Transcriptomic analyses and machine-learning methods reveal dysregulated key genes and potential pathogenesis in human osteoarthritic cartilage.

Aims: This study aimed to explore the biological and clinical importance of dysregulated key genes in osteoarthritis (OA) patients at the cartilage level to find potential biomarkers and targets for diagnosing and treating OA. Methods: Six sets of gene expression profiles were obtained from the Gene Expression Omnibus database. Differential expression analysis, weighted gene coexpression network analysis (WGCNA), and multiple machine-learning algorithms were used to screen crucial genes in osteoarthritic cartilage, and genome enrichment and functional annotation analyses were used to decipher the related categories of gene function. Single-sample gene set enrichment analysis was performed to analyze immune cell infiltration. Correlation analysis was used to explore the relationship among the hub genes and immune cells, as well as markers related to articular cartilage degradation and bone mineralization. Results: A total of 46 genes were obtained from the intersection of significantly upregulated genes in osteoarthritic cartilage and the key module genes screened by WGCNA. Functional annotation analysis revealed that these genes were closely related to pathological responses associated with OA, such as inflammation and immunity. Four key dysregulated genes (cartilage acidic protein 1 (CRTAC1), iodothyronine deiodinase 2 (DIO2), angiopoietin-related protein 2 (ANGPTL2), and MAGE family member D1 (MAGED1)) were identified after using machine-learning algorithms. These genes had high diagnostic value in both the training cohort and external validation cohort (receiver operating characteristic > 0.8). The upregulated expression of these hub genes in osteoarthritic cartilage signified higher levels of immune infiltration as well as the expression of metalloproteinases and mineralization markers, suggesting harmful biological alterations and indicating that these hub genes play an important role in the pathogenesis of OA. A competing endogenous RNA network was constructed to reveal the underlying post-transcriptional regulatory mechanisms. Conclusion: The current study explores and validates a dysregulated key gene set in osteoarthritic cartilage that is capable of accurately diagnosing OA and characterizing the biological alterations in osteoarthritic cartilage; this may become a promising indicator in clinical decision-making. This study indicates that dysregulated key genes play an important role in the development and progression of OA, and may be potential therapeutic targets.

Risk factors for postoperative surgical site infections after anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

OBJECTIVES: The primary aim was to evaluate risk factors for surgical site infections after anterior cruciate ligament reconstruction (ACLR). The secondary aim was to investigate the surgical site infection incidence rate and the mean time to postoperative surgical site infection symptoms. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase and Web of Science were searched from database inception to September 2021 and updated in April 2022. ELIGIBILITY CRITERIA: Quantitative, original studies reporting potential risk factors for surgical site infections after ACLR were included. RESULTS: Twenty-three studies with 3871 infection events from 469 441 ACLRs met the inclusion criteria. Male sex (OR 1.78, p< 0.00001), obesity (OR 1.82, p=0.0005), tobacco use (OR 1.37, p=0.01), diabetes mellitus (OR 3.40, p=0.002), steroid use history (OR 4.80, p<0.00001), previous knee surgery history (OR 3.63, p=0.02), professional athlete (OR 4.56, p=0.02), revision surgery (OR 2.05, p=0.04), hamstring autografts (OR 2.83, p<0.00001), concomitant lateral extra-articular tenodesis (OR 3.92, p=0.0001) and a long operating time (weighted mean difference 8.12, p=0.005) were identified as factors that increased the risk of surgical site infections (superficial and deep) after ACLR. Age, outpatient or inpatient surgery, bone-patellar tendon-bone autografts or allografts and a concomitant meniscus suture did not increase the risk of surgical site infections. The incidence of surgical site infections after ACLR was approximately 1% (95% CI 0.7% to 1.2%). The mean time from surgery to the onset of surgical site infection symptoms was approximately 17.1 days (95% CI 13.2 to 21.0 days). CONCLUSION: Male sex, obesity, tobacco use, diabetes mellitus, steroid use history, previous knee surgery history, professional athletes, revision surgery, hamstring autografts, concomitant lateral extra-articular tenodesis and a long operation time may increase the risk of surgical site infections after ACLR. Although the risk of surgical site infections after ACLR is low, raising awareness and implementing effective preventions for risk factors are priorities for clinicians to reduce the incidence of surgical site infections due to its seriousness.

