Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

The incidence and risk factors of preoperative deep vein thrombosis in non-fracure patients awaiting for total joint arthroplasty / 中华骨科杂志

Objective:To explore the incidence and risk factors of preoperative deep vein thrombosis (DVT) of elective total joint arthroplasty (TJA).Methods:Data of 500 patients before TJA from March 2015 to August 2016 who underwent ultrasound surveillance were retrospectively analyzed. All patients were divided into DVT group and non-DVT group according to results of ultrasound. Parameters including demographic data, basic medical history, and surgical information and laboratory indexes were collected. Risk factors were assessed via univariate, multivariate and logistic regression analysis.Results:Preoperative DVT was detected in 23 cases (4.6%, 23/500), all of which occurred in the intermuscular vein with no symptom, and among them there were 16 cases (5.6%, 16/285) before total knee arthroplasty and 7 cases (3.3%, 7/215) before total hip arthroplasty. Univariate analysis showed that age ( t=2.266, P=0.024), female patients ( χ2=4.028, P=0.045), history of hypertension ( χ2=7.907, P=0.005), D-dimer ≥0.5 μg/ml ( χ2=13.171, P < 0.001) were significantly higher than those in non-DVT group, and the differences were statistically significant. Multivariate analysis showed that D-dimer ≥0.5 μg/ml [ OR=6.655, 95% CI (1.929, 22.960), P=0.003] and history of hypertension [ OR=2.715, 95% CI (1.017, 7.250), P=0.046] were independent risk factors for preoperative DVT. Among them, the thrombus of 14 cases located in the operation side, 6 cases in non-operation side, and 3 cases in bilateral sides. Postoperative ultrasound showed that newly DVT occurred in 9 patients of whom 5 cases located in the contralateral muscular veins and 4 cases in the nearby muscular veins. After discharge, 22 patients (95.7%) with preoperative DVT were further evaluated by ultrasound. The average follow-up time was 3.0 months (range from 6 weeks to 9 months). The results showed that thrombus of 7 cases were completely dissolved, 13 cases were partially dissolved, and 2 cases remained unchanged. Thrombus extensions to proximal veins or symptomatic PE were not found. Conclusion:The incidence of preoperative DVT in patients with elective joint replacement was about 4.6%, among which D-dimer ≥0.5 μg/ml and history of hypertension were the risk factors for preoperative thrombosis.

Comparison of notch width indexes between tibial intercondylar eminence avulsion fracture and anterior cruciate ligament injury / 中华创伤骨科杂志

Objective To find out if there is any difference in intercondylar fossa width and notch width index (NWI) between tibial intercondylar eminence avulsion fracture and anterior cruciate ligament (ACL) injury.Methods A retrospective study was conducted of the patients who had sought medical attention at Department of Sports Medicine and Adult Reconstructive Surgery,Drum Tower Hospital from June 2014 to May 2018.There were 10 patients with tibial intercondylar eminence avulsion fracture (4 males and 6 females with an average age of 32.7 ± 9.2 years),13 patients with ACL injury (8 males and 5 females with an average age of 31.8 ± 10.9 years) and 22 patients with simple meniscus injury as controls (13 males and 9 females with an average age of 30.9 ± 10.6 years).They all had MRI examination of the knee before surgery.The width of intercondylar fossa and the width and height of bilateral femoral condyles were measured on high resolution images of MRI axial view.NWI was calculated.The 3 groups were compared in intercondylar fossa width and NWI.Results The 3 groups of patients were comparable because there were no significant differences in gender,age,height,weight or BMI between them (P ＞ 0.05).The intercondylar fossa width in the ACL injury group (17.4 ± 3.5 mm) was significantly smaller than that in the avulsion fracture group (20.8 ± 1.1 mm) or in the control group (20.2 ±2.6 mm) (P ＜ 0.05),but no significant difference was detected between the avulsion fracture group and the control group (P ＞ 0.05).NWI in the avulsion fracture group (0.301 ±0.011) was similar to that in the control group (0.280 ±0.039) (P ＞ 0.05) but significantly higher than that in the ACL injury group (0.25 ± 0.05) (P ＜ 0.05).NWI in the ACL injury group was significantly lower than that in the control group (P ＜ 0.05).Conclusions Intercondylar notch stenosis may be a risk factor for ACL injury but may not be associated with tibial intercondylar eminence avulsion fracture.The difference in pathogenesis between tibial intercondylar eminence avulsion fracture and ACL injury may be associated with their difference in NWI.

