Downregulation of extracellular matrix protein 1 effectively ameliorates osteoarthritis progression in vivo.

Osteoarthritis (OA) is the most common joint disease whose important pathological feature is degeneration of articular cartilage. Although extracellular matrix protein 1 (ECM1) serves as a central regulator of chondrocyte proliferation and hypertrophy, its role in OA remains largely unknown. This study aims to decipher the roles of ECM1 in OA development and therapy in animal models. In the present study, ECM1 expression was examined in clinical OA samples, experimental OA mice and OA cell models. Mice subjected to destabilised medial meniscus (DMM) surgery were intra-articularly injected with adeno-associated virus (AAV) expressing ECM1 (AAV-ECM1) or AAV containing shECM1 (AAV-shECM1). Histological analysis was performed to determine cartilage damage. mRNA sequencing was performed to explore the molecular mechanism. In addition, the downstream signaling was further confirmed by using specific inhibitors. Our data showed that ECM1 was upregulated in the cartilage of patients with OA, OA mice as well as OA cell models. Moreover, ECM1 over-expressing in knee joints by AAV-ECM1 accelerated OA progression, while knockdown of ECM1 by AAV-shECM1 alleviated OA development. Mechanistically, cartilage destruction increased ECM1 expression, which consequently exacerbated OA progression partly by decreasing PRG4 expression in the TGF-ß/PKA/CREB-dependent manner. In conclusion, our study revealed the important role of ECM1 in OA progression. Targeted ECM1 inhibition is a potential strategy for OA therapy.

Assessment of surgical management for locked fracture-dislocations of the proximal humerus in patients of different ages.

Background: Locked fracture-dislocation of the proximal humerus (LFDPH) is a very severe complex injury; neither arthroplasty nor internal plating are fully satisfactory. This study aimed to evaluate different surgical treatments for LFDPH to determine the optimal option for patients of different ages. Methods: From October 2012 to August 2020, patients who underwent open reduction and internal fixation (ORIF) or shoulder hemiarthroplasty (HSA) for LFDPH were retrospectively reviewed. At follow-up, radiologic evaluation was performed to evaluate bony union, joint congruence, screw cut-out, avascular necrosis of the humeral head, implant failure, impingement, heterotopic ossification, and tubercular displacement or resorption. Clinical evaluation comprised the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire and Constant-Murley and visual analog scale (VAS) scores. Additionally, intraoperative and postoperative complications were assessed. Results: Seventy patients (47 women and 23 men) with final evaluation results qualified for inclusion. Patients were divided into three groups: group A: patients aged under 60 years who underwent ORIF; group B: patients aged ≥60 years who underwent ORIF; and group C: patients who underwent HSA. At a mean follow-up of 42.6 ± 26.2 months, function indicators, namely shoulder flexion, and Constant-Murley and DASH scores, in group A were significantly better than those in groups B and C. Function indicators in group B were slightly but not significantly better compared with group C. Regarding operative time and VAS scores, there were no significant differences between the three groups. Complications occurred in 25%, 30.6%, and 10% of the patients in groups A, B, and C, respectively. Conclusions: ORIF and HSA for LFDPH provided acceptable but not excellent results. For patients aged <60 years, ORIF might be optimal, whereas, for patients aged ≥60 years, both ORIF and HSA provided similar results. However, ORIF was associated with a higher rate of complications.

Extra-articular locking plate and trans-articular clavicle hook plate for displaced medial clavicle fractures.

