Klf10 is involved in extracellular matrix calcification of chondrocytes alleviating chondrocyte senescence.

Osteoarthritis (OA) is a chronic degenerative disease resulting joint disability and pain. Accumulating evidences suggest that chondrocyte extracellular matrix calcification plays an important role in the development of OA. Here, we showed that Krüppel-like factor 10 (Klf10) was involved in the regulation of chondrocyte extracellular matrix calcification by regulating the expression of Frizzled9. Knockdown of Klf10 attenuated TBHP induced calcification and reduced calcium content in chondrocytes. Restoring extracellular matrix calcification of chondrocytes could aggravate chondrocyte senescence. Destabilization of a medial meniscus (DMM) mouse model of OA, in vivo experiments revealed that knockdown Klf10 improved the calcification of articular cartilage and ameliorated articular cartilage degeneration. These findings suggested that knockdown Klf10 inhibited extracellular matrix calcification-related changes in chondrocytes and alleviated chondrocyte senescence.

Overall survival comparison between pediatric and adult Ewing sarcoma of bone and adult nomogram construction: a large population-based analysis.

Background: Ewing sarcoma (ES) is a common primary bone tumor in children. Our study aimed to compare overall survival (OS) between pediatric and adult bone ES patients, identify independent prognostic factors and develop a nomogram for predicting OS in adult patients with ES of bone. Methods: We retrospectively analyzed data for the 2004-2015 period from the Surveillance, Epidemiology, and End Results (SEER) database. To guarantee well-balanced characteristics between the comparison groups, propensity score matching (PSM) was used. Kaplan-Meier (KM) curves were used to compare OS between pediatric and adult patients with ES of bone. Univariate and multivariate Cox regression analyses were used to screen independent prognostic factors for ES of bone, and a prognostic nomogram was constructed by using the factors identified. The prediction accuracy and clinical benefit were evaluated using receiver operating characteristic (ROC) curves, areas under the curves (AUCs), calibration curves, and decision curve analysis (DCA). Results: Our results showed that adult ES patients had lower OS than younger ES patients. Age, surgery, chemotherapy, and TNM stage were independent risk factors for bone ES in adults and were used to develop a nomogram. AUCs for 3-, 5-, and 10-year OS were 76.4 (67.5, 85.3), 77.3 (68.6, 85.9) and 76.6 (68.6, 84.5), respectively. Calibration curves and DCA results indicated excellent performance for our nomogram. Conclusion: We found that ES pediatric patients have better OS than adult ES patients, and we constructed a practical nomogram to predict the 3-, 5- and 10-year OS of adult patients with ES of bone based on independent prognostic factors (age, surgery, chemotherapy, T stage, N stage and M stage).

Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy.

Osteoarthritis (OA) is the most prevalent degenerative joint disease in the elderly. Accumulation of evidence has suggested that chondrocyte senescence plays a significant role in OA development. Here, we show that Krüppel-like factor 10 (Klf10), also named TGFß inducible early gene-1 (TIEG1), is involved in the pathology of chondrocyte senescence. Knocking down the Klf10 in chondrocytes attenuated the tert-butyl hydroperoxide (TBHP)-induced senescence, inhibited generation of reactive oxygen species (ROS), and maintained mitochondrial homeostasis by activating mitophagy. These findings suggested that knocking down Klf10 inhibited senescence-related changes in chondrocytes and improved cartilage homeostasis, indicating that Klf10 may be a therapeutic target for protecting cartilage against OA.

A Novel Role for RILP in Regulating Osteoclastogenesis and Bone Resorption.

Increased bone resorption caused by excessive number or activity of osteoclasts is the main cause of osteoporosis. Osteoclasts are multinucleated cells that are formed by the fusion of precursor cells. Although osteoclasts are primarily characterized by bone resorption, our understanding of the mechanisms that regulate the formation and function of osteoclasts is poor. Here we showed that the expression level of Rab interacting lysosomal protein (RILP) was strongly induced by receptor activator of NF-κB ligand in mouse bone marrow macrophages. Inhibition of RILP expression induced a drastic decrease in the number, size, F-actin ring formation of osteoclasts, and the expression level of osteoclast-related genes. Functionally, inhibition of RILP reduced the migration of preosteoclasts through PI3K-Akt signaling and suppressed bone resorption by inhibiting the secretion of lysosome cathepsin K. Treatments with siRNA-RILP attenuated pathologic bone loss in disease models induced by lipopolysaccharide. Thus, this work indicates that RILP plays an important role in the formation and bone resorption function of osteoclasts and may have a therapeutic potential to treat bone diseases caused by excessive or hyperactive osteoclasts.

