Effect of electroacupuncture on the expression of P53 and P21 in articular cartilage and subchondral bone of aged rats with knee osteoarthritis / 中国组织工程研究

BACKGROUND:There are many treatment methods for knee osteoarthritis,among which electroacupuncture,as an important non-drug treatment,is effective in the treatment of knee osteoarthritis,but its exact mechanism is not clear. OBJECTIVE:Effect of electroacupuncture on the expression of p53 and P21 in articular cartilage and subchondral bone of aged rats with knee osteoarthritis. METHODS:Eight 6-month-old male Sprague-Dawley rats were included in the young group and sixteen 24-month-old male Sprague-Dawley rats were randomly divided into old group(n=8)and electroacupuncture group(n=8).The rats in the electroacupuncture group received electroacupuncture stimulation once a day,5 days a week,for 8 continuous weeks,and the other two groups did not do any treatment.Eight weeks later,the level of type Ⅱ collagen C-terminal peptide in peripheral blood was detected by ELISA,the morphology of left knee cartilage and subchondral bone was observed by safranin O-fast green staining,the degree of knee cartilage degeneration was evaluated by modified Mankin's score,the microstructure of left knee cartilage and subchondral bone was detected by micro-CT,and the expression levels of matrix metalloproteinase 13,P53,P21 Mrna and protein were detected by RT-PCR and western blot respectively. RESULTS AND CONCLUSION:Compared with the young group,the level of C-terminal peptide of type Ⅱ collagen in the peripheral blood was increased in the old group(P<0.05).The micro-CT results showed that the bone volume fraction,bone mineral density and the number of bone trabeculae were decreased in the old group compared with the young group(P<0.05),while the trabecular separation increased(P<0.05).Safranin O-fast green staining showed that in the old group,the surface layer of cartilage was uneven with fissures,the morphology of chondrocytes was irregular and stained unevenly,the boundary between the cartilage and subchondral bone was blurred,and the matrix loss was serious.The Mankin's score was higher in the old group than the young group(P<0.05).The expression of matrix metalloproteinase 13,P53,P21 at Mrna and protein levels increased in the old group compared with the young group(P<0.05).Compared with the old group,electroacupuncture decreased the level of C-terminal peptide of type Ⅱ collagen(P<0.05),increased the bone volume fraction,bone mineral density and the number of bone trabeculae(P<0.05),and decreased the trabecular separation(P<0.05).Safranin O-fast green staining showed that in the electroacupuncture group,the surface of cartilage was smooth and red staining was uniform,and the cell morphology and structure were between the young group and the old group.Following electroacupuncture treatment,the Mankin's score(P<0.05),matrix metalloproteinase 13 and P21 Mrna expression(P<0.05),and matrix metalloproteinase 13 and P53 protein expression decreased(P<0.05),while there was a decreasing trend of P53 Mrna and P21 protein expression,but with no statistical significance(P>0.05).To conclude,electroacupuncture may delay articular cartilage degeneration and subchondral osteoporosis in aged rats by inhibiting the expression of P53 and P21,so as to protect joints and delay joint aging.

Strontium ranelate-loaded sodium alginate/collagen hydrogel promotes bone defect repair in osteoarthritis / 中国组织工程研究

BACKGROUND:Cartilage degeneration and subchondral bone damage are the main pathological features of osteoarthritis,and treatment based on this pathological feature will be a promising improvement for osteoarthritis. OBJECTIVE:To design and study an annotated strontium ranelate-loaded drug delivery system and to observe its therapeutic effect on promoting cartilage repair and improving subchondral bone structure in osteoarthritis. METHODS:(1)In vitro experiment:Strontium ranelate was loaded into sodium alginate/collagen hydrogel matrix to construct in situ drug delivery system,and the in vitro slow release performance of the system was characterized.Strontium ranelate-loaded sodium alginate/collagen hydrogel(experimental group)and alginate sodium/collagen hydrogel(control group)were co-cultured with bone marrow mesenchymal stem cells,respectively,and cultured cells were used as a blank control group to detect cell proliferative activity.After chondroblast-induced differentiation,saffron O staining,Alcian blue staining and RT-qPCR were performed respectively.The two hydrogels were co-cultured with osteoblasts,and the cultured cells were used as a blank control group for immunofluorescence staining and RT-qPCR.(2)In vivo experiment:A total of 18 adult SD rats were selected and the model of right posterior knee osteoarthritis was established by the method of medial meniscectomy.After 1 week,the rats were divided into three groups by the random number table method:The blank group did not receive any treatment.The control group was injected with sodium alginate/collagen hydrogel in the knee,and the experimental group was injected with strontium ranelate-loaded sodium alginate/collagen hydrogel,with 6 rats in each group.After 6 weeks,the samples were subjected to Micro-CT scanning,hematoxylin-eosin staining,saffron O-solid green staining and immunofluorescence staining. RESULTS AND CONCLUSION:(1)In vitro experiment:Strontium ranelate-loaded sodium alginate/collagen hydrogel had porous microstructure and sustainable release of strontium ranelate.At 21 days,the cumulative release reached(60.89±0.58)%.Bone marrow mesenchymal stem cell staining showed that both hydrogels had good cytocompatibility.The results of the CCK-8 assay demonstrated that strontium ranelate-loaded sodium alginate/collagen hydrogel could promote the proliferation of bone marrow mesenchymal stem cells.The results of Safranin O staining,Alcian blue staining,immunofluorescence staining and RT-qPCR exhibited that strontium ranelate-loaded sodium alginate/collagen hydrogel could promote chondrogenic differentiation of bone marrow mesenchymal stem cells.Immunofluorescence staining and RT-qPCR revealed that strontium ranelate-loaded sodium alginate/collagen hydrogel could decrease bone resorptivity by increasing the ratio of osteophosphorin/nuclear factor κB receptor activator ligand.(2)In vivo experiment:Micro-CT scan verified that compared with the blank group and control group,the subchondral bone volume fraction and bone mineral density of the knee of rats were increased in the experimental group(P<0.05,P<0.01).Histological staining displayed that compared with the blank group and control group,the knee cartilage injury was significantly reduced;the expression of type II collagen was promoted,and the expression of matrix metalloproteinase 2 protein was inhibited in the experimental group(P<0.05,P<0.01).(3)These results confirm that the strontium ranelate-loaded sodium alginate/collagen hydrogel can promote the repair of cartilage defects in osteoarthritis and reconstruct the complex interface between cartilage and subchondral bone.