INTRODUCTION: Fracture of the medial end of the clavicle is very rare. There is no consensus on the standard surgical strategy for medial clavicle fracture, and treatment is challenging. This study aimed to retrospectively evaluate the efficacy of internal plate fixation for displaced medial clavicle fracture. METHODS: Patients who underwent internal plating of a displaced medial clavicle fracture were included in this retrospective study. Each patient underwent open reduction and fixation with an internal extra-articular locking plate or trans-articular hook plate based on their fracture type. Postoperative follow-up included radiographs for assessment of bone union, Constant-Murley score for shoulder function, Disability of the Arm, Shoulder, and Hand (DASH) questionnaire for upper limb function, and visual analog scale (VAS) for pain. Any complications were also recorded. RESULTS: Between May 2014 and July 2021, 34 patients (9 females, 25 males; mean age, 50.0 ± 14.8 years) were treated with internal plate fixation and included in this study. The fracture line was located in the medial fifth of the clavicle in 32 patients, and 20 patients had intra-articular fracture. Eighteen patients had the fracture fixed with a locking plate, namely an inverted distal clavicle plate (n = 7), straight locking plate (n = 3), distal fibular plate (n = 3), and T-plate (n = 5); the other 16 patients were treated with a clavicle hook plate. During a mean follow-up of 30.7 ± 26.5 months, 33 patients achieved bone healing, the average Constant-Murley score was 90.9 ± 11.0 points, the mean DASH score was 6.0 ± 6.6 points, and the mean VAS was 0.4 ± 1.1 points. Complications occurred in five patients. CONCLUSIONS: Both locking plates and hook plates are effective in treating displaced medial clavicle fracture. A locking plate is recommended when there is enough bone stock in the medial fragment for stable fixation. A clavicle hook plate is recommended for cases in which the medial clavicle fracture is too small, comminuted, or has signs of sternoclavicular joint instability.

Ablation of myeloid discoidin domain receptor 2 exacerbates arthritis and high fat diet induced inflammation.

Chronic systemic inflammation leads to sever disorders and diseases. It is of great importance to explore novel target for effective treatment. Discoidin domain receptor 2 (Ddr2) is a member of receptor tyrosine kinase (RTK) family and is implicated in skeletal and fat hemostasis. However, the role of Ddr2 in myeloid cells remains obscure. In this study, we conditionally deleted Ddr2 in myeloid lineage cells to generate cKO mice to investigate the role of Ddr2 in myeloid lineage cells. We found that cKO mice exhibited more severe inflammation both in collagen antibody-induced arthritis (CAIA) and high-fat diet (HFD)-induced obesity, indicating the protective role of Ddr2 against inflammation. Mechanistically, Ddr2 promotes macrophage repolarization from the M1 to M2 phenotype, and protect against systemic inflammation. Our study reveals for the first time that Ddr2 modulates macrophage repolarization and plays critical roles in macrophage-mediated inflammation, providing potential target for the intervention of inflammation and related diseases.

Simultaneous bilateral traumatic clavicle fractures: incidence, characteristics, and surgical outcomes.

BACKGROUND: Although clavicle fractures are common injuries in adults, simultaneous bilateral clavicle fractures are rarely reported. The present report describes 13 patients with simultaneous bilateral traumatic clavicle fractures who were treated with surgical management and followed for more than 12 months postoperatively. METHODS: This retrospective chart review involved skeletally mature patients with traumatic clavicle injuries. Patients with bilateral clavicle fractures who were followed up for at least 12 months after surgery were included. Data regarding the patients' demographics, injury characteristics, fracture classification, comorbidities, concomitant injuries, and treatment strategies were collected. Each displaced fracture was managed with open reduction and internal fixation. Postoperative follow-up included radiographs for assessment of bone union; calculation of the Constant-Murley score for shoulder function; administration of the Disability of the Arm, Shoulder, and Hand questionnaire for upper limb function; determination of the visual analogue scale score for pain; and assessment of complications. RESULTS: From October 2013 to November 2021, 15 patients (10 men, 5 women) were diagnosed with bilateral clavicle fractures among 1542 patients with clavicle injuries (overall incidence of 1.0%). Of these 15 patients, this study included 13 patients (8 men, 5 women; mean age, 38.3 ± 15.3 years) who were followed up for more than 12 months postoperatively. Among the 13 patients, 10 (77.0%) had associated concomitant injuries, and 25 sides were fixed with internal plate fixation. After a follow-up period of 29.9 ± 28.5 months, all fractures achieved bone healing. Eleven patients attained excellent shoulder function on both sides and returned to their pre-injury daily activities, and the remaining two patients had unilateral shoulder dysfunction. No complications occurred. CONCLUSIONS: Bilateral clavicle fractures are extremely rare and associated with polytrauma. Open reduction and internal fixation is recommended for such patients, especially those with severe chest injuries, because osteosynthesis of the clavicle can improve respiratory function and reduce the duration of functional disability.