Socioeconomic status influences on bone mineral density in American men: findings from NHANES 2011-2020.

The association between socioeconomic status (SES) and bone mineral density (BMD) in men remains controversial. We showed that SES was positively associated with BMD in American men. Confounding factors like race/ethnicity and age could affect the association. INTRODUCTION: Based on the data from the National Health and Nutrition Examination Survey (NHANES), 2011-2020, this article aims to investigate the association of SES (poverty income ratio (PIR) and education level) with the BMD in American men. METHODS: We evaluated the association of SES with BMD in 4446 men aged ≥ 20 years (mean age, 41.0 ± 13.4 years) from the NHANES 2011-2020. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine. We used multivariate linear regression models to examine the relationship between SES and total spine BMD, adjusted for a large range of confounding factors. RESULTS: Compared with other PIR quarters, individuals in the highest quarter of PIR were more likely to be older and white and had fewer smoking or drinking behaviors. After adjusting for race/ethnicity, age, drinking and smoking behavior, body mass index (BMI), total protein, serum calcium, serum uric acid, cholesterol, serum phosphorus, and blood urea nitrogen, PIR was positively correlated with total spine BMD (ß = 0.004 95% CI: 0.001-0.007, P = 0.006). Individuals with the highest degree (college degree or above) had a 0.057 g/cm2 greater BMD than that of the lowest degree (less than 9th grade) (ß = 0.057 95% CI: 0.037-0.077, P < 0.001). CONCLUSIONS: Our study indicates that SES was positively associated with the lumbar BMD among American men. Clinicians, healthcare providers, and policymakers should consider the unequal SES of men when implementing osteoporosis prevention and treatment strategies.

Inhibition of Cpt1a alleviates oxidative stress-induced chondrocyte senescence via regulating mitochondrial dysfunction and activating mitophagy.

Osteoarthritis (OA) is an age-related chronic degenerative disease, and chondrocyte senescence has been established to play an important role in the pathological process. There is ample evidence to suggest that lipid metabolism plays an important role in the aging process. However, the effect of lipid metabolism on chondrocyte senescence and OA remains unclear. Accordingly, we constructed a TBHP-induced senescent chondrocytes model and a destabilization of the medial meniscus (DMM) mouse model. We found that lipid accumulation and fatty acid oxidation were enhanced in senescent chondrocytes. Interestingly, carnitine palmitoyltransferase 1A (Cpt1a), the rate-limiting enzyme for fatty acid oxidation, was highly expressed in senescent chondrocytes and murine knee cartilage tissue. Suppressing Cpt1a expression using siRNA or Etomoxir, an inhibitor of Cpt1a, could attenuate oxidative stress-induced premature senescence and OA phenotype of primary murine chondrocytes, decrease cellular ROS levels, restore mitochondrial function, and maintain mitochondrial homeostasis via activating mitophagy. In vivo, pharmacological inhibition of Cpt1a by Etomoxir attenuated cartilage destruction, relieved joint space narrowing and osteophyte formation in the DMM mouse model. Overall, these findings suggested that knockdown of Cpt1a alleviated chondrocyte senescence by regulating mitochondrial dysfunction and promoting mitophagy, providing a new therapeutic strategy and target for OA treatment.

CircHIPK3 prevents chondrocyte apoptosis and cartilage degradation by sponging miR-30a-3p and promoting PON2.

Osteoarthritis (OA) is a common joint disease featured by the deterioration of articular cartilage and chondrocyte death. Emerging evidence has indicated that circular RNAs (circRNAs) play an essential role in OA progress. Here, we found that the expression of circHIPK3 was significantly decreased in human and mouse OA cartilage. Knocking down circHIPK3 increased apoptosis and intracellular ROS level in HC-a chondrocytes. We performed proteomic studies and identified that circHIPK3 regulated chondrocyte apoptosis through the mitochondrial pathway. Results of JC-1 staining and western blot further confirmed that mitochondrial outer membrane permeabilization was promoted in HC-a chondrocytes transfected by circHIPK3 siRNA. In terms of mechanism, we showed that PON2 functioned as a potential target of circHIPK3 to regulate chondrocyte apoptosis. Moreover, we revealed that circHIPK3 interacted with miR-30a-3p to regulate PON2 expression in chondrocytes. Taken together, our findings suggested that circHIPK3 regulated chondrocyte apoptosis by mitochondrial pathway, and targeting the circHIPK3/miR-30a-3p/PON2 axis might be a potential strategy for OA treatment.