An insight into the mechanism of iron overload in knee osteoarthritis under the theory of blood stasis / 中国组织工程研究

BACKGROUND:Knee osteoarthritis is a common disease in middle-aged and elderly people.It is a kind of disease that seriously affects the quality of life of patients and even has the risk of disability.Therefore,the pathogenesis and treatment of knee osteoarthritis have become the focus of research.In Chinese medicine,knee osteoarthritis is often treated as"biness,"which is closely related to"biness"caused by blood stasis and blood vessels blocking collaterals in the theory of"blood stasis"in traditional Chinese medicine.Iron overload is a kind of pathological state caused by iron metabolism disorder,which highly coincides with the pathogenic characteristics and clinical manifestations of the"blood stasis"theory of traditional Chinese medicine,and is a risk factor that promotes the development of knee osteoarthritis. OBJECTIVE:Based on the"blood stasis"theory,to summarize the effects of iron overload on cartilage metabolism and subchondral bone reconstruction,to lay a new theoretical foundation for the treatment of knee osteoarthritis with traditional Chinese medicine,and to explore the therapeutic effect of traditional Chinese medicine for promoting blood circulation after interfering with bone tissue. METHODS:CNKI,WanFang database,PubMed and Web of Science databases were searched for relevant literature.The Chinese search terms were"ferroptosis,iron,iron overload,osteoarthritis,blood stasis"and the English search terms were"ferroptosis,iron,iron overload,osteoarthritis,TCM."In the end,76 articles were included for further review. RESULTS AND CONCLUSION:First of all,we explored the potential of the"blood stasis"theory in treating knee osteoarthritis,and found that"blood stasis"is a crucial part in the progress of knee osteoarthritis,indicating that the"blood stasis"theory is the key to the treatment of knee osteoarthritis in traditional Chinese medicine.Secondly,"blood stasis"and iron overload have a high degree of similarity in pathogenic factors,clinical manifestations,and pathogenic characteristics,suggesting the possibility of"blood stasis"theory in treating iron overload.This finding reminds us that iron overload may be an important mechanistic basis for the"blood stasis"theory in the treatment of knee osteoarthritis.The extracts of blood-activating drugs can relieve iron overload and treat knee osteoarthritis,but the specific mechanism is still unclear.Therefore,we believe that the relationship between"blood stasis"theory and iron overload and related mechanisms are important research directions for knee osteoarthritis in the future.The related mechanism of"blood stasis"theory to alleviate iron overload and then treat knee osteoarthritis also provides a theoretical basis for the modernization of traditional Chinese medicine,such as the development of new drugs and innovative usage,and has certain guiding significance for clinical practice.

Stepwise treatment strategy for spontaneous osteonecrosis of the medial femoral condyle of the knee joint / 中国组织工程研究

BACKGROUND:Currently,there have been a variety of conservative and surgical treatment plans for spontaneous osteonecrosis of the knee,achieving excellent results.However,a broad consensus on indication and guide of surgical treatment has not been announced.In clinical practice,there is still a misunderstanding that unicondylar replacement or total knee arthroplasty should be performed upon the discovery of spontaneous osteonecrosis of the knee,while an urgent need for universal access to the concept of stepwise therapy. OBJECTIVE:To summarize and find the factors leading to the poor effect of conservative treatment in spontaneous osteonecrosis of the knee,which occurred on the medial femoral condyle,from the literature and clinical cases,at the same time,combined with the Koshino stage,to propose the strategy of stepwise spontaneous osteonecrosis of the knee treatment on the medial femoral condyle. METHODS:A systematic search of the literature database was conducted to summarize the factors leading to poor outcomes of conservative treatment in spontaneous osteonecrosis of the medial femoral condyle.Meanwhile,according to the Clinical&Health Records for analytics&Sharing system,the cases receiving conservative and surgical treatment in spontaneous osteonecrosis of the medial femoral condyle in the Department of Orthopedics of Guangdong Provincial Hospital of Chinese Medicine from January 2017 to January 2023 were analyzed retrospectively,then the causes of success and failure in typical cases were summarized and analyzed. RESULTS AND CONCLUSION:(1)Early diagnosis and treatment of spontaneous osteonecrosis of the knee were very important for prognosis.For sudden knee pain in some patients,if no obvious abnormality was found in the X-ray examination,and the symptoms persisted and could not be relieved for more than 1 week,an MRI examination was recommended to detect early spontaneous osteonecrosis of the knee.(2)The X-ray images of Koshino stage 1 and stage 2 of spontaneous osteonecrosis of the medial femoral condyle were difficult to be distinguished,which needed to be probed by MRI.MRI images of Koshino stage 1 were mainly characterized by bone marrow edema,and an osteonecrosis area with a clear boundary was not formed,while MR images of Koshino stage 2 showed a necrotic area with a clear boundary.(3)Five factors leading to the poor effect of conservative treatment on spontaneous osteonecrosis of the medial femoral condyle were summarized:a.The necrotic area was＞5 cm2;b.The necrotic area accounted for more than 40%of the condyle;c.relative compression percentage of medial meniscus≥33%(with or without medial meniscus injury and subchondral bone marrow edema);d.MRI depth of necrotic area(anterior-posterior diameter of sagittal necrotic area)＞20 mm;e.varus deformity of lower limb＞6°.(4)Conservative treatment of spontaneous osteonecrosis of the knee in Koshino stage 1 was good.For spontaneous osteonecrosis of the knee in Koshino stage 2,conservative treatment was preferred or combined with drilling decompression.If there was no relief or improvement of symptoms or in MRI after 3 months,while the patient had any of the previous five factors,then knee preservation surgery should be considered.For spontaneous osteonecrosis of the knee in Koshino stage 3 and stage 4,knee preservation surgery should be selected based on the previous five factors,including age,gender and activity level of the patient.Total knee arthroplasty was used for spontaneous osteonecrosis in Koshino stage 4,which was associated with symptomatic patellofemoral arthritis,valgus alignment,or necrotic area,which greatly affected the stability of unicondyle prosthesis.