Chromatin Regulator-Related Gene Signature for Predicting Prognosis and Immunotherapy Efficacy in Breast Cancer.

Background: Many studies have found that chromatin regulators (CRs) are correlated with tumorigenesis and disease prognosis. Here, we attempted to build a new CR-related gene model to predict breast cancer (BC) survival status. Methods: First, the CR-related differentially expressed genes (DEGs) were screened in normal and tumor breast tissues, and the potential mechanism of CR-related DEGs was determined by function analysis. Based on the prognostic DEGs, the Cox regression model was applied to build a signature for BC. Then, survival and receiver operating characteristic (ROC) curves were performed to validate the signature's efficacy and identify its independent prognostic value. The CIBERSORT and tumor immune dysfunction and exclusion (TIDE) algorithms were used to assess the immune cells infiltration and immunotherapy efficacy for this signature, respectively. Additionally, a novel nomogram was also built for clinical decisions. Results: We identified 98 CR-related DEGs in breast tissues and constructed a novel 6 CR-related gene signature (ARID5A, ASCL1, IKZF3, KDM4B, PRDM11, and TFF1) to predict the outcome of BC patients. The prognostic value of this CR-related gene signature was validated with outstanding predictive performance. The TIDE analysis revealed that the high-risk group patients had a better response to immune checkpoint blockade (ICB) therapy. Conclusion: A new CR-related gene signature was built, and this signature could provide the independent predictive capability of prognosis and immunotherapy efficacy for BC patients.

Characteristics of subsequent contralateral proximal femoral fracture: more convenient access is needed to treat osteoporosis.

BACKGROUND: Patients with proximal femoral fracture (PFF) have high mortality and many complications. Osteoporosis increases the risk of subsequent fractures, leading to subsequent contralateral PFF. This study was performed to analyze the features of individuals with subsequent PFF following surgical therapy of first PFF and to ascertain whether such patients received an examination or treatment of osteoporosis. The reasons for lack of examination or treatment were also analyzed. METHODS: This retrospective study involved 181 patients with subsequent contralateral PFF who underwent surgical treatment in Xi'an Honghui hospital from September 2012 to October 2021. The patients' sex, age, hospital day, mechanism of injury, surgical procedure, fracture interval, fracture type, fracture classification, and Singh index of the contralateral hip at the time of the initial and subsequent fractures were recorded. Whether the patients took calcium and vitamin D supplements, used anti-osteoporosis medication, or underwent a dual X-ray absorptiometry (DXA) scan was recorded, as was the start time of each. Patients who had never undergone a DXA scan or received anti-osteoporosis medication took part in a questionnaire. RESULTS: The 181 patients in this study comprised 60 (33.1%) men and 121 (66.9%) women. Patients with initial PFF and subsequent contralateral PFF had a median age of 80 years (range 49-96 years) and 82 years (range 52-96 years), respectively. The median fracture interval was 24 (7-36) months. Contralateral fractures occurred at the highest incidence between 3 months and 1 year (28.7%). The Singh index was not significantly different between the two fractures. In 130 (71.8%) patients, the fracture type was the same. No significant difference was found in the fracture type or fracture stability classification. A total of 144 (79.6%) patients had never received a DXA scan or anti-osteoporosis medication. The main reason for not treating osteoporosis further was concern about the safety of drug interactions (67.4%). CONCLUSIONS: Patients with subsequent contralateral PFF were of advanced age, had a higher proportion of intertrochanteric femoral fractures, had more severe osteoporosis, and had longer hospital stays. The difficulty managing such patients requires multidisciplinary involvement. Most of these patients were not screened or formally treated for osteoporosis. Advanced-age patients with osteoporosis need reasonable treatment and management.

