 0.001), and VAS score (from 6.8 ± 1.4 to 4.9 ± 1.3, P < 0.01) were observed. Importantly, the incidence of complications was 15.6% and the satisfaction was 100% in our mid-term study. CONCLUSION: Under elaborative and comprehensive management, TKA is effective and safe in patients with advanced HA on the basis of mid-term follow-up outcomes.

Aucubin prevents steroid-induced osteoblast apoptosis by enhancing autophagy via AMPK activation.

Steroid-induced osteoblast apoptosis is a crucial pathological process in steroid-induced osteonecrosis of the femoral head (SONFH). Autophagy can resist apoptosis and AMPK plays an important role in autophagy regulation. Aucubin from the small tree Eucommia ulmoides Oliv., which has a long history of use in orthopaedics and traumatology in Asian medicine, can promote bone formation, but whether it can slow or prevent steroid-osteoblast apoptosis is unclear. Therefore, we investigated the pathogenesis of SONFH and how the osteoblast responds to aucubin under the dexamethasone stimulation. In human femoral head osteonecrosis specimens, we found that the autophage and apoptosis level were increased, and the AMPK signalling was crucial to autophagy. We observed that aucubin could prevent dexamethasone-induced apoptosis in osteoblasts by enhancing the level of autophagy. Further, we confirmed that the regulatory effect of aucubin on autophagy and apoptosis was achieved by activating AMPK signalling. We have demonstrated a mechanism of disease progression and shown that aucubin could enhance autophagy through AMPK signalling to prevent osteoblast apoptosis. These findings provide a basis for the further investigation of the potential therapeutic role of aucubin in the SONFH.

Inflammation, angiogenesis and sensory nerve sprouting in the synovium of bony ankylosed and not bony ankylosed knees with end-stage haemophilic arthropathy.

INTRODUCTION: Clinical practice showed that patients with haemophilia (PwH) with bony ankylosed end-stage haemophilic arthropathy knees reported milder pain than those with not bony ankylosed knees. AIM: To compare the differences in pain sensation and the histopathological differences in synovial samples of affected knee joints between PwH with bony ankylosed end-stage haemophilic arthropathy knees and those with not bony ankylosed knees. METHODS: From January 2011 to December 2019, the synovial samples of knee joints were collected during total knee arthroplasty (TKA) surgery for end-stage haemophilic arthropathy. The visual analogue scale (VAS, 0-10) pain score was reviewed from the chart data of the patients. The thickness of the inner layer of the synovium in haematoxylin and eosin (H&E) staining sections was measured. The expression levels of Ki67, IL-1ß, TNF-α, CD31, VEGF, NGF and PGP9.5 in the synovium were detected by immunohistochemistry (IHC) method. RESULTS: Fifty-two end-stage haemophilic arthropathy knee synovial samples from 36 male PwH (34 type A and 2 type B) were collected. Fifteen knees had bony ankylosed (BA-group), and 37 were not bony ankylosed (Not-BA-group). The mean age of patients at TKA surgery of BA-group and Not-BA-group was 32 years (15) and 32 years (10), respectively (p = 0.824). Before TKA surgery, the mean VAS pain scores of patients in the Not-BA-group were significantly higher than those in the BA-group (p < 0.001). The mean thickness of the inner layer of the synovium, the mean rate of Ki67+ cells, the mean density of CD31+ vascular endothelial cells and the expression levels of IL-1ß, TNF-α, VEGF and NGF in samples in the Not-BA-group was significantly higher than those in samples in the BA-group (p < 0.001, p = 0.02, p = 0.001, p = 0.117, p < 0.001, p = 0.003 and p = 0.008), respectively. The mean density of PGP9.5+ sensory neural fibres in the Not-BA-group was slightly higher than in the BA-group (p = 0.131). Linear regression analysis showed a significant positive correlation between the VAS pain score and indicators including the synovial thickness, the rate of Ki67+ cells, the expression level of IL-1ß, TNF-α, VEGF, NGF and the densities of CD31+ vascular endothelial cells and PGP9.5+ nerve fibres (p < 0.05). CONCLUSIONS: Worsened hypertrophic synovitis, angiogenesis and sensory nerve sprouting in the synovium may play a critical role in causing worse pain sensation in PwH with not bony ankylosed haemophilic arthropathy knees than in those with bony ankylosed knees.

Pathological mechanism of joint destruction in haemophilic arthropathy.

Haemophilic arthropathy (HA), caused by intra-articular haemorrhage, is one of the most common complications in patients with haemophilia. Factor replacement therapy provides missing coagulation factors to prevent children with haemophilia from joint bleeding and decreases their risk for HA. However, haemophilia patients in developing countries are still suffering from HA due to insufficient replacement therapy. Symptoms such as pain and activity limitations caused by HA seriously affect the functional abilities and quality of life of patients with HA, causing a high disability rate in the haemophilia cohort. The pathological mechanism of HA is complicated because the whole pathological mainly involves hypertrophic synovitis, osteopenia, cartilage and bone destruction, and these pathological changes occur in parallel and interact with each other. Inflammation plays an important role in the whole complex pathological process, and iron, cytokines, growth factors and other factors are involved. This review summarizes the pathological mechanism of HA to provide background for clinical and basic research.

Platelet-rich plasma promotes bone formation, restrains adipogenesis and accelerates vascularization to relieve steroids-induced osteonecrosis of the femoral head.

Steroid-associated necrosis of the femoral head (SANFH) is one of the most common and refractory chronic diseases with increasing incidence. The typical pathological changes of SANFH include decreased osteogenic differentiation, enhanced intramedullary adipocytes deposition and impaired osseous circulation. In this study, we investigated the effects and potential mechanisms of Platelet-rich plasma (PRP) on SANFH. Sixty Sprague-Dawley rats were randomly divided into the control, PRP donor, model, and PRP groups. Compared to the model group, PRP treatment significantly increased the hemorheological indexes and serum levels of bone gla-protein (BGP) and vascular endothelial growth factor (VEGF), while decreased the levels of triglyceride (TG) and total cholesterol (TC). Meanwhile, Micro-CT and histopathological stain (Hematoxylin-eosin and Alcian blue-hematoxylin/orange G staining) were performed on the femoral head for morphological and histopathological evaluation, indicating that bone trabecular microstructure and bone mineral density (BMD) were significantly improved after PRP treatment. Immunohistochemical analysis revealed that PRP remarkably up-regulated the expression of osteogenic markers including ß-catenin and alkaline phosphatase (ALP), angiogenic markers containing VEGF and platelet endothelial cell adhesion molecule-1 (CD31), while down-regulated adipogenic markers involving fatty acid-binding protein (FABP-4), and peroxisome proliferator-activated receptor gamma (PPAR-γ) in SANFH rat models. In summary, for the first time, PRP was demonstrated to prevent the development of SANFH through stimulating bone formation and vascularization as well as retarding adipogenesis.