Applicable techniques for subchondral separation of femoral head necrosis treated by tissue engineering / 中国组织工程研究

BACKGROUND:The appearance of the crescent sign in femoral head necrosis is a"turning point"in the progression of the disease,and repairing and stabilizing the bone-cartilage interface is particularly important in preventing further progression and collapse of the femoral head.Tissue engineering offers potential advantages in the simultaneous repair and integration of the bone-cartilage interface. OBJECTIVE:To review potentially suitable techniques addressing the subchondral separation in femoral head necrosis. METHODS:Relevant articles from January 1970 to April 2023 were searched in PubMed,Web of Science,and China National Knowledge Infrastructure(CNKI)using English search terms"femoral head necrosis,avascular necrosis of femoral head,osteonecrosis of femoral head"and Chinese search terms"femoral head necrosis,subchondral bone,cartilage,integration of cartilage and subchondral bone".A total of 114 articles were included for review and analysis. RESULTS AND CONCLUSION:(1)Structural defects,ischemic and hypoxic environment,inflammatory factors,and stress concentration may cause subchondral separation in osteonecrosis of the femoral head.Subchondral bone collapse and failure of hip-preserving surgery may be associated.Integration of tissue engineering scaffolds with the bone-cartilage interface is one potential approach for treating subchondral separation in osteonecrosis of the femoral head.(2)Current literature suggests that multiphase scaffolds,gradient scaffolds,and composite materials have shown improvements in promoting cell adhesion,proliferation,and deposition of bone and cartilage matrix.These advancements aid in the integration of scaffolds with the bone-cartilage interface and have implications for the treatment of subchondral separation in osteonecrosis of the femoral head.(3)Surface modifications of scaffolds can enhance interface integration efficiency,but they have their advantages and disadvantages.Scaffolds providing different environments can induce differentiation of mesenchymal stem cells and facilitate integration between different interfaces.(4)Future scaffolds for subchondral separation in osteonecrosis of the femoral head are expected to be composite materials with gradient and differentiated biomimetic structures.Surface modifications and stem cell loading can promote integration between the bone-cartilage interface and scaffolds for therapeutic purposes,but further experimental verification is still needed.Challenges include synchronizing scaffold degradation rate with repair progress and ensuring stability between different interfaces.

Electroacupuncture improves motor function of rats with osteoarthritis by alleviating joint inflammation through the Wnt-7B/β-catenin signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of electroacupuncture on osteoarthritis in rats and explore the possible mechanism.@*METHODS@#Thirty SD rats were randomly divided into osteoarthritis model group, electro-acupuncture group and control group (n=10), and in the former two groups, early osteoarthritis was induced using a modified DMM surgical modeling method. After successful modeling, the rats in the electro-acupuncture group were treated with electro-acupuncture at bilateral "Housanli" and "Anterior knee point". Behavioral tests of the rats were performed and scored using the LequesneMG scale. Subchondral bone degeneration was observed in each group, and serum levels of IL-1β, ADAMTS-7, MMP-3 and COMP were measured using ELISA. The mRNA and protein expressions of IL-1β, Wnt-7B, β-catenin, ADAMTS-7, and MMP-3 in the cartilage tissue of the knee joints were detected using RT-PCR and Western blotting.@*RESULTS@#In behavioral tests, the rats in the model and electroacupuncture groups had significantly higher LequesneMG scores after modeling than those in the control group (P < 0.05). After 20 days of treatment, LequesneMG scores were significantly lowered in rats in the electroacupuncture as compared with the model rats (P < 0.05). Imaging examination revealed obvious subchondral bone damage in both the electroacupuncture group and the model group, but the damages were significantly milder with former group. Compared with the model rats, the rats receiving electroacupuncture had significantly lower serum levels of IL-1β, ADAMTS-7, MMP-3 and COMP (P < 0.05) with also lower expressions of IL-1β, Wnt-7B, β-catenin, ADAMTS-7 and MMP-3 in the cartilage tissues at both the mRNA and protein levels (P < 0.05).@*CONCLUSION@#Electroacupuncture can alleviate joint pain and improve subchondral bone damage in rats with osteoarthritis by reducing IL-1β levels in the joint cartilage tissue and serum to alleviate joint inflammation and by reducing such cytokines as ADAMTS-7 and MMP-3 via regulating the Wnt-7B/β-catenin signaling pathway.