Neuropeptide Y Promotes mTORC1 to Regulate Chondrocyte Proliferation and Hypertrophy.

Peripheral neuropeptide Y (NPY) has been reported to regulate bone metabolism and homeostasis; however, its potential roles in growth plate chondrogenesis remain unclear. Here, we found that NPY expression decreased during chondrocyte differentiation in vitro and in vivo. NPY was required for chondrocyte proliferation; in contrast, knockdown of NPY facilitated chondrocyte hypertrophic differentiation. Administration of recombinant NPY in rat chondrocytes and metatarsal bones uncoupled normal proliferation and hypertrophic differentiation during chondrogenesis and thereby inhibited growth plate chondrogenesis and longitudinal bone growth. Remarkably, NPY activated the mTORC1 pathway in chondrocytes, whereas attenuation of mTORC1 activity by administration of rapamycin in vitro partially abrogated NPY-mediated effects on chondrocyte proliferation and hypertrophic differentiation. In addition, a combination of Y2R antagonist but not Y1R antagonist with NPY abolished NPY-mediated inhibition of metatarsal growth and growth plate chondrogenesis. Mechanistically, NPY activated Erk1/2 by NPY2R, then phosphorylated ERK1/2 activated mTORC1 to initiate PTHrP expression, which in turn promoted chondrocyte proliferation and inhibited chondrocyte hypertrophic differentiation. In conclusion, our data identified NPY as a crucial regulator of chondrogenesis and may provide a promising therapeutic strategy for skeletal diseases.

Treatment of bipolar clavicle injury with internal plating: a case series and literature review.

BACKGROUND: Bipolar clavicle injury is a rare injury involving any combination of dislocation and/or fracture at both ends of the clavicle. Most reports of bipolar clavicle injury have been based on a single case, and treatment of this injury remains controversial. The present study was performed to evaluate the efficacy of surgical management with internal plating for bipolar clavicle injuries. METHODS: We performed internal plating to treat seven consecutive bipolar clavicle injuries with different injury patterns from May 2013 to June 2021. A clavicle hook plate was used for five sternoclavicular joint injuries (including a revision surgery) and three acromioclavicular joint dislocations, a T plate was used for one sternoclavicular joint injury, and an anatomic plate was used for one distal clavicle fracture. At follow-up, radiographs were assessed for bone alignment, joint congruity, fracture union or malunion, and implant failure or migration. Clinical evaluation included determination of the Disability of the Arm, Shoulder, and Hand (DASH) score; Constant-Murley score; visual analog scale (VAS) score; and complications. RESULTS: The patients were regularly followed up after the operation, and functional parameters were assessed over time. At a mean follow-up of 28.1 ± 22.0 months, each fracture had solid bone union, and each dislocation showed no sign of recurrent instability. The mean shoulder forward flexion was 159.3° ± 7.9°, and the mean DASH score was 8.8 ± 5.1. The mean Constant-Murley score was 88.9 ± 7.9, with six cases assessed as excellent and one case assessed as good. The mean VAS score was 1.0 ± 1.5, and the mean patient satisfaction score was 9.3 ± 0.8. No complications occurred, and each patient was able to resume their preinjury daily activity and was highly satisfied with their treatment. CONCLUSIONS: In the present study, internal plating for bipolar clavicle injury allowed early mobilization and resulted in good joint function. We recommend fixation of the more severely affected side first because the other side may be passively reduced and acquire stability once the more severely affected side has been fixed. Internal fixation of the other end may therefore be unnecessary unless residual instability exists.