Risk Factors for Revision or Rerupture After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: The rerupture or need for revision after anterior cruciate ligament reconstruction (ACLR) is a serious complication. Preventive strategies that target the early identification of risk factors are important to reduce the incidence of additional surgery. PURPOSE: To perform a systematic review and meta-analysis to investigate risk factors for revision or rerupture after ACLR. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: Literature searches were performed in PubMed, Embase, and Web of Science from database inception to November 2021 and updated in January 2022. Quantitative, original studies reporting potential adjusted risk factors were included. Odds ratios (ORs) were calculated for potential risk factors. RESULTS: A total of 71 studies across 13 countries with a total sample size of 629,120 met the inclusion criteria. Fifteen factors were associated with an increase in the risk of revision or rerupture after ACLR: male sex (OR, 1.27; 95% CI, 1.14-1.41), younger age (OR, 1.07; 95% CI, 1.05-1.08), lower body mass index (BMI) (OR, 1.03; 95% CI, 1.00-1.06), family history (OR, 2.47; 95% CI, 1.50-4.08), White race (OR, 1.32; 95% CI, 1.08-1.60), higher posterolateral tibial slope (OR, 1.15; 95% CI, 1.05-1.26), preoperative high-grade anterior knee laxity (OR, 2.30; 95% CI, 1.46-3.64), higher baseline Marx activity level (OR, 1.07; 95% CI, 1.02-1.13), return to a high activity level/sport (OR, 2.03; 95% CI, 1.15-3.57), an ACLR within less than a year after injury (OR, 2.05; 95% CI, 1.81-2.32), a concomitant medial collateral ligament (MCL) injury (OR, 1.62; 95% CI, 1.31-2.00), an anteromedial portal or transportal technique (OR, 1.36; 95% CI, 1.22-1.51), hamstring tendon (HT) autografts (vs bone-patellar tendon-bone [BPTB] autografts) (OR, 1.60; 95% CI, 1.40-1.82), allografts (OR, 2.63; 95% CI, 1.65-4.19), and smaller graft diameter (OR, 1.21; 95% CI, 1.05-1.38). The other factors failed to show an association with an increased risk of revision or rerupture after ACLR. CONCLUSION: Male sex, younger age, lower BMI, family history, White race, higher posterolateral tibial slope, preoperative high-grade anterior knee laxity, higher baseline Marx activity level, return to a high activity level/sport, an ACLR within less than a year from injury, a concomitant MCL injury, an anteromedial portal or transportal technique, HT autografts (vs BPTB autografts), allografts, and smaller graft diameter may increase the risk of revision or rerupture after ACLR. Raising awareness and implementing effective preventions/interventions for risk factors are priorities for clinical practitioners to reduce the incidence of revision or rerupture after ACLR.

Does anti-nerve growth factor monoclonal antibody treatment have the potential to replace nonsteroidal anti-inflammatory drugs and opioids in treating hip or knee osteoarthritis? A systematic review of randomized controlled trials.

Purpose: Considering the adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids for treating osteoarthritis (OA), development of drugs that are more effective and better tolerated than existing treatments is urgently needed. This systematic review aimed to evaluate the efficacy and safety of anti-nerve growth factor (NGF) monoclonal antibodies vs active comparator therapy, such as NSAIDs and oxycodone, in treating hip or knee OA. Methods: Databases were comprehensively searched for randomized controlled trials (RCTs) published before January 2022. Efficacy and safety outcomes were assessed. Results: Six RCTs that included 4325 patients were identified. Almost all the RCTs indicated that moderate doses of anti-NGF monoclonal antibody treatment significantly improved efficacy outcomes based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, the WOMAC physical function score and the Patient's Global Assessment compared with those of the active comparator. At least half of the RCTs indicated that the incidence of severe adverse events, withdrawals due to adverse events (AEs) and total joint replacement were not significantly different between anti-NGF monoclonal antibody treatment and active comparator therapy, but the outcomes of some studies may have been limited by a short duration of follow-up. Most RCTs suggested that anti-NGF monoclonal antibody treatment had a lower incidence of gastrointestinal and cardiovascular AEs. However, the majority of RCTs reported a higher incidence of abnormal peripheral sensation with anti-NGF monoclonal antibody treatment. Furthermore, the higher incidence of rapidly progressive osteoarthritis (RPOA) with anti-NGF monoclonal antibody treatment should also not be overlooked, and the identification of patient characteristics that increase the risk of RPOA is critical in further studies. Conclusion: Based on the current research evidence, anti-NGF monoclonal antibodies are not yet a replacement for analgesic drugs such as NSAIDs but might be a new treatment option for hip or knee OA patients who are intolerant or unresponsive to nonopioid or opioid treatment. Notably, however, considering the inconsistency and inconclusive evidence on the safety outcomes of recent studies, more research is needed, and long-term follow-up is required.