TGF-ß1 regulates chondrocyte proliferation and extracellular matrix synthesis via circPhf21a-Vegfa axis in osteoarthritis.

BACKGROUND: The transforming growth factor-beta (TGF-ß) signaling pathway is an important pathway associated with the pathogenesis of osteoarthritis (OA). This study was to investigate the involvement of circRNAs in the TGF-ß signaling pathway. METHODS: Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to detect the proliferation of primary mouse chondrocytes (PMCs). RNA-sequencing together with bioinformatics analysis were used to systematically clarify TGF-ß1 induced alternations of circRNAs in PMCs. The regulatory and functional role of circPhf21a was examined in PMCs. Downstream targets of circPhf21a were explored by RNA-sequencing after overexpression of circPhf21a and verified by RT-qPCR in PMCs. Finally, the role and mechanism of circPhf21a in OA were explored in mouse models. RESULTS: We found that TGF-ß1 promoted the proliferation of PMCs. Meanwhile, RT-qPCR and western blotting indicated that TGF-ß1 promoted extracellular matrix (ECM) anabolism. RNA-sequencing revealed that a total of 36 circRNAs were differentially expressed between PMCs treated with and without TGF-ß1. Of these, circPhf21a was significantly decreased by TGF-ß1. Furthermore, circPhf21a knockdown promoted the proliferation and ECM synthesis of PMCs, whereas overexpression of circPhf21a showed the opposite effects. Mechanically, the expression profiles of the mRNAs revealed that Vegfa may be the target of circPhf21a. Additionally, we found that circPhf21a was significantly upregulated in the mouse OA model, and inhibition of circPhf21a significantly relieved the progression of OA. CONCLUSIONS: Our results found that TGF-ß1 promoted the proliferation and ECM synthesis of PMCs via the circPhf21a-Vegfa axis, which may provide novel therapeutic targets for OA treatment. Video abstract.

Leukemia/lymphoma-related factor (LRF) or osteoclast zinc finger protein (OCZF) overexpression promotes osteoclast survival by increasing Bcl-xl mRNA: A novel regulatory mechanism mediated by the RNA binding protein SAM68.

RANKL induces NFATc1, a key transcriptional factor to induce osteoclast-specific genes such as cathepsin K, whereas transcriptional control of osteoclast survival is not fully understood. Leukemia/lymphoma-related factor (LRF) in mouse and osteoclast zinc finger protein (OCZF) in rat are zinc finger and BTB domain-containing protein (zBTB) family of transcriptional regulators, and are critical regulators of hematopoiesis. We have previously shown that differentiation and survival were enhanced in osteoclasts from OCZF-Transgenic (Tg) mice. In the present study, we show a possible mechanism of osteoclast survival regulated by LRF/OCZF and the role of OCZF overexpression in pathological bone loss. In the in vitro cultures, LRF was highly colocalized with NFATc1 in cells of early stage in osteoclastogenesis, but only LRF expression persisted after differentiation into mature osteoclasts. LRF expression was further enhanced in resorbing osteoclasts formed on dentin slices. Osteoclast survival inhibitor such as alendronate, a bisphosphonate reduced LRF expression. Micro CT evaluation revealed that femurs of OCZF-Tg mice showed significantly lower bone volume compared to that of WT mice. Furthermore, OCZF overexpression markedly promoted bone loss in ovariectomy-induced osteolytic mouse model. The expression of anti-apoptotic Bcl-xl mRNA, which is formed by alternative splicing, was enhanced in the cultures in which osteoclasts are formed from OCZF-Tg mice. In contrast, the expression of pro-apoptotic Bcl-xs mRNA was lost in the culture derived from OCZF-Tg mice. We found that the expression levels of RNA binding splicing regulator, Src substrate associated in mitosis of 68 kDa (Sam68) protein were markedly decreased in OCZF-Tg mice-derived osteoclasts. In addition, shRNA-mediated knockdown of Sam68 expression increased the expression of Bcl-xl mRNA, suggesting that SAM68 regulates the expression of Bcl-xl. These results indicate that OCZF overexpression reduces protein levels of Sam68, thereby promotes osteoclast survival, and suggest that LRF/OCZF is a promising target for regulating pathological bone loss.