Proportion of stable femoral neck fracture types in different age groups: a population-based study.

OBJECTIVE: The treatment and incidence of femoral neck fracture (FNF) in older patients is controversial. We investigated the new AO (Arbeitsgemeinschaft für Osteosynthese) classification in patients with FNF by age to determine the proportions of stable fracture and change trends according to patients' age. METHODS: We divided patients with FNF hospitalized in Xi'an Honghui Hospital from 2018 to 2020 into five groups according to age: young (<50 years), middle-aged (50-59 years), young-elderly (60-69 years), middle-elderly (70-79 years), and very elderly (≥80 years) groups. We retrospectively collected data of patients' sex, admission date, fracture side, mechanism of injury, and new AO classification. RESULTS: In total, 2071 patients were included for analysis, with 1329 women (64.2%); 1106 patients (53.4%) had left-side fracture. The main mechanism of injury was falling. In the young-elderly, middle-elderly, and very-elderly groups, 33.3%, 29.2%, and 24.1% had stable fracture type, respectively). The proportion of patients with FNF did not show a change trend by age during the 3-year investigation period. CONCLUSION: In our study, the proportion of older patients with FNF did not increase, and as many as a third of patients with FNF aged 50 to 70 years had stable fracture.

A novel bone graft technique combined with plating for aseptic recalcitrant long bone nonunion.

BACKGROUND: To evaluate the outcomes and efficacy of a new technique of autogenous iliac crest bone grafting combined with locking compression plate (LCP) vertical fixation for aseptic recalcitrant long bone nonunion. METHODS: From July 2010 to September 2020, 36 aseptic recalcitrant long bone nonunions were treated with a bone-forming channel technique and internal LCP fixation. All the patients had received one or more failed treatments. The injury mechanism, nonunion type and duration, and prior treatments were recorded pre-operation. The routine treatment process included nonunion area exposure, previous implant removal, sclerotic bone debridement, LCP fixation, bone-forming channel creation, and iliac bone grafting, and a second LCP fixation when required. At follow-up, X-ray images were obtained to assess bone healing and implant failure. Visual analog scale (VAS), fracture site stability, limb function, activity, muscle strength, limb length, and complications were recorded. RESULTS: A total of 34 patients (24 males and 10 females) were finally enrolled, with a mean age of 49.8 ± 12.3 years. At a mean follow-up of 35.6 ± 22.0 months, 32 patients displayed bone union, with a healing rate of 94.1% and mean union time of 6.8 ± 2.4 months. The VAS score was 0.7 ± 1 at the final follow-up. The functional results showed that 19 patients were excellent, 11 patients were good, 2 patients were poor, and 2 patients did not heal. CONCLUSION: Bone-forming channel technique combined with LCP vertical fixation is an excellent option to treat recalcitrant long bone nonunion. LEVEL OF EVIDENCE: Therapeutic Level IV.

Mendelian randomization study of circulating lipids and biliary tract cancer among East Asians.