Clinical study on the subchondral screw compression technique assisted reduction of residual or secondary collapse of lateral tibial plateau / 中国修复重建外科杂志

OBJECTIVE@#To explore the reduction and support effect of the subchondral screw compression technique for residual or secondary collapse of the lateral tibial plateau during operation.@*METHODS@#Between January 2020 and June 2021, 11 patients with residual or secondary collapse of the lateral tibial plateau during operation were treated with the subchondral screw compression technique. There were 6 males and 5 females, aged 52.3 years old (range, 27-64 years). The fractures were caused by traffic accident in 10 cases and falling from height in 1 case and located at the left knee in 6 cases and the right knee in 5 cases. According to Schatzker classification, there were 5 cases of type Ⅱ fractures, 4 cases of type Ⅲ fractures, and 2 cases of type Ⅴfractures. According to the three columns classification, there were 5 cases of lateral column, 4 cases of lateral column and posterior column, and 2 cases of three columns. The time from injury to operation was 4.5 days (range, 3-7 days). During the follow-up, X-ray films were obtained and the Rasmussen standard was used to evaluate the quality of fracture reduction, meanwhile fracture healing was observed. The medial proximal tibial angle (mPTA), posterior tibial slope angle (pTSA), and articular surface collapse were measured at immediate and 12 months after operation. The knee joint range of motion was evaluated at last follow-up, and the knee joint function was evaluated using the Hospital for Special Surgery (HSS) score.@*RESULTS@#All operations were successfully completed, with a mean operation time of 71.4 minutes (range, 55-120 minutes), and a mean hospital stay of 8.0 days (range, 5-13 days). The incisions all healed by first intention, without complications such as infection, flap necrosis, or vascular and nerve injury. All patients were followed up 16.5 months on average (range, 12-24 months). X-ray films showed that the fracture reduction score was 14-18 (mean, 16.7) according to Rasmussen score criteria; and 5 cases were rated as excellent and 6 as good. All fractures healed clinically with a mean clinical healing time of 14.9 weeks (range, 12-16 weeks), and there was no complications such as plate or screw loosening. At 12 months after operation, the mPTA and pTSA were (87.5±1.7)° and (6.2±3.1)°, respectively; there was no significant difference when compared to the values at immediate after operation [(87.6±1.8)° and (6.5±3.1)°] ( P>0.05). The articular surface of the tibial plateaus was effectively supported, and it collapsed again by 0-1.0 mm at 12 months, with an average of 0.4 mm. At last follow-up, the knee joint range of motion was 115°-135° (mean, 126.8°) and the HSS score for knee joint function was 87-98 (mean, 93.9). Five patients underwent secondary operation to remove the internal fixator at 12-18 months after operation.@*CONCLUSION@#The subchondral screw compression technique is helpful for the reduction of residual or secondary collapse of the lateral tibial plateau during operation, and can provide good support for osteochondral blocks.

Observation of the growth and development of subchondral bone in rat condyles exposed to fluoride at the level of bone microarchitecture / 中华地方病学杂志

Objective:To observe the effect of fluoride on growth and development of bone microstructure of rats condyle subchondral bone (RCSB).Methods:Forty two 3-week-old SD rats (half male and half female) were fed adaptively for 1 week, and 3 females and 3 males were sacrificed and recorded as 0 month. The remaining rats were randomly divided into control group ( n = 18) and fluoride exposed group ( n = 18) according to their body weight (55 - 70 g), half male and half female. The fluoride exposed group was fed with 150 mg/L sodium fluoride (NaF) aqueous solution, and the control group was fed with tap water. The two groups of experimental animals were sacrificed at 3, 5 and 7 month, respectively, 6 rats in each group, half male and half female. The right mandibular condyle was separated, and Micro CT scanning was performed to detect the microstructure parameters of RCSB. Results:In fluoride exposed group (3 month), bone surface/tissue volume (BS/TV), bone surface/bone volume (BS/BV), trabecular thickness (Tb.Th), trabecular number (Tb.N), structure model index (SMI), connectivity, connectivity density (Conn.D) and total porosity of female rats were significantly different from those of male rats ( t = - 5.10, - 5.58, 4.52, - 4.32, - 4.03, - 2.81, - 6.71, - 3.32, P < 0.05). There was no significant difference in each index between female and male rats in fluoride exposed group (5, 7 month, P > 0.05). Conclusion:In chronic fluorine exposure bone environment, the RCSB bone microarchitecture of male and female rats is different with time, showing the tendency of fluoride injury that the bone changes of female rats are slowed and the bone changes of male rats are active.