Comparisons of the Efficacy and Safety of Total Knee Arthroplasty by Different Surgical Approaches: A Systematic Review and Network Meta-analysis.

The purpose of this network meta-analysis was to investigate the efficacy and safety of total knee arthroplasty (TKA) considering seven different surgical approaches. Four databases (PubMed, Cochrane Library, EMBASE, Web of Science) were searched for clinical randomized controlled trials (RCTs) involving TKA with different surgical approaches. STATA 14.0 was used to construct network maps and publication bias graphs and conduct inconsistency tests, network meta-analyses, and surface under the cumulative ranking (SUCRA) calculations. A total of 51 RCTs involving 4061 patients and 4179 knees from 18 countries were included. Among the seven surgical approaches, the midvastus approach (MV) was the top choice to reduce tourniquet use time, the subvastus approach (SV) had the shortest operation time, the mini-midvastus approach (Mini-SV) was associated with the least amount of time to achieve straight leg raise (SLR) after surgery, the mini-medial parapatellar approach (Mini-MP) reduced postoperative pain effects, and the medial parapatellar approach (MP) was the best approach to improve range of motion (ROM). Excluding the quadriceps-sparing approach (QS), which was not compared, the use of the mini-midvastus (Mini-MV) may shorten the hospital stay. There were no significant differences in blood loss, postoperative complications, American Knee Society Score (AKSS) objective, or AKSS functional between the seven surgical approaches (P > 0.05).

Based on minimal clinically important difference values, a moderate dose of tanezumab may be a better option for treating hip or knee osteoarthritis: a meta-analysis of randomized controlled trials.

BACKGROUND: Tanezumab is a nerve growth factor monoclonal antibody that may regulate pain in hip or knee osteoarthritis (OA). This meta-analysis was performed to evaluate the efficacy and safety of low and moderate doses of tanezumab in treating hip or knee OA. METHODS: PubMed, EMBASE, the Cochrane Library, and Web of Science were comprehensively searched for clinical trials published before 1 May 2021. Patients were assessed via efficacy and safety outcomes. RESULTS: Twelve randomized controlled trials including 6022 patients were identified. Both low and moderate doses of tanezumab significantly improved efficacy outcomes. However, only the point estimates (mean difference, MD) of moderate-dose tanezumab significantly exceeded the minimal clinically important differences (MCIDs). There were no significant differences in the incidence of treatment-related adverse events (AEs), withdrawals due to AEs, serious AEs, and total joint replacement between the tanezumab and placebo groups, whereas the incidence of AEs was higher in the tanezumab group (relative risk, RR = 1.10; 95% confidence interval, 95% CI = 1.04-1.17). The incidence of rapidly progressive OA was significantly higher in the combined low- and moderate-dose tanezumab groups than in the placebo group (RR = 5.01; 95% CI = 1.17-21.33). Furthermore, both low and moderate doses of tanezumab significantly increased the incidence of abnormal peripheral sensation (RR = 1.99, 95% CI = 1.21-3.28; RR = 2.64, 95% CI = 1.91-3.67, respectively). Compared with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, tanezumab showed significantly improved efficacy outcomes (p < 0.05). However, the point estimates (MD) of tanezumab were not greater than the MCID. Pooled analysis showed no significant differences between tanezumab and NSAIDs and opioids in safety outcomes (p > 0.05). CONCLUSION: Tanezumab is efficacious in patients with hip or knee OA. Tanezumab is relatively well tolerated and safe but increases the incidence of AEs and reversible abnormal peripheral sensation. Additional studies on the occurrence of rapidly progressive OA are needed. A moderate dose of tanezumab may maximize the benefits for hip or knee OA.