BACKGROUND: Associations of High-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (CHL), and triglyceride (TRG) concentrations with risk of biliary tract cancer (BtC) were conflicting in observational studies. We aim to investigate the causal link between circulating lipids and BtC using genetic information. METHODS: Single nucleotide polymorphisms of the four circulating lipids (n = 34,421) and BtC (418 cases and 159,201 controls) were retrieved from two independent GWAS studies performed in East Asian populations. Two-sample univariate and multivariate Mendelian Randomization (MR) analyses were conducted to determine the causal link between circulating lipids and BtC. RESULTS: No significant horizontal pleiotropy was detected for all circulating lipids according to the MR-PRESSO global test (P = 0.458, 0.368, 0.522, and 0.587 for HDL, LDL, CHL, and TRG, respectively). No significant evidence of heterogeneity and directional pleiotropy was detected by the Cochran's Q test and MR-Egger regression. Univariate MR estimates from inverse variance weighting method suggested that one standard deviation (1-SD) increase of inverse-normal transformed HDL (OR = 1.38, 95% CI 0.98-1.94), LDL (OR = 1.46, 95% CI 0.96-2.23), and CHL (OR = 1.34, 95% CI 0.83-2.16) were not significantly associated with BtC risk. Whereas 1-SD increase of inverse-normal transformed TRG showed a significantly negative association with BtC risk (OR = 0.48, 95% CI 0.31-0.74). In multivariate MR analyses including all the four lipid traits, we found that 1-SD increase of LDL and TRG was significantly associated with elevated (OR = 1.32, 95% CI 1.04-2.01) and decreased (OR = 0.54, 95% CI 0.42-0.68) risk of BtC, respectively. CONCLUSION: Circulating lipids, particularly LDL and TRG, may have roles in the development of BtC. However, the results of this study should be replicated in MR with larger GWAS sample sizes for BtC.

KIF15 knockdown suppresses gallbladder cancer development.

Gallbladder cancer (GBC) is commonly regarded as one of the most lethal malignant tumor types with poor prognosis. Kinesin family member 15 (KIF15) is reported to be tightly related with progression of multiple cancer types which, however, has not been clarified in GBC so far. KIF15 was significantly up-regulated in clinical GBC tissues compared with that in para-carcinoma tissues and the expression level was also correlated with tumor malignancies. In addition to tissues, GBC cells also exhibited a high expression abundance of KIF15. After down-regulating KIF15 via lentiviral transfection, GBC cell proliferation and migration were both inhibited, while cell apoptosis was promoted markedly. Likewise, silencing KIF15 significantly interfered the growth of nude mouse xenografts. Our experiments in GBC cell lines also demonstrated that KIF15 overexpression accelerated cell proliferation but lessened cell apoptosis in both GBC-SD and SGC-996 cells. Further investigation of the mechanism occurring in GBC inhibition mediated by KIF15 knockdown revealed that KIF15 deficiency led to decreased activity of several signaling pathways (TNF, PI3K/AKT and MAPK), a reduction of CDK6 expression regulated by enhanced p21, and HSP60 absence. Following the treatment of shCtrl- and shKIF15-transfected cells with AKT activator, we found that anti-tumor effects resulting from KIF15 deficiency could be relieved by AKT activator in both experimental cells. Overall, for the first time, we demonstrated that KIF15 was overexpressed in GBC and displayed a close relationship between KIF15 levels and GBC clinical stages. Furthermore, low expression of KIF15 resulted in obvious anti-tumor effects.

Double plating with autogenous bone grafting as a salvage procedure for recalcitrant humeral shaft nonunion.

BACKGROUND: Although most cases of humeral shaft nonunion respond well to surgical intervention, surgeons still encounter patients with humeral shaft nonunion who have already undergone repeated surgeries for nonunion. This study retrospectively analyzed the efficacy of double locking compression plate (LCP) fixation in combination with autogenous iliac crest bone grafting for recalcitrant humeral shaft nonunion. METHODS: A consecutive series of patients with aseptic recalcitrant humeral shaft nonunion underwent surgical treatment between May 2010 and August 2017 in our institution. Standardized treatment included thorough debridement, double LCP and screw fixation, and autogenous iliac bone grafting. The injury type and the duration of nonunion were recorded for all patients. The main outcome measurements were the Constant and Murley scale for shoulder function, Mayo elbow performance index (MEPI) for elbow function, and visual analog scale (VAS) for pain. In addition, all complications were documented. RESULTS: The study cohort comprised six females and nine males with a mean age of 45.3 ± 13.1 years. Each patient had already undergone at least one failed surgery for humeral shaft nonunion. The average duration of nonunion before the index intervention was 126.8 ± 124.2 months. All patients achieved bone union without implant failure. At final follow-up, the mean Constant and Murley score and mean MEPI were significantly improved, and the mean VAS score was significantly decreased. Each patient was very satisfied with the treatment. Four patients had complications, including one with a superficial wound infection, one with radial nerve palsy, one with ulnar nerve palsy, and one with discomfort at the iliac crest. CONCLUSION: Double plate fixation combined with autogenous iliac crest bone grafting results in successful salvage of humeral shaft nonunion after prior failed surgical interventions.