Experimental study on the regulation of subchondral bone plate osteoprotegerin/receptor activator of nuclear factor kappa-B ligand system by berberine to retard the development of osteoarthritis in rabbits / 中国骨伤

OBJECTIVE@#To investigate the effect of intra-articular berberine injection on the structural remodeling of subchondral bone plate and osteoprotegerin/receptor activator of nuclear factor kappa-B ligand(OPG/RANKL) system expression in rabbits with osteoarthritis(OA).@*METHODS@#Forty 12-month-old male rabbits with an average of(2.73±0.18) kg of body weight, underwent left anterior cruciate ligament transection(ACLT), and were divided into berberine group and placebo groups after operation, 20 rabbits in each group. The berberine group received intra-articular injection of 100 μmol/L berberine 0.3 ml every week for 6 weeks. In placebo group, the same dose of 0.9% sodium chloride injection was injected into the left knee joint cavity every week for 6 weeks. Another 20 12-month-old male rabbits, weighing (2.68±0.18) kg, underwent sham operation on the left knee joint without intra-articular injection intervention (sham operation group). On the last day of the sixth week after operation, three groups of animals were sacrificed to obtain knee joint specimens. The femoral medial condyle samples were obtained for histological evaluation of cartilage and subchondral bone, Mankin scoring system was used to evaluate articular cartilage structure. Image-Pro Plus(IPP) software was used to evaluate subchondral bone plate bone volume(BV), bone volume/total volume(BV/TV), trabecular circumference(TC), mean trabecular thickness (Tb.Th). Real-time quantitative reverse transcription polymerization Enzyme chain reaction(reverse transcription-polymerase chain reaction, RT-PCR) was used to detect the mRNA expression levels of OPG and RANKL in subchondral bone tissue at 6 weeks after operation.@*RESULTS@#The cartilage structure evaluation showed that the surface of cartilage tissue in the sham operation group was smooth and flat, and the safranin coloration was full in the full thickness of the cartilage;the cartilage tissue in the berberine group showed uneven surface layer, and the staining of safranin O was mildly decreased;the surface layer fibrosis was seen in placebo group, Safranin O faded significantly. The Mankin score in the berberine group was lower than that in placebo group(P<0.01), but higher than that in sham operation group(P<0.01). The structural evaluation of subchondral bone plate showed that the trabecular bone in sham-operated group was densely arranged;after berberine intervention, the trabeculae were closely arranged;the subchondral bone trabeculae in placebo group were relatively sparse, and the distance between trabeculae was wider. Subchondral bone plate IPP software evaluation showed that BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group(P<0.01), BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group(P<0.01), while lower than the sham operation group (P<0.01). PCR test results showed that the expression of OPG mRNA in the berberine group was significantly higher than that in placebo group(P<0.01), and OPG mRNA in the berberine group was lower than that in sham operation group (P<0.01). There was no significant difference in mRNA expression of RANKL among three groups(P>0.05);the ratio of OPG/RANKL in berberine group was higher than that in placebo group(P<0.01), but lower than that in sham operation group(P<0.01).@*CONCLUSION@#Intra-articular injection of berberine can effectively inhibit the resorption of subchondral bone in the early stage of OA and delay the development of the disease. The specific mechanism may be that berberine maintains the balance of OPG/RANKL system by up-regulating the expression of OPG gene in subchondral bone.

The latest research progress on pathogenesis and drug regulation of osteoarthritis / 中国药理学通报

Osteoarthritis (OA) is one of the most disabling dis¬eases with high incidence, which involves the entire joint and its diseased tissues include cartilage, subchondral bone and synovi¬um.For the exploration of its pathogenesis, the current research focuses on: ( 1 ) cartilage damage caused by cartilage metabo¬lism imbalance.'Hie reasons include aging, trauma, obesity, biological rhythm changes, biological mechanics and other fac¬tors: (2) abnonnal bone remodeling of subchondral bone, resul¬ting in subchondral bone sclerosis and bone spurs; ( 3 ) cartilage debris leads to synovial inflammation caused by synovial macro¬ phages and T cells.At present, there have been clinical and pre-clinical studies of a variety of targeted small molecule drugs for the above symptoms.This review focuses on the current un¬derstanding of the underlying pathogenesis of OA, and emphasi-zes the important role of chondrocytes, macrophages, and osteo¬clasts, as well as the latest research progress in drug therapy at this stage.

Which clinical outcome scores are more frequently used in the literature on osteochondral lesions of the talus? a systematic review / Quais escores de desfechos clínicos são usados com mais frequência na literatura lesões osteocondrais do tálus? uma revisão sistemática

ABSTRACT Objective: This study aimed to identify the most used scales in the assessment of the clinical outcomes for the treatment of osteochondral lesions of the talus. Methods: We performed a systematic review of the PubMed/MEDLINE databases from September 1999 to September 2019, based on the guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The research strategy was: osteochondral [All Fields], AND ("talus" [MeSH Terms] OR "talus" [All Fields]) AND lesion [All Fields]. Of the 364 articles found in the literature, 166 (45%) were included in the study and 198 (55%) excluded. In total, 23 clinical assessment tools were used in the studies. Results: We found 49.4% of the studies to use the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS Ankle-Hindfoot Scale) and 29.5% the Visual Analogue Scale (VAS). Conclusion: The use of AOFAS increased in relation to VAS in the last 6 years (p = 0.046), and these two scales, either alone or combined, were the most used for studying osteochondral lesions of the talus. Level of Evidence III, Systematic Review of Level II studies.