Prevalence and treatment rate of osteoporosis in patients undergoing total knee and hip arthroplasty: a systematic review and meta-analysis.

PURPOSE: Due to age and gender, patients awaiting total knee or hip arthroplasty (TKA/THA) are at a higher risk of osteoporosis. In joint arthroplasty, low bone mineral density (BMD) is a risk factor for implant osseointegration, durability, and prosthesis complications. This study aims to investigate the prevalence and treatment rate of osteoporosis in patients undergoing total joint arthroplasty (TJA). METHODS: We applied a comprehensive literature search through PubMed, Cochrane Library, and EMBASE from inception to July 10, 2021, for studies investigating the prevalence and treatment rate of osteoporosis in TJA patients. The aggregated prevalence was calculated with the random-effects model, and the heterogeneity between studies was checked by Cochran's Q test and quantified by the I2 statistic. We performed subgroup analyses and meta-regression analyses to determine the source of heterogeneity. Publication bias was assessed by a funnel plot and verified by Egger's test. Anti-osteoporosis treatment for TJA patients was described qualitatively and quantitatively. RESULTS: Of 4561 citations identified by the search strategy, 11 studies including 3462 patients were eligible for inclusion. The pooled prevalence of osteoporosis and osteopenia in TJA patients was 24.8% (95%CI: 14.1-37.2%) and 38.5% (95%CI: 29.3-48.0%), respectively. The prevalence of osteoporosis/osteopenia in TJA patients was 64.0% (95%CI: 45.8-80.3%). In terms of gender, the pooled prevalence of osteoporosis in males, females, and postmenopausal females were 5.5% (95%CI: 1.5-11.4%), 29.0% (95%CI: 18.3-41.1%), and 38.3% (95%CI: 13.2-67.1%), respectively. The treatment rate of osteoporosis in TJA patients was 32.9% (95%CI: 15.2-53.1%) by a random-effects model. CONCLUSIONS: Osteoporosis is highly prevalent in patients undergoing TJA, especially in postmenopausal females. However, the treatment rate of osteoporosis is low. Considering the possibility of surgical complications, clinicians should strengthen their awareness of pre-operative BMD assessment and manage osteoporosis in high-risk patients.

Procollagen I N-terminal peptide correlates with inflammation on sacroiliac joint magnetic resonance imaging in ankylosing spondylitis but not in non-radiographic axial spondyloarthritis: A cross-sectional study.

OBJECTIVES: To identify disease activity scores and biomarkers that reflect magnetic resonance imaging (MRI)-determined sacroiliac joint (SIJ) inflammation in ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). METHODS: Patients who had AS and nr-axSpA were enrolled. All the patients underwent SIJ MRI. SpondyloArthritis Research Consortium of Canada (SPARCC) method was used to score bone marrow edema in the inflammatory lesions on MRI. Radiographic assessment of the spine was performed using modified Stoke Ankylosing Spondylitis Spine Score. Clinical variables, inflammatory markers, serum alkaline phosphatase, osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX-I), and procollagen I N-terminal peptide (PINP) were measured. Correlation analysis between MRI-determined SIJ inflammation scores and disease activity scores and laboratory variables was performed. RESULTS: Thirty-five patients had AS and 36had nr-axSpA. Significant differences were noted between the AS group and the nr-axSpA group in terms of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ankylosing Spondylitis Disease Activity Score (ASDAS)-ESR, ASDAS-CRP, PINP, and SPARCC (p < .001, p = .004, p < .001, p < .001, p = .030, p < .001, respectively). MRI-determined SIJ inflammatory scores correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), OC, CTX-I, and PINP in AS (p = .036, p = .023, p = .002, p = .041, p = .004, respectively) and correlated with ESR, CRP, ASDAS-ESR, ASDAS-CRP, BASDAI, and BASFI in nr-axSpA (p = .003, p = .002, p < .001, p < .001, p = .010, p = .007, respectively). Multivariate analysis showed that PINP exhibited a positive correlation independent of the MRI inflammatory score and that age exhibited a negative correlation independent of the MRI inflammatory score. CONCLUSIONS: In AS, PINP and age independently correlated with active inflammation on SIJ MRI. PINP may be useful as a marker of objective inflammation in AS.