The effects of common variants in MDM2 and GNRH2 genes on the risk and survival of osteosarcoma in Han populations from Northwest China.

Accumulating evidence has shown that both MDM2 and GNRH2 might be related to Osteosarcoma (OS) susceptibility. The study aimed to evaluate the effects of common variants in MDM2 and GNRH2 genes on the risk and survival of osteosarcoma in Han populations from Northwest China. In the study, we recruited 2292 subjects including 596 OS patients and 1696 healthy controls and genotyped 16 selected tag SNPs (6 from GNRH2 and 10 from MDM2). Genetic association analyses were performed at the genotypic and allelic levels. Survival curves were made for OS patients with different genotypes. Two SNPs, rs1690916 (MDM2, P = 0.0002) and rs3761243 (GNRH2, P = 0.0004), were identified to be significantly associated with OS risk. Moreover, SNP rs3761243 was strongly associated with pathological fracture (P = 2.61 × 10-14), metastasis (P < 2.2 × 10-16), and Enneking stage (P < 2.2 × 10-16) in the OS group. Furthermore, survival curves based on different genotypes of SNP rs3761243 were found to be significantly different (P = 0.0003), suggesting increased risk with more copies of C alleles. Our results provide supportive evidence for genetic associations of MDM2 and GNRH2 genes with susceptibility to OS, and for the positive correlation of SNP rs3761243 in GNRH2 with the survival status of OS patients in Han populations from Northwest China.

Balser Plate Stabilization for Traumatic Sternoclavicular Instabilities or Medial Clavicle Fractures: A Case Series and Literature Review.

OBJECTIVE: This study was performed to observe the effect of internal Balser plate fixation for treating unstable sternoclavicular joints (SCJ) and displaced medial clavicle fractures. METHODS: From April 2009 to September 2016, 17 consecutive patients who underwent open reduction and internal Balser plate fixation for SCJ dislocations or medial clavicle fractures were retrospectively reviewed. There were 11 male and six female patients, with a mean age of 45.6 ± 15.5 years. Standardized treatment procedures consisted of reduction, creating a space posterior dorsal osteal face of the sternal manubrium, an inverted Balser plating, and postoperative immobilization. At follow-up, plain radiographs were assessed for fracture union, implant loosening, degenerative changes, and joint congruity. Clinical evaluation included: completion of the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire; determination of the Constant and Murley score and visual analog scale (VAS) score; and assessment of intraoperative and postoperative complications. RESULTS: All patients were followed up, at a mean follow-up of 20.1 ± 7.9 months, each fracture had a solid union, and each dislocation showed no sign of recurrent dislocation. The mean shoulder forward flexion was 162.9° ± 8.1°. The mean DASH score was 5.2 ± 5.2 points. The mean Constant and Murley joint function score was 93.7 ± 7.9 points, with 15 excellent cases and two good cases. The mean VAS score was 1.1 ± 1.4 points, showing significant improvement compared with the VAS score preoperatively. Postoperative complications included one wound hematoma which was healed after a debridement and one recurrent instability due to hook migration, which underwent revision reconstruction. All patients were satisfied with their treatment outcome at the final follow-up. CONCLUSION: Sternoclavicular joints dislocation or medial clavicle fractures can be treated successfully with Balser plate fixation. This technique permits early functional exercise while preserving the SCJ.

Progranulin modulates cartilage-specific gene expression via sirtuin 1-mediated deacetylation of the transcription factors SOX9 and P65.