The feasibility of management with acute proximal deep vein thrombosis without insertion of inferior vena cava filter before hip arthroplasty / 中华骨科杂志

Objective To evaluate the feasibility of anticoagulant therapy for acute proximal deep vein thrombosis without inferior vena cava filter placement for femoral neck patients before hip arthroplasty.Methods From January 2013 to August 2017,9 femoral neck fractures patients with acute proximal deep vein thrombosis before hip arthroplasty were enrolled into this study.There were 3 men and 6 women.The average age was 76.44±5.39 years old (range,69 to 83 years old).The average injured time before admission was 4.00±4.06 days.All patients received anticoagulant therapy without placement of inferior vena cava filter before hip arthroplasty.Four patients received Rivaroxaban 10mg,two times per day,while two patients received Enoxaparin 0.4 ml,two times per day;3 cases received Batroxobin 0.5 ml,every other day combined with Rivaroxaban 10 mg one time per day or Enoxaparin 0.4 ml,one time per day.The size of thrombus before and after treatment,changes of coagulation markers,the outcome of thrombosis before surgery,during surgery,postoperatively and during follow-up,the related complications were recorded.Results The diagnosis time for proximal DVT was 3.89±3.01 days after admission.8 patients showed proximal DVT combined with distal thrombus and 1 patient showed isolated proximal DVT.The average length of proximal thrombus was 10.78±6.10 cm (range,4.0-20.0 cm).The mean duration of treatment was 14.22±7.03 days.The results showed 5 proximal DVTs have complete disappeared,3 cases significantly improved,and 1 case had no change but showed stable.After treatment,the length of the proximal thrombus was significantly decreased (10.77±6.10 cm vs.4.39±6.50 cm),there were statistically significant between two groups (t=3.429,P=0.009);D-dimer was significantly lower after treatment (10.47±4.87 μg/ml vs.2.59± 1.60 μg/ml) with statistical difference (t=4.970,P=O.O01).However,no statistical significance was found in other coagulation parameters such as plasma prothrombin time,the international normalized ratio,activated partial thromboplastin time,thrombin time,fibrinogen.Incision exudate occurred in one patient and anticoagulant therapy was paused,however,two days later,DVT recurred and then the patient received continuous therapy with drug anticoagulation.The average time for postoperative follow-up was 8.3±7.6 months.At the latest follow-up,4 cases had thoroughly recovered with the thrombi fully resolved;4 cases had significantly improved including three thrombi partly locating in the muscular veins and one partly locating in the infra-popliteal vein.One case became more severe after discharge and received continuous anticoagulant therapy.No death,symptomatic pulmonary embolism,bleeding and other adverse events occurred.Conclusion Inferior vena cava filter placement for femoral neck fracture patients with acute proximal venous thrombosis before hip arthroplasty may not be potent.Anticoagulant therapy which make the proximal thrombus completely dissolved or stabilized before surgery may be effective.

The characteristics of proximal deep vein thrombosis after total knee and hip arthroplasty / 中华骨科杂志