Identification of circular RNAs hsa_circ_0140271 in peripheral blood mononuclear cells as a novel diagnostic biomarker for female rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease, which commonly affects women. Accumulating evidence shows that differentially expressed circular RNAs (circRNAs) play crucial roles in the progress of RA. However, the roles of circRNAs in female RA remains unclear. This study explores potential role and diagnostic value of hsa_circ_0140271 from peripheral blood mononuclear cells (PBMC) in female RA. METHODS: Differential expression of circRNAs was determined by RNA-sequencing in PBMC from 4 healthy controls (HC) and 4 RA patients, and we further measured the level of hsa_circ_0140271 in a validation cohort consisting of 47 RA and 47 HC via RT-qPCR. Besides, correlation studies with clinical variables were also examined. What's more, we performed bioinformatics analysis to predict the potential role of hsa_circ_0140271. RESULTS: PBMC expression of hsa_circ_0140271 of female RA was significantly higher than that of female HC, and it was positively correlated with antistreptolysin (ASO). Furthermore, the receiver operating characteristic (ROC) curve indicated that hsa_circ_0140271 could distinguish female RA from female HC and female patients with ankylosing spondylitis (AS) or osteoarthritis (OA). Besides, the combined diagnosis anti-cyclic citrullinated peptide (Anti-CCP) + hsa_circ_0140271 could improve diagnostic accuracy with an area under the curve (AUC) of 0.818 to compared with Anti-CCP. Furthermore, KEGG pathway enrichment analysis indicated hsa_circ_0140271 may act as microRNA sponge and participate in fatty acid metabolism pathways. CONCLUSION: Hsa_circ_0140271 was likely to be used as a promising diagnostic biomarker for female RA; it may act as microRNA sponge to regulate fatty acid metabolism pathways in RA.

Comprehensive expression profiles of CircRNAs, LncRNAs, and mRNAs in PBMCs from patients with the ossification of the posterior longitudinal ligament

Ossification of the posterior longitudinal ligament (OPLL), one of spinal disease causing myelopathy, is characterized by the ectopic ossification and narrowing of the spinal cord. However, the pathogenesis of OPLL is largely unclear. In this study, transcriptome expression profiles (circRNAs, lncRNAs, and mRNAs) were identified via high-throughput sequencing using peripheral blood mononuclear cells (PBMCs) from OPLL and non-OPLL patients. We found that 1150 mRNAs, 331 circRNAs, and 1429 lncRNAs were significantly differentially expressed in the PBMCs of OPLL patients. GO and KEGG enrichment analyses revealed that most mRNAs were associated with inflammation. The co-expression networks indicated that circRNAs and lncRNAs could regulate the mRNAs through influencing the inflammation of OPLL. The circRNA-miRNA-mRNA integrated network showed that circRNA-regulated mRNAs associated with TGF-ß and TNF-α signaling pathways. These analyses indicate that circRNAs, lncRNAs, and mRNAs from PBMCs might contribute to inflammation in OPLL.

Diagnostic and therapeutic values of PMEPA1 and its correlation with tumor immunity in pan-cancer.

AIMS: The prostate transmembrane protein, androgen induced 1 (PMEPA1) is differentially expressed in pan-cancer. However, PMEPA1 specific role in cancers has not been fully clarified. This study aims to explore the potential role of Pmepa1 in pan-cancer and specific cancer, with a view to deepening the research on the pathological mechanism of cancer. MAIN METHODS: The Perl language and R language were used to identify the correlation between PMEPA1 expression level and clinical indicators, prognosis values, tumor microenvironment, immune cells' infiltration, immune checkpoint genes, TMB and MSI. The Therapeutic Target Database was used for identifying potential therapeutic drugs that target the pathways that are significantly affected by PMEPA1 expression. KEY FINDINGS: PMEPA1 differential expression significantly correlated with patients' age, race, tumors' stage and status. PMEPA1 high expression was closely correlated with poor prognosis in many cancer types, excluding prostate adenocarcinoma. PMEPA1 expression was closely related to tumor cells and the immune microenvironment in stromal and immune cells' level, immune cells' infiltration, immune checkpoint genes, tumor mutational burden and microsatellite instability. We also found that the activity of the olfactory transduction pathway was closely related to PMEPA1 expression. In pan-cancer, Trifluoperazine and Halofantrine have the potential to reduce PMEPA1 expression. SIGNIFICANCE: This study integrated existing data to explore PMEPA1 potential function in cancers, provided insights for the future cancer-related studies.