Progranulin (PGRN) is an autocrine growth factor that exerts crucial roles within cartilage tissue; however, the molecular mechanisms underlying PGRN-mediated cartilage homeostasis remain elusive. In the present study, we investigated the role of PGRN in regulating chondrocyte homeostasis and its therapeutic potential for managing osteoarthritis (OA). We found that PGRN levels are significantly increased in human cartilage in mild OA and that its expression is decreased in the cartilage in severe OA. In vitro, treatment of primary rat chondrocytes with recombinant PGRN significantly enhanced the levels of collagen type II α 1 chain (COL2A1) and aggrecan, and attenuated TNFα-induced up-regulation of matrix metallopeptidase 13 (MMP13) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) in chondrocytes. These effects were abrogated in SIRT1-/- cells, indicating a causative role of SIRT1 in the effects of PGRN on protein expression in chondrocytes. Mechanistically, PGRN increased SIRT1 expression and activity, which reduced the acetylation levels of SRY-box transcription factor (SOX9) and transcription factor P65 (P65) and thereby promoted nuclear translocation of SOX9 and inhibited TNFα-induced P65 nuclear accumulation to maintain chondrocyte homeostasis. In conclusion, our findings reveal a mechanism of action for PGRN that maintains cartilage homeostasis and supports the notion that PGRN up-regulation may be a promising strategy for managing OA.

Evaluation of genetic susceptibility of common variants in SOX9 in patients with congenital talipes equinovarus in the Han Chinese population.

BACKGROUND: Congenital talipes equinovarus (CTEV) is a common birth defect that causes severe deformities of one or both feet. Genetics have been proven to play a key role in the risk of CTEV. Our study aimed to evaluate the genetic susceptibility of common variants in the SOX9 gene to CTEV in a Han Chinese population. METHODS: In this study, we recruited 2,205 study participants, including 692 CTEV patients and 1513 healthy controls. A total of seven selected single-nucleotide polymorphisms (SNPs) within the SOX9 gene were genotyped, and environmental variables, including maternal smoking and alcoholic drinking habits, were assessed. In addition, bioinformatics analyses were performed to explore the potential biological functions of the associated SNPs. RESULTS: The SNP rs73354570 was identified to be significantly associated with the risk of CTEV (OR = 1.53, P = 2.11 × 10-5), and the C allele was associated with an increased risk of CTEV. A dose-dependent pattern could be observed in genotypic analyses. The OR for individuals with AC genotypes was 1.37 (95% CI 1.09-1.71), and the OR for individuals with CC homozygotes was 1.47 (95% CI 1.18-1.82). Further analyses identified that rs73354570 is located within a region of multiple binding proteins, including CEBPB and POLR2A, which suggested that this SNP was also part of genetic motifs that are found within several cell types. CONCLUSION: Our results provide evidence supporting the important role of the SOX9 gene in the contribution to the risk of CTEV.

Coumarin-containing hybrids and their antibacterial activities.

Infections caused by Gram-positive and -negative bacteria are one of the foremost causes of morbidity and mortality globally. Antibiotics are the mainstay of therapy for bacterial infections, but the emergence and wide spread of drug-resistant pathogens have already become a huge issue for public healthcare systems. The coumarin moiety, which is ubiquitous in nature, could bind to the B subunit of DNA gyrase in bacteria and inhibit DNA supercoiling by blocking the ATPase activity; hence, coumarin derivatives possess potential antibacterial activity. Several coumarin-containing hybrids such as coumermycin A1, clorobiocin, and novobiocin have already been used in clinical practice for the treatment of various bacterial infections; thus, it is conceivable that hybridization of the coumarin moiety with other antibacterial pharmacophores may provide opportunities for the development of novel antibiotics. This review outlines the advances in coumarin-containing hybrids with antibacterial potential in the recent 5 years and the structure-activity relationships are also discussed.