Objective To analyze the characteristics of proximal deep vein thrombosis (DVT) after total joint arthroplasty.Methods 40 cases of proximal DVT were collected from May 2007 to October 2016 which were all diagnosed by lower limb venography or sonography.There were 9 males and 31 females aged from 38 to 86 years,average 67 years,and body mass index was from 16.94 to 31.25kg/m2,with an average of 24.3 kg/m2.29 cases of THA patients and 11 cases of TKA patients.The anatomical distribution,size,radiological performance,local physical findings were recorded and multivariable analysis was performed to evaluate the relationship between distribution of proximal DVT and related parameters including age,gender (male/female),side of leg(left/right),surgery type(knee and hip),preoperative diagnosis(femoral neck fracture/other disease),time of diagnosis with DVT (during hospitalization/after discharge).Results Among 40 proximal DVT cases,31 cases diagnosed by phlebography and 9 cases were diagnosed by ultrasound.2 cases were isolated proximal DVT while 38 cases connected with distal DVTs.9 cases of blood clots in the proximal and distal thrombosis connected discontinuously.There was no isolated proximal DVT in TKA group and 10 cases (90.9％) of blood clots in the proximal and distal thrombosis connected continuously while there were 2 cases (6.9％) isolated proximal DVTs in THA group and 21 (77.8％) of blood clots in the proximal and distal thrombosis connected discontinuously,and there was no statistic significant difference between the two groups.The average length of proximal was 8.85±9.3 1cm (range from 2-35cm) with 5.0±2.05 cm in TKA group and 10.31 ± 10.55 cmin THA group.A significant difference was found between the 2 groups (P=0.014).13 cases located in femoral veins and upper venous region which were all from THA group.There was a significant difference in the distribution between surgery type and preoperative diagnosis.However,there was no significant difference between other potential factors and distribution of proximal DVT.25 cases accepted the evaluation of symptom of DVT before scanning.However,no significant difference were found in edema,VAS score,Homans sign,Neuof sign between 9 TKA and 16 THA cases.Conclusion Proximal DVTs after knee and hip arthroplasty are more preferred to connect with distal DVT continuously.Surgery type and preoperative diagnosis have a significant effect on the distribution of proximal DVT.Proximal DVTs in THA and patients with preoperative femoral neck fracture could be more easily involving femoral veins and upper parts.

Primary usage of a new designed extramedullary femoral alignment system in total knee arthroplasty / 中华骨科杂志

Objective To investigate the outcome of a new designed extramedullary femoral alignment system and to compare with conventional intramedullary system in clinical results.Methods Twenty consecutive patients (3 males and 17females with an average age of 70.1 (range,52-82 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) who were treated with the extramedullary method between January 2015 to August 2015 and 20 consecutive patients (5 males and 15 females with an average age of 65.9 (range,52-87 years old) with OA or RA treated with conventional intramedullary method between April 2015 to September 2015 were studied.In extramedullary group,CT scan was used to evaluate the relation between the hip (femoral head) center and anterior superior iliac spine preoperatively.During the total knee arthroplasty,the hip joint center was defined according to the anterior superior iliac spine (ASIS).Knee joint center was defined as the center of the line connecting medial and lateral epicondyle.The terminal femoral bone cut plane was defined as the line between femoral and knee center.In intramedullary group,the traditional intramedullary method was adopted.The coronal and sagittal alignment,blood loss and drainage at one week postoperatively and the range of motion at one week,6 weeks and 3 months were evaluated.Results There was no significant difference in age,hip-knee-ankle (HKA) angle,the Hospital for Special Surgery (HSS) Knee Score,BMI,operation time within the two groups.Blood loss and drainage in extramedullary group (121 ±64 ml and 181±149 ml) was significantly less than that in intramedullary group (177±47 ml and 292±156 ml).There was no significant difference in coronal alignment of the femoral prosthesis within the two groups (89.8°±2.1° v.s.89.8°±2.2°,P＞0.05).However,the two groups had significant difference in sagittal alignment (-0.8°±2.2° v.s.2.5°±2.1 °,P＜0.05).The alignment of extramedullary group had much more tendency in flexion degree.No difference was found in range of motion at 1 week,6 weeks and 3 months postoperatively (103.8°±7.8° v.s.102.5°±7.2°,108.5°±8.0° v.s.108.3°±7.4°,117.0°±7.1° v.s.114.5°±8.1°,P＞0.05).Conclusion The present designed extramedullary system is practical in total knee arthroplasty and has more accuracy in sagittal plane.The patients treated with extramedullary system have less blood loss and drainage and have similar range of motion in early stage after operation when compared with the intramedullary method.