Clock knockdown attenuated reactive oxygen species-mediated senescence of chondrocytes through restoring autophagic flux.

AIMS: Articular cartilage degeneration has been recognized as the primary pathological change in osteoarthritis (OA). Mechanisms that govern the shift from cartilage homeostasis to OA remain unknown. Previous studies have reported that intrinsic circadian clock in chondrocytes could function to optimize cartilage repair/remodeling to optimum times of day, but little is known about its molecular mechanisms. This study attempted to investigate the potential role and mechanism of circadian gene Clock in OA pathology. MATERIALS AND METHODS: The expression of Clock in OA chondrocytes and cartilage was detected by qRT-PCR, western blot and immunohistochemistry. Temporal gene expression changes were analyzed using qRT-PCR in chondrocytes transfected with siClock following dexamethasone synchronization. In addition, the effect of Clock knockdown on senescent phenotypes and autophagic flux was evaluated in chondrocytes treated with siClock or siCntrl. KEY FINDINGS: The expression of Clock was up-regulated in OA cartilage from humans and mouse models. Clock knockdown had no influence on rhythmic expression of the downstream genes in primary chondrocytes. We also found that Clock knockdown elevated antioxidant enzyme activities, diminished reactive oxygen species (ROS) production and attenuated senescence of chondrocytes via restoring autophagic flux. SIGNIFICANCE: Clock knockdown can attenuate ROS-mediated senescence of chondrocytes through restoring autophagic flux in non-circadian manner, providing a potential therapeutic target for OA.

PMEPA1 and NEDD4 control the proton production of osteoclasts by regulating vesicular trafficking.

Osteoclast bone resorption activity is critically regulated to maintain bone homeostasis. Osteoclasts resorb bone by producing protons and acid hydrolase via lysosomal secretion, however, a detailed mechanism remains elusive. PMEPA1 is a vesicular membrane protein, which binds to the NEDD4 family member of ubiquitin ligases. We have previously reported that Pmepa1 is highly expressed in bone resorbing osteoclasts, and regulates bone resorption. Here, we investigated the mechanism of bone resorption regulated by PMEPA1. Mutant mice lacking NEDD4-binding domains of PMEPA1 displayed enhanced bone volume, and reduced bone resorption activity in comparison with those of WT mice. Analysis with pH-sensitive fluorescence probe revealed that proton secretion from osteoclasts significantly decreased in Pmepa1 mutant osteoclasts. Immunofluorescence analysis revealed that PMEPA1 was colocalized with NEDD4, V0A3, and V0D2 subunits of vacuolar ATPase, which regulate the proton production of osteoclasts. In addition, Nedd4 knockdown reduced bone resorption and proton secretion of osteoclasts. Furthermore, Pmepa1 mutation and Nedd4 knockdown altered the cytoplasmic distribution of components of V-ATPase and expression of autophagy-related proteins, suggesting that lysosomal secretion is affected. Collectively, these findings indicate that PMEPA1 controls proton secretion from osteoclasts via NEDD4 by regulating vesicular trafficking, and NEDD4 is an important regulator of bone resorption.