Exercise or Dietotherapy Is Not Better than Returning to a Regular Diet to Rebuild Lipid Homeostasis of Rats.

Our aim was to explore the effects of dietary and behavior interventions on lipometabolism caused by an unhealthy high-fat diet and the best method to rebuild lipid homeostasis of this lifestyle. Apart from normal diet rats, 34 rats were fed with high-fat emulsion for 4 weeks and then intervened for another 4 weeks. Eight of them were classified into high-fat control group, and 9 were sorted into high-fat diet with rice vinegar group. Meanwhile, 10 were put into high-fat diet in swimming group, and 7 were just for refeeding normal diet group. Then, the data of body weight was recorded and analyzed. Indexes of serum samples were tested by kits. AMPKα, HNF1α, and CTRP6 in pancreas, liver, cardiac, and epididymis adipose tissues were detected by western blot. According to our experiments, swimming and refeeding groups reflected a better regulation on lipid homeostasis mainly by upregulating the expression of pancreas AMPKα. To be more specific, the refeeding rats showed lower T-CHO (P < 0.001) and LDL-C (P < 0.05), but higher weight gain (P < 0.001), insulin level (P < 0.01), and pancreas AMPKα (P < 0.01) than high-fat control rats. Compared with rats intervened by swimming or rice vinegar, they showed higher weight gain (P < 0.001), insulin level (P < 0.01), and HNF1α, but lower of CTRP6. In summary, refeeding diet functioned better in regulating the lipometabolic level after high-fat diet. Whatever approach mentioned above we adopted to intervene, the best policy to keep the balance of lipid homeostasis is to maintain a healthy diet.

Intra-Articular Injections of Platelet-Rich Plasma, Adipose Mesenchymal Stem Cells, and Bone Marrow Mesenchymal Stem Cells Associated With Better Outcomes Than Hyaluronic Acid and Saline in Knee Osteoarthritis: A Systematic Review and Network Meta-analysis.

PURPOSE: To perform a network meta-analysis to evaluate clinical efficacy and treatment-related adverse events (AEs) of intra-articular hyaluronic acid (HA), leukocyte-poor platelet-rich plasma (LP-PRP), leukocyte-rich platelet-rich plasma (LR-PRP), bone marrow mesenchymal stem cells (BM-MSCs), adipose mesenchymal stem cells (AD-MSCs), and saline (placebo) during 6 and 12 months of follow-up. METHODS: Six databases were searched for randomized controlled trials. Outcome assessment included the visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain subscore, WOMAC score, International Knee Documentation Committee (IKDC) subjective score, and treatment-related AEs. Main inclusion criteria were at least one of the aforementioned outcome measurements, a minimum follow-up period of 5 months, and >80% patient follow-up. Treatments combined with the use of other operations or drugs were excluded. RESULTS: Forty-three studies meeting the eligibility criteria were included. At 6 months, VAS scores and WOMAC pain subscores showed that AD-MSCs were the best treatment option (surface under the cumulative ranking curve [SUCRA] = 96.7%, SUCRA = 85.3%, respectively). According to WOMAC scores and subjective IKDC scores, LP-PRP was the most effective treatment (SUCRA = 86.0%, SUCRA = 80.5%, respectively). At 12 months, only AD-MSCs were associated with improved VAS scores compared with the placebo (weighted mean difference [WMD] = -20.93, 95% credibility interval [CrI], -41.71 to -0.78). Both LP-PRP and AD-MSCs were more beneficial than the placebo for improving WOMAC pain subscores (WMD = -30.08; 95% CrI, -53.59 to -6.25; WMD = -34.85; 95% CrI, -68.03 to -4.86, respectively). For WOMAC scores, LP-PRP and LR-PRP were significantly associated with improved WOMAC scores compared with the placebo after sensitivity analysis was performed (WMD = -35.26; 95% CrI, -64.99 to -6.01; WMD = -38.69; 95% CrI, -76.21 to -2.76). LP-PRP exhibited relatively better efficacy in improving subjective IKDC scores than the placebo (WMD = 13.67; 95% CrI, 4.05-23.39). Regarding safety, all treatments except for LP-PRP (relative risk = 1.83; 95% CrI, 0.89-4.64) increased treatment-related AEs compared with the placebo. CONCLUSIONS: Based on the results of current research findings, during 6 months of follow-up, AD-MSCs relieved pain the best; LP-PRP was most effective for functional improvement. During the 12-month follow-up, both AD-MSCs and LP-PRP showed potential clinical pain relief effects; functional improvement was achieved with LP-PRP. Unfortunately, AD-MSC/LP-PRP functional comparisons were only based on WOMAC scores due to missing IKDC scores. BM-MSCs seem to have potentially beneficial effects, but the wide credibility interval makes it impossible to draw a well-supported conclusion. HA viscosupplementation clinical efficacy was lower than that of biological agents during follow-up, which may be related to the properties of the drugs. Considering the evaluation of treatment-related AEs, LP-PRP is the most advisable choice; although the AEs of these treatments are not serious, they may affect treatment compliance and satisfaction. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II studies.

