TCF12 regulates the TGF-ß/Smad2/3 signaling pathway to accelerate the progression of osteoarthritis by targeting CXCR4.

Objective: Osteoarthritis (OA), which involves total joint damage and dysfunction, is a leading cause of disability worldwide. However, its exact pathogenesis remains unclear. Here, we identified TCF12 as an important regulator of the progression of OA. Methods: qRT-PCR, immunoblotting and immunohistochemistry (IHC) were used to detect the expression level of TCF12. The interaction of TCF12 with its downstream factor CXCR4 was assessed by Western blotting, immunofluorescence, qRT-PCR and luciferase assays. A mouse model was generated to examine the functions and mechanism of TCF12 in vivo. Result: TCF12 expression was upregulated in chondrocytes stimulated with IL-1ß and osteoarthritic chondrocytes. TCF12 upregulates the expression of CXCR4 and leads to dysfunction of the TGF-ß signaling pathway. Furthermore, knockdown of TCF12 alleviated cartilage damage in a mouse model generated by destabilization of the medial meniscus (DMM). Conclusion: TCF12 aggravates the progression of OA by targeting CXCR4 and then activating the TGF-ß signaling pathway, suggesting that TCF12 may be a new target for the treatment of OA. The translational potential of this article: Transcription Factor 12(TCF12), is known to regulate cell development and differentiation, It has been widely studied in various organs and diseases, but its role in OA remains unclear. Here, we identified Transcription Factor 12(TCF12) as an important regulator mediating chondrocyte senescence and cartilage extracellular matrix degradation indicating its role in OA. We found that TCF12 expression was upregulated both locally and systemically as OA advanced in patients with OA, and in mice after DMM surgery to induce OA. TCF12 expression caused striking progressive articular cartilage damage, synovial hyperplasia in OA mice, and remarkably, it was relieved by intra-articular administration of mutant mouse TCF12 lentiviral vector (shTCF12). Furthermore, TCF12 upregulated the expression of CXCR4, leading to exacerbation of experimental OA partially through activation of TGF-ß signaling in chondrocytes. TCF12 expression was upregulated in chondrocytes treated with IL-1ß and osteoarthritic chondrocytes. Our findings established an essential role of TCF12 in chondrocyte senescence and cartilage extracellular matrix degradation during OA, and identified intra-articular injection of TCF12 as a potential therapeutic strategy for OA prevention and treatment.

[A medium term analysis on of therapeutic effects of bio-lengthend stem hemiarthroplasty in the treatment of unstable osteoporotic intertrochanteric fractures in elderly patients].

OBJECTIVE: To retrospectively study medium term follow up outcomes effects of effect of bio-lengthend stem hemiarthroplasty in the treatment of unstable osteoporotic intertrochanteric fractures in elderly patients. METHODS: Total of 32 elderly patients with the osteoporotic intertrochanteric fractures were treated with bio-lengthend stem hemiarthroplasty from Jan. 2016 to Jan. 2019 including 14 males and 22 females, aged from 85 to 95 years old with an average of (89.5±4.5) years old. According to classification of Evans, there were 12 cases with type Ⅲ, 11 with type Ⅳ and 9 with type Ⅳ. The time from injury to operation ranged from 0.5 to 9 days with an average of (4.5±3.9) days. The operation time, blood loss and postoperative complications were analyzed. Functional outcome was assessed by Parker Palmer mobility score(PPMS) and Harris hip score. RESULTS: Four patients died within one year after operation, and the mortality was 12.5%. The follow up time for the rest 28 patients ranged from 24 to 60 months with an average of (28.5±4.5) months. The mean operative time was (54.2±22.5) min;the mean blood loss (hidden blood loss+obvious blood loss) was (450±140) ml;the first weight bearing was (3.35±1.35) days. No perioperative death occurred. PPMS were(6.63±1.25), (6.94±1.18), (7.11±0.83), (7.32±1.11) and Harris scores were(67.85±6.19), (71.42±5.57), (73.41±5.62), (77.32±5.24) respectively at 1, 3, 6 months and the final follow-up after operation. There were no significant difference in PPMS and Harris score at 1, 3, 6 months after operation and the final follow-up(P>0.05). There were no complications such as joint dislocation and prosthesis loosening occure at the final follow-up. CONCLUSION: On the premise of strictly mastering the case selection criteria, the bio-lengthend stem hemiarthroplasty in the treatment of unstable osteoporotic intertrochanteric fractures in elderly patients has a satisfied medium term follow-up outcomes. It can restore hip function in the early stage and improve the quality of life of patients.

Network Pharmacology-Based Prediction and Verification of the Potential Targets of Pinoresinol Diglucoside for OA Treatment.