Gene Expression Profiling Analysis to Identify Key Genes and Underlying Mechanisms in Meniscus of Osteoarthritis Patients.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease that seriously affects the quality of life of elderly. Regrettably, the pathological mechanism for OA has not yet been fully elucidated. METHODS: This study is committed to distinguishing key genes and the underlying mechanisms for OA. Raw data was acquired from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs), hub genes, and key genes through bioinformatics analysis. Subsequently, we predicted the microRNAs (miRNAs) and circular RNAs (circRNAs) associated with these key genes that may play key roles in OA using web tools. We also constructed a protein- drug network and found potentially effective drugs by analyzing the relationships between the drugs and the key genes. RESULTS: The analysis revealed 360 DEGs, 24 hub genes, and 15 key genes enriched in many categories potentially related to the pathological mechanism of OA. hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p were predicted to be important miRNAs for OA, while hsa_circ_0025119, hsa_circ_0025113, hsa_circ_0009897, and hsa_circ_0002447 were predicted to be the most important circRNAs. Further studies indicated that Ocriplasmin and Collagenase clostridium histolyticum may be effective drugs for the treatment of OA. Finally, CD34 and VWF were inferred to be the most meaningful biomarkers for OA. CONCLUSION: In conclusion, we determined the underlying key genes, miRNAs, and circRNAs for OA, predicted potentially effective drugs, and identified the most meaningful biomarkers for the disease. Our findings may provide insight into the pathological mechanism of OA and guide future research.

Relationship between body mass index and the risk of periprosthetic joint infection after primary total hip arthroplasty and total knee arthroplasty.

BACKGROUND: Periprosthetic joint infection (PJI) is a disastrous complication after total hip arthroplasty (THA) and total knee arthroplasty (TKA). The relationship between body mass index (BMI) and the incidence of PJI remains controversial. To better understand the impact of increasing BMI on PJI, we conducted this study to investigate the dose-response relationship between BMI and the risk of PJI after primary THA or TKA. METHODS: A systematic search was conducted in PubMed, Embase, and Cochrane Library databases from inception to August 17, 2019. After study selection and data extraction, a dose-response meta-analysis was performed to investigate the relationship between BMI and PJI. Adjusted relative risks (RRs) with 95% confidence intervals (CIs) were pooled using fixed-effects or random-effects models. RESULTS: Eleven studies comprising 505,303 arthroplasties were included. The dose-response analysis showed a significant non-linear relationship between BMI and the risk of PJI (Pnon-linearity <0.001). Patients following THA (RR, 1.489; 95% CI, 1.343-1.651; P<0.001) were more likely to suffer from PJI than patients following TKA. Furthermore, American Society of Anesthesiologists (ASA) score ≥3 (RR, 2.287; 95% CI, 1.650-3.170; P<0.001), lung disease (RR, 1.484; 95% CI, 1.208-1.823; P<0.001) and diabetes (RR, 1.695; 95% CI, 1.071-2.685; P=0.024) were identified as risk factors for PJI, but male (RR, 1.649; 95% CI, 0.987-2.755; P=0.056) and hypertension (RR, 0.980; 95% CI, 0.502-1.916; P=0.954) were not recognized as risk factors for PJI. CONCLUSIONS: The J-shaped non-linear relationship demonstrated that increased BMI was associated with an increased risk for PJI after primary THA or TKA. Patients following THA were more likely to suffer from PJI than patients following TKA. Also, patients with ASA score ≥3, lung disease and diabetes have a higher risk of PJI. Gender and hypertension did not influence the incidence of PJI.

Incidence and risk factors of joint stiffness after Anterior Cruciate Ligament reconstruction.

BACKGROUND: Joint stiffness is a common complication after anterior cruciate ligament (ACL) reconstruction, which seriously affects the efficacy of the operation and patient satisfaction. After ACL reconstruction, the identification of joint stiffness' risk factors can help its prevention. This meta-analysis was conducted to evaluate joint stiffness' risk factors and incidence after ACL reconstruction and provide guidance on its prevention. METHODS: PubMed, Embase, and Cochrane Library were searched to obtain relevant studies. The odds ratios (ORs) with 95% confidence intervals (CIs) for all potential risk factors were analyzed using fixed or random-effects meta-analysis in RevMan 5.2. RESULTS: In total, there were 37 studies and 113,740 patients that were included in this study. After ACL reconstruction, joint stiffness' incidence negatively correlated with the studies publication time (R = -0.62, P = 0.0094). After ACL reconstruction, the joint stiffness overall pooled incidence was 3% (95% CI, 3-4%). Gender (OR, 0.51; 95% CI, 0.38-0.68; P < 0.00001) was identified as a risk factor. Potential risk factors, such as trauma to surgery time interval, graft type, and concomitant surgery with meniscus injury, have no significant correlation with joint stiffness after ACL reconstruction. CONCLUSION: This study indicated that joint stiffness' incidence after ACL reconstruction is 3% and that gender is a risk factor for joint stiffness after ACL reconstruction.