[Network Meta-analysis of oral Chinese patent medicine in treatment of knee osteoarthritis].

To evaluate the efficacy and safety of Chinese patent medicine in the treatment of knee osteoarthritis(KOA) with network Meta-analysis, and provide evidence-based medicine evidences for clinical practice. PubMed, Cochrane Library, EMbase, CNKI, Wanfang, VIP and CBM were used to search for clinical randomized controlled trials(RCTs) on Chinese patent medicines for treatment of knee osteoarthritis, with a time limit from the establishment of each database to March 2020. The bias risk assessment tool recommended by Cochrane was used to evaluate the quality of the included RCTs. The network Meta-analysis was performed by Stata 14.0 software. A total of 5 788 patients in 58 RCTs were included, involving 9 kinds of Chinese patent medicines. The results of the network Meta-analysis indicated that in terms of total effective rate, the top three optimal medication regimens were Jinwu Gutong Capsules + Amino Acid Glucose(AAG), Xianling Gubao + AAG and Biqi Capsules; the top three interventions to reduce the VAS score were Panlongqi Tablets > Xianling Gubao + AAG > Xianling Gubao + non steroidal anti-inflammatory drugs(NSAIDs); the top three interventions to reduce the total score of WOMAC were Jintiange Capsules+NSAIDs> Jinwu Gutong Capsules + AAG > Biqi Capsules + NSAIDs; the top three medication schemes with better curative effect to reduce Lequesnse index were Xianling Gubao + NSAIDs > Biqi Capsules + NSAIDs > Jintiange Capsules + NSAIDs; the top three interventions to reduce TNF-α level Xianling Gubao + AAG > Jintiange Capsules > Jintiange Capsules + AAG=Jinwu Gutong Capsules + AAG. In terms of safety, the top five interventions with the least adverse reactions were Biqi Capsules > Jinwu Gutong Capsules > Biqi Capsules + NSAIDs > Xianling Gubao + NSAIDs > Jintiange Capsules. The combined application of Chinese patent medicine and NSADIs or AAG can improve the clinical treatment effect and reduce adverse reactions in KOA patients.

The clinical efficacy of leukocyte-poor platelet-rich plasma in arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of platelet-rich plasma (PRP) in the arthroscopic treatment of rotator cuff injury has been reported in the literature. However, conclusions have been inconsistent and more often related to differences in the types of PRP used. Therefore, to minimize these differences, we performed a meta-analysis of only studies investigating leukocyte-poor PRP to evaluate whether PRP promotes and improves the effects of arthroscopic rotator cuff repair. METHODS: A comprehensive search of the PubMed, Embase, and Cochrane Library databases was conducted to evaluate the efficacy of leukocyte-poor PRP in arthroscopic rotator cuff repair. The available data were extracted, and the methodologic quality of the included studies was evaluated by the Cochrane risk-of-bias assessment tool. RESULTS: In total, 10 randomized controlled trials involving 742 patients were included. The results of the meta-analysis showed that treatment with leukocyte-poor PRP performed better than the control treatment in relieving postoperative pain in the short-term (mean difference [MD], -0.57; 95% confidence interval [CI], -0.79 to -0.35; P < .0001) and medium- and long-term (MD, -0.18; 95% CI, -0.34 to -0.03; P = .02) follow-up groups. However, the changes in the MD in the visual analog scale score were below the minimal clinically important difference. Regarding the Constant shoulder (MD, 3.35; 95% CI, 1.68-5.02; P < .0001) and University of California, Los Angeles (MD, 1.73; 95% CI, 0.94-2.52; P < .0001) scores, statistically significant differences were found in favor of leukocyte-poor PRP over the control treatment. However, the changes in the MD in both the Constant and University of California, Los Angeles scores were below the minimal clinically important difference. Moreover, during medium- and long-term follow-up, the retear rate in the leukocyte-poor PRP group was lower than that in the control group regardless of the rotator cuff tear size (small and medium [<3 cm] [risk ratio (RR), 0.64; 95% CI, 0.43-0.97; P = .03] vs. medium and large [>3 cm] [RR, 0.51; 95% CI, 0.34-0.77; P = .001]) and surgical repair method (single-row repair [RR, 0.61; 95% CI, 0.43-0.87; P = .007] vs. double-row suture bridge repair [RR, 0.57; 95% CI, 0.38-0.84; P = .005]). CONCLUSION: According to our study, leukocyte-poor PRP can significantly reduce the postoperative retear rate in the medium and long term regardless of the tear size and the method used for rotator cuff repair. However, the use of leukocyte-poor PRP failed to show clinically meaningful effects in terms of postoperative pain and patient-reported outcomes.