RESUMO Objetivo: Este estudo propõe revisar sistematicamente a literatura para identificar as escalas mais utilizadas da avaliação clínica de resultados do tratamento das LOTs. Métodos: Foi realizada revisão sistemática das bases de dados do PubMed/MEDLINE, desde setembro de 1999 a setembro 2019 baseado nas diretrizes PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses). A estratégia de pesquisa foi: osteochondral [All Fields], AND ("talus" [MeSH Terms] OR "talus" [All Fields]) AND lesion [All Fields]. De 364 artigos, foram incluídos no estudo 166 (45%) e excluídos 198 (55%). Foram observadas 23 escalas de avaliação clínica utilizadas. Resultados: A escala AOFAS e EVA de dor foram as mais utilizadas, ocorrendo em 49,4% e 29,5% dos artigos, respectivamente. Foi observado aumento de uso de AOFAS e diminuição EVA nos últimos 6 anos (p = 0,046). Conclusão: As ferramentas Escala AOFAS e EVA para dor demonstraram ser as mais usadas na literatura para avaliação de resultados do tratamento da lesão osteocondral de tálus, tanto isoladamente, quanto combinadas. Nível de Evidência III, Revisão Sistemática de Estudos de Nível II.

Progress of research on disease-modifying osteoarthritis drugs / 中国药科大学学报

@#Osteoarthritis (OA) is a common chronic joint disease,whose main pathological changes are the degeneration of articular cartilage and secondary bone hyperplasia.The limitation of current treatment methods including pain relief and joint replacement surgery is that they cannot fundamentally improve the damage of articular cartilage.The emergence of disease-modifying osteoarthritis drugs (DMOAD) may break the above limitations.They fundamentally inhibit the structural degeneration of articular cartilage by participating in the regulation of cartilage metabolic balance, regulation of subchondral bone remodeling,and control of local inflammation.Thereby,OA patients will get symptom improvement including pain relief and joint function restoration,delay the artificial joint replacement surgery, and improve the quality of life. There are still no DMOAD drugs widely available on the market worldwide.This paper reviews the background of R&D,the classification of mechanisms of action and research progress of representative drugs under different inechanisms so as to provide reference for future research.

Molecular mechanism of icariin effects on articular chondrocytes, subchondral bone and synovium in the treatment of osteoarthritis / 中国组织工程研究

BACKGROUND: Icariin is the main effective component of Epimedium, which functions to tonify the kidney, and strengthen tendons and bones. In recent years, a large number of studies have found that icariin plays a significant role in the treatment of osteoarthritis. OBJECTIVE: To review the research progress in the molecular mechanism of icariin in the treatment of osteoarthritis. METHODS: The first author used “Icariin, Osteoarthritis, Cartilage, Subchondral bone, Synovial membrane, synovium, Inflammation" as search words in English and Chinese to search PubMed, CNKI, WanFang, and VIP databases. According to the inclusion criteria and exclusion criteria, 42 articles were included for final analysis. RESULTS AND CONCLUSION: Icariin can promote the cartilage differentiation of bone marrow mesenchymal stem cells and enhance the proliferation of cartilage cells and osteoblasts, to inhibit the degradation of cartilage extracellular matrix, reduce the activity of osteoclasts and alleviate synovial inflammation caused by inflammatory factors. It is an effective treatment for osteoporosis. However, the optimal effective dose and concentration safety of icariin still need a large number of experimental studies. Currently, most of the experiments are still in animal and tissue cell experiments. Numerous clinical studies are needed to continue to explore its specific mechanism in order to provide evidence-based medical evidence for icariin in the treatment of osteoarthritis.

MicroRNA profile and its regulatory network in the subchondral bone between Kashin-Beck disease and knee osteoarthritis / 西安交通大学学报(医学版)

【Objective】 To compare the MicroRNA (miRNA) expression profiles in the subchondral bone between patients with Kashin-Beck disease and knee osteoarthritis and to conduct target gene prediction and biological function and signal pathway analysis so as to construct the regulatory network of miRNAs and target genes. 【Methods】 The subchondral bone samples were collected from four pairs of patients with Kashin-Beck disease and osteoarthritis. The total RNA was extracted and the miRNA array profiling was performed using Affymetrix miRNA 4.0 Array. The target gene prediction was performed using six different prediction programs including miRWalk. Cytoscape software was used to construct the regulatory network of significantly different miRNAs and predicted target genes; GO biological function and KEGG pathway enrichment analysis were performed based on target genes. 【Results】 A total of 124 miRNAs were significantly downregulated in the subchondral bone of patients with Kashin-Beck disease than that in patients with osteoarthritis. Target genes were predicted for eight miRNAs with a fold change more than 5, and 542 target genes and 1094 miRNA-mRNA regulatory relationships were obtained. Enrichment analysis of target genes in the regulatory relationship showed that these target genes were mainly involved in protein digestion and absorption, focal adhesion, PI3K-Akt signaling pathway and ECM-receptor interaction, and other signaling pathways. 【Conclusion】 Differentially expressed miRNAs in the subchondral bone of patients with Kashin-Beck disease and osteoarthritis may be used as the differential diagnostic markers between the two diseases. In addition, we preliminarily explored the potential molecular mechanism of changes in the subchondral bone of Kashin-Beck disease by bioinformatics analysis.