Objective: This study aimed to explore the effects and related mechanisms of pinoresinol diglucoside (PDG) on osteoarthritis (OA) via a combination of pharmacology and animal experiments. Methods: Traditional Chinese Medicine Database and Analysis Platform (TCMSP) Drugbank, Online Mendelian Inheritance in Man, and GeneCards databases were used to predict the putative targets of PGD against OA. A protein protein interaction (PPI) network was constructed in STING database to analyze the interaction network of these targets. Enrichment analysis was performed with DAVID database. The OA model was built by anterior cruciate ligament transection and then injected with PDG for 5 weeks. Hematoxylin and eosin (HE) staining and safranin-fixed green staining were used to evaluate the pathological change. ELISA was applied to measure the serum levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Immunohistochemistry was employed to detect the protein levels of kinase B (AKT), BAX, Bcl2, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), and phosphatidylinositol 3 kinase (PI3K) in knee cartilage tissues. Results: Seventy-one key targets were identified, including AKT1, epidermal growth factor receptor, SRC, estrogen receptor 1 (ESR1), and MMP9. Enrichment analysis revealed a series of pathway related to cancer, PI3K-Akt signaling pathway, and proteoglycans in cancer. Animal experiments showed that PDG alleviated the abnormal histomorphological changes of OA; suppressed TIPM, serum IL-1ß, IL-6, and TNF-α levels, and PI3K and AKT activation; and increased MMP-1 expression and Bcl2/Bax ratio. Conclusion: PDG has a cartilage-protecting effect associated with PI3K/AKT signaling pathway in rabbit with OA and therefore might serve as a potential agent for the treatment of this disease.

[Transoral plate internal fixation for treatment of instability atlas fracture].

OBJECTIVE: To evaluate the efficacy and safety of transoral plate internal fixation for instability atlas fracture. METHODS: A retrospective study was performed in eight patients with instability atlas fractures, who were treated by a transoral plate internal fixation from July 2007 to June 2011. There were 6 males and 2 females,with an average age of 39.5 years old ranging from 23 to 48 years. Among them, 5 case were falling injury, 3 cases were traffic accident injury. Three patients had bilateral fractures of the anterior arch (prehalf Jefferson fractures, Landells type I), 5 had anterior are fracture associated posterior are fracture (Half-ring Jefferson fractures, Landells type II), and 2 had anterior and posterior are fracture associated with single lateral mass fractures (Landells type III). RESULTS: All patients were followed up for 6 to 24 months after operation (av- eraged 13 months), and all the patients had the clinical symptoms improved to some extent. Operation time ranged from 80 to 140 min (averaged 98 min); the intra-operative blood loss was 120 to 300 ml (averaged 180 ml); and the average fluoroscopic time was 55 s. No patients happened neurological and vertebral artery injuries-related complications or other complications after operation. The followed-up X-ray and CT manifested osseous fusion in all the 8 patients,no loosening or breakage of the screws. CONCLUSION: Transoral plate internal fixation for instability atlas fracture is a reliable and safety technique that allows maintenance of rotatory mobility in the C1,2 joint and restoration of congruency in the atlanto-occipital and atlanto-axial joints.

[Research on osteoporosis model rats with kidney deficiency syndrome].

OBJECTIVE: To observe general conditions, physiological condition, viscera wet weight and kidney asthenia serological index in osteoporosis model rats established by bilateral ovarian resection, and provide basis for treating osteoporosis by invigorating kidney. METHODS: Twenty-four female SD rats were randomly divided into 3 groups as model group, sham group and normal group. After anesthesia,model group were treated by bilateral ovarian resection, sham group by sham operation, and normal group without any processing. Pathological tissue and bone mineral density (BMD) of femur was performed 3 months postoperatively. The general conditions and physiological conditions were processed after successfully modeling. Electronic balance was used to collect the weight of kidney, drenal, pituitary, and uterus. Estrogen (E2), Adrenocorticotropic hormone (ACTH), Three typical thyroid original acid (T3), Four typical thyroid original acid (T4) were detected by ELISA. RESULTS: Osteoporosis model appeared with syndromes of kidney deficiency, such as body hair without burnish, chills, cluster, sluggishness, eyes dark, eye movement slow, slow to respond to the delay, decreased appetite, activities slow, body fat, and drowsiness, defecate slightly thin andclear abundant urine. Mobility, anal temperature and food-intake were lower than normal and sham group; the level of ACTH, E2, T3, T4 lower than sham and normal group; the weight of kidney, drenal, pituitary, and uterus also lower than other two groups. CONCLUSION: Osteoporotic model rats, established by bilateral ovarian resection, have manifestation of organic and functional performance of kidney deficiency. Therefore, osteoporotic model rats have the pathogenesis of kidney asthenia and clinical manifestations of kidney deficiency.

[Analysis of concurrent intravertebral vacuum sign in thoracolumbar fractures after posterior internal fixation].

OBJECTIVE: To investigate the importance of TLICS classification to surgical options of thoracolumbar fractures by analyzing the cause of intravertebral vacuum sign, vertebral collapse and vertebral pseudarthrosis. METHODS: From January 2006 to December 2010, the clinical data about 15 patients with postoperative complications by thoracolumbar fracture after posterior internal fixation were retrospectively analyzed. There were 9 males and 6 females, ranging in age from 18 to 75 years, with an average of 54.6 years. Of them, fracture site in T12 was 7 cases, L1 was 5 cases, L2 was 3 cases; compression fractures was in 12 cases and burst fracture was in 3 cases; according to classification of TLICS, 12 cases were of type I ,3 cases of type III. And the causes of complications after posterior fixation were analyzed according clinical manifestation and imaging finding combined with review literatures. RESULTS: After 10 to 20 months following-up (with average of 15 months), loss of vertebral height found in 9 cases (4 cases existed vertebral collapse, as well as 3 cases occurred screw loosening) and Intravertebral Vacuum Sign appeared in 6 cases. CONCLUSION: In order to avoid the vertebral vacuum and fixation failure, the clinical data of patients should be roundly and carefully evaluated, surgical indications should be strictly controlled and the surgical approach should be selected according to correct classification. Particularly, the reconstruction of the stability of former spinal column shoud be paid more attention.