Prevalence of ankylosing spondylitis in a Chinese population: a systematic review and meta-analysis.

Ankylosing spondylitis (AS) is a common inflammatory rheumatic disease that affects the axial skeleton. In this study, we systematically reviewed Chinese AS epidemiological studies from the past 15 years to elucidate its prevalence and provide scientific data for China's health care system. AS epidemiological research in China was summarized by conducting a literature review. A review and statistical analysis of the literature on the epidemiology of AS in mainland China published from May 2005 to May 2019 were performed via a meta-analysis. We calculated the prevalence of AS and analysed differences by sex, region, and population source using STATA12.0 software. Eleven papers including 122,558 subjects from mainland China were included. Over the past 15 years, the total prevalence of AS in mainland China was 0.29% (95% CI 0.22-0.35%), ranging from 0.42% (95% CI 0.31-0.52%) in males to 0.15% (95% CI 0.13-0.18%) in females; the difference in the prevalence of AS by sex was statistically significant (P < 0.001). The prevalence of AS in both southern and northern China was 0.31% (95% CI 0.21-0.42% and 0.21-0.40%, respectively), with no significant difference noted (P = 0.816 > 0.005). The prevalence of AS in Chinese military populations was 0.27% (95% CI 0.09-0.45%), and in community populations, it was 0.29% (95% CI 0.23-0.35%). There was no statistically significant difference in the prevalence of AS by sampling resource (P = 0.115 > 0.005). The prevalence of AS in China was 0.29% and continues to increase. Sex differences in its prevalence were identified; the prevalence rate was 2.8 times higher in males than in females. Epidemiologists in China should formulate precise scientific investigations to provide additional authoritative epidemiological data for the prevention and treatment of AS.

Does Routine Anti-Osteoporosis Medication Lower the Risk of Fractures in Male Subjects? An Updated Systematic Review With Meta-Analysis of Clinical Trials.