A comparison between arthroscopic drilling and microfracturing technique in treatment of osteochondral lesions of the talus / 中华创伤骨科杂志

Objective To compare the outcomes of bone marrow stimulation techniques-drilling by a Kirschner needle versus microfracturing technique in the treatment of small osteochondral lesions of the talus.Methods From February 2014 to June 2017,57 patients were treated at Department of Orthopaedics,Sun Yat-sen Memorial Hospital for small osteochondral lesions of the talus.Of them,26 were treated by arthroscopic drilling with a Kirschner needle.They were 15 males and 11 females,aged from 20 to 57 years.The areas of osteochondral lesion ranged from 0.6 to 1.4 cm2.By the Berndt & Harty classification of ankle osteochondral lesions based on X-ray films,there were 9 cases of stage Ⅰ,8 cases of stage Ⅱ,6 cases of stage Ⅲ and 3 cases of stage Ⅳ.The other 31 patients of them were treated by arthroscopic microfracturing technique.They were 17 males and 14 females,aged from 24 to 55 years.The areas of osteochondral lesion ranged from 0.5 to 1.5 cm2.By the Berndt & Harty classification of ankle osteochondral lesions based on X-ray films,there were 10 cases of stage Ⅰ,11 cases of stage Ⅱ,8 cases of stage Ⅲ and 2 cases of stage Ⅳ.The 2 groups were compared in terms of visual analogue scale (VAS),the American Orthopaedic Foot and Ankle Society (AOFAS) score,the ankle activity score (AAS) and the Berndt & Harty staging of osteochondral lesions based on ankle X-ray films at the final follow-up.Results All the 57 patients were followed up for 13 to 27 mouths.The VAS,AOFAS and AAS scores and Berndt & Harty stages at the final follow-up were significantly improved in all the patients compared with their preoperative values (P ＜ 0.05).There were no significant differences between the 2 groups in the VAS (2.2 ± 1.6 versus 2.1 ± 1.4),AOFAS (89.1 ±6.3versus 90.4±5.8) or AAS scores (6 versus 6) at the final follow-up (P ＞ 0.05).There was no significant difference between the 2 groups either in the excellent and good rate by the AOFAS ankle-hindfoot scoring [88.5％ (23/26) versus90.3％ (28/31)] at the final follow-up (x2 =0.052,P=0.820).Conclusion In the treatment of small osteochondral lesions of the talus,both arthroscopic drilling with a Kirschner needle and microfracturing technique can achieve satisfactory short-term curative effects,but the long-term effects need to be further studied.

The role of Wnt signaling pathway in osteoarthritis via the dual-targeted regulation of cartilage and subchondral bone / 中国修复重建外科杂志

Objective: To summarize the active changes of Wnt signaling pathway in osteoarthritis (OA) as well as the influence and mechanism of dual-targeted regulation on cartilage and subchondral bone and the role of crosstalk between them on OA process. Methods: The relevant literature concerning the articular cartilage, subchondral bone, and crosstalk between them in OA and non-OA states by Wnt signaling pathway in vivo and vitro experimental studies and clinical studies in recent years was reviewed, and the mechanism was analyzed and summarized. Results: Wnt signaling can regulate the differentiation and function of chondrocytes and osteoblasts through the classic β-catenin-dependent or non-classical β-catenin-independent Wnt signaling pathway and its cross-linking with other signaling pathways, thereby affecting the cartilage and bone metabolism. Moreover, Wnt signaling pathway can activate the downstream protein Wnt1-inducible-signaling pathway protein 1 to regulate the progress of OA and it also can be established gap junctions between different cells in cartilage and subchondral bone to communicate molecules directly to regulate OA occurrence and development. Intra-articular injection of Wnt signaling inhibitor SM04690 can inhibit the progress of OA, and overexpression of Wnt signaling pathway inhibitor Dickkopf in osteoblasts can antagonize the role of vascular endothelial growth factor work on chondrocytes and inhibit the catabolism of its matrix. Conclusion: The regulation of metabolism and function of cartilage and subchondral bone and crosstalk between them is through interactions among Wnt signaling pathway and molecules of other signaling. Therefore, it plays an vital role in the occurrence and development of OA and is expected to become a new target of OA treatment through intervention and regulation of Wnt signaling pathway.

Research Progress on Changes and Interaction Mechanisms of Aging Articular Cartilage and Subchondral Bone / 医用生物力学

Aging is a major risk factor for diseases such as osteoarthritis (OA) and osteoporosis. However, they are not necessarily the results of aging, and the relationship between changes in bone and cartilage associated with aging and disease progression is still unclear. Studies have shown that the development and progression of OA is not a simple cartilage wear process, while its occurrence involves complex biological, chemical and mechanical changes in the tissues of the entire joint, especially the interaction of mechanics and biochemistry between cartilage and subchondral bone. Aging contributes to the occurrence and development of OA, but it is not the cause of OA. Changes associated with aging provide a foundation for OA to start, making joints more susceptible to other factors such as abnormal biomechanics and biochemistry, thereby promoting the development of OA. Therefore, understanding the basic mechanisms by which aging affects joint tissue may provide new targets for slowing or preventing the development of OA. In this paper, the related research progresses are reviewed from three aspects, i.e. age-related changes in cartilage and subchondral bone, mechanical conduction and angiogenesis.

Relationship of Subchondral Plate-Rod Structure and Cartilage Degeneration with Lower Limb Alignment / 医用生物力学

Objective To study the relationship of the tibial plateau subchondral trabecular bone (STB) microstructure and the cartilage degeneration with the lower limb alignment based on individual trabecula segmentation (ITS) and histology analysis in knee osteoarthritis (OA). Methods Hip-knee-ankle (HKA) angles were measured on the full-length lower extremity films of patients before total knee arthroplasty (TKA). The tibial plateau excised from the TKA were collected for micro-CT scanning and ITS analysis. The cartilage degeneration was evaluated by histology. The relationship between the HKA angle and the changes in microstructural parameters of STB and cartilage degeneration were analyzed. ResultsThe plate, rod and axial bone trabecular volume fraction (BV/TV, pBV/TV, pBV/TV), ratio of trabecular plate versus rod (P/R), plate trabecular number density (pTb.N), plate trabecular thickness (pTb.Th), trabecular plate surface area (pTb.S), trabecular rod length (rTb.L), and plate-plate and plate-rod junction density (P-P Junc.D, P-R Junc.D) of the subchondral bone of the tibial plateau were significantly related to the cartilage degeneration OARSI score and the HKA angle. The greater the deviation of the lower limb alignment, the greater the number of subchondral trabeculae, the thicker the trabeculae, the greater the bone mass, the stronger the connectivity, especially the plate trabeculae on the affected side of tibial plateau, and the higher the OARSI score of cartilage degeneration. Conclusions Abnormal lower limb alignment may cause abnormal microstructure of the plate and rod STB of the tibial plateau by changing the stress distribution of the knee, especially the significant increase and thickening of the plate trabecular and axial trabecular bone, which may be an important risk factor that further aggravates the degeneration of articular cartilage and the progress of OA. Therefore, lower limb alignment correction with surgical intervention and improving STB with bone metabolism agents may efficiently contribute to preventing cartilage damage and mitigate OA progression.

Expression and role of retinoblastoma RB1-inducible coiled-coil 1 in the subchondral bone of osteoarthritis / 中国组织工程研究

BACKGROUND: Osteoarthritis is mainly characterized by degeneration of the articular cartilage and reconstruction of the subchondral bone. The specific pathogenesis of osteoarthritis is still unclear. Most studies have used cartilage and subchondral bone as the main entry point to explore the molecular mechanism and signal pathway changes in the disease progression, providing new biological targets and research direction for the diagnosis and treatment of osteoarthritis. OBJECTIVE: To investigate the expression of RB1-inducible coiled-coil 1 (RB1CC1) in the subchondral bone during the development of osteoarthritis. METHODS: Eight-week-old C57 mice were randomly divided into experimental group and sham operation group. Experimental group was then randomly divided into two subgroups of 4 weeks and 8 weeks. In the experimental group, the tibia ligament of the right knee was cut off to dissociate the medial meniscus to induce osteoarthritis. In the sham operation group, only the joint capsule was cut without medial ligament resection and meniscus dissociation. The study was implemented with an experimental animal ethic approval from the Third Affiliated Hospital of Southern Medical University, China (approval No. 44007200038731) on December 13, 2017. RESULTS AND CONCLUSION: Compared with the sham operation group, the Osteoarthritis Research Society International scores were increased significantly in the experimental group. Compared with the sham operation group, the expression of collagen II was decreased, and RB1CC1 in the subchondral bone was gradually increased in the experimental group, which was consistent with the expression trend of BSP2. To conclude, with the development of osteoarthritis, the expression of RB1CC1 in the subchondral bone is gradually increased, which may be related to the increase of hyperplasia in the subchondral bone and remodeling.

Artesunate relieves subchondral bone osteoclast-mediated osteoarthritis pain / 中国组织工程研究

BACKGROUND: Studies have shown that osteoclasts induce aberrant in growth of sensory nerves into the subchondral bone by secreting netrin-1, resulting in a reduced pain threshold in an osteoarthritis animal model. Therefore, we assume that inhibition of osteoclasts can alleviate sensory nerve-mediated pain symptoms. OBJECTIVE: To investigate whether artesunate inhibits subchondral bone osteoclasts and reduces sensory nerve-mediated pain, providing experimental data for the treatment of osteoarthritis pain using artesunate. METHODS: C57BL/6J male mice were randomly assigned to a sham operation group, a placebo group and an artesunate group, with 10 mice per group. The mice in the sham operation group were only subjected to right knee capsulotomy with no damage to the other structures. Moreover, there was no intervention after operation. In the other two groups, the mice received an anterior cruciate ligament transection of the right knee to establish the osteoarthritis model, followed by treatment with artesunate (artesunate group, 100 mg/kg per day) or equivalent volume of 5% NaHCO3 (placebo group) via intraperitoneal injection. Fourteen days after surgery, the footprint trial was performed, and the levels of tartrate-resistant acid phosphatase 5b (TRAcP5b), cathepsin K and carboxy-terminal telopeptide of type I collagen (CTX-I) in the peripheral blood were detected using ELISA. The knee joint specimens of each group were subjected to Safranin O-Fast Green staining, histological scoring, tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemical staining with netrin-1 and calcitonin gene-related peptide (CGRP). RESULTS AND CONCLUSION: The percentage of ipsilateral contact area of the right hindpaw in the footprint trial was significantly higher in the sham operation group and artesunate group than the placebo group (P 0.05). No significant differences were observed in the serum levels of TRAcP5b, cathepsin K and CTX-I between the groups (P > 0.05). Based on the Safranin O-Fast Green staining, the cartilage histology score was significantly lower in the sham operation group and the artesunate group than the placebo group (P 0.05). TRAP staining indicated that compared with the placebo group, the Trap+ osteoclasts were significantly lower in the sham operation group and the artesunate group (P 0.05). Compared with the placebo group, the netrin-1+ and CGRP+ sensory nerves in the subchondral bone were significantly decreased in the sham operation group and the artesunate group (P 0.05). Our findings from this study indicate that artesunate improves sensory nerve-mediated pain by inhibiting netrin-1 secreted by subchondral bone osteoclasts, and has therapeutic potential to alleviate osteoarthritis pain.