Background: Several epidemiological articles have reported the correlations between anti-osteoporosis medication and the risks of fractures in male and female subjects, but the specific efficacy of anti-osteoporosis medication for male subjects remains largely unexplored. Objective: The aim of this study was to evaluate the correlation between anti-osteoporosis medication and the risk of fracture in relation to low bone mass [including outcomes of osteoporosis, fracture, and bone mineral density (BMD) loss] in male subjects analyzed in studies within the updated literature. Methods: Randomized controlled trials (RCTs) that analyzed the effectiveness of a treating prescription for male subjects with osteoporosis (or low BMD) and that focused on the outcomes of fracture were included. Relevant studies from Embase, Web of Science, PubMed, and Chinese database of CNKI were retrieved from inception to January 30th, 2019. Two staff members carried out the eligibility assessment and data extraction. The discrepancies were settled by consultation with another researcher. We calculated the pooled relative risks (RRs) based on 95% confidence intervals (CIs). Results: Twenty-seven documents (28 studies) with 5,678 subjects were identified. For the category of bisphosphonates, significant results were observed in pooled analyses for decreased risk of the vertebral fracture domain (RR, 0.44 [95% CI, 0.31-0.62]), nonvertebral fracture domain (RR, 0.63 [95% CI, 0.46-0.87]), and clinical fracture domain (RR, 0.59 [95% CI, 0.48-0.72]) compared with those of controls. Participants with bisphosphonates had a 56% (95% CI = 38-69%) lower risk of vertebral fractures, 37% (95% CI = 13-54%) lower risk of nonvertebral fractures, and 41% (95% CI = 28-52%) lower risk of clinical fractures. Furthermore, meta-analyses also demonstrated a decreased risk of the vertebral fracture domain via treatment with risedronate (RR, 0.45 [95% CI, 0.28-0.72]) and alendronate (RR, 0.41 [95% CI, 0.23-0.74]), but not with calcitriol, calcitonin, denosumab, ibandronate, monofluorophosphate, strontium ranelate, teriparatide, or zoledronic acid, compared with that of controls. Conclusions: This systematic review confirms that bisphosphonates were connected with a decreased risk of vertebral fractures, nonvertebral fractures, and clinical fractures for male subjects with osteoporosis. Future research is needed to further elucidate the role of nonbisphosphonates in treating fractures of osteoporosis subjects.

Can increasing the prevalence of vegetable-based diets lower the risk of osteoporosis in postmenopausal subjects? A systematic review with meta-analysis of the literature.

OBJECTIVES: Several epidemiological investigations have assessed the association between vegetable-based diet intake (VDI) and risk of osteoporosis in postmenopausal subjects (OPS), but the outcomes have been inconsistent. We performed a review of the updated literature to evaluate this correlation. METHODS: We searched for relevant studies published in September 2018 or earlier. Two researchers conducted eligibility assessment and data extraction. Discrepancies were resolved through consultation with a third expert. Pooled odds ratios (ORs) were calculated with 95% confidence intervals (CIs). RESULTS: Ten studies, which included 14,247 subjects, were identified. On comparing the highest category of VDI consumption with the lowest category of VDI consumption, the pooled OR for OPS was 0.73 (95% CI = 0.57-0.95), i.e., participants with a higher intake of vegetables had a 27% (95% CI = 5-43%) lower risk of OPS. Significant benefits were found on subgroup analyses of case-control studies (OR, 0.61 [95% CI, 0.48-0.78]), but not on subgroup analyses of cross-sectional studies (OR, 0.82 [95% CI, 0.57-1.16]). The synthesized effect estimates were in the direction of decreased risk of OPS on subgroup analyses of the femoral region (OR, 0.57, 95% CI = 0.41-0.80) and the lumbar spine (OR = 0.55, 95% CI = 0.38-0.81), but not on subgroup analyses of the calcaneus (OR = 0.85, 95% CI = 0.33-2.16) and the lumbar and/or femoral region (OR = 1.04, 95%CI = 0.79-1.38). Positive results were observed on pooled analyses of the Dual energy X-ray absorptiometry (DEXA) measurement method (OR, 0.72 [95% CI, 0.54-0.95]), but not on pooled analyses of the Standardized Quantitative Ultrasound (QUS) measurement method (OR, 0.85 [95% CI, 0.33-2.16]). This might have resulted from a type II error due to wide confidence intervals and less number of included studies. CONCLUSION: This meta-analysis seemingly confirms that higher consumption of VDI was associated with a lower risk of OPS. Taken together, these results highlight the need for future high-quality design-based trials on quantified vegetable intake and OPS.

Can Dietary Intake of Vitamin C-Oriented Foods Reduce the Risk of Osteoporosis, Fracture, and BMD Loss? Systematic Review With Meta-Analyses of Recent Studies.

Background: Several epidemiological studies have been performed to evaluate the association of dietary intake of vitamin C-oriented foods (DIVCF) with risk of fracture and bone mineral density (BMD) loss, but the results remain controversial. Therefore, we conducted a systematic meta-analysis to assess this correlation. Methods: We searched EmBase, PubMed, Web of Science, and the Chinese database CNKI for relevant articles published up to August 2019. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the random- or fixed-effects model. Discrepancies were resolved by consultation with a third expert. Results: A total of 13 eligible articles (including 17 studies) with 19,484 subjects were identified for the present meta-analysis. The pooled RR of hip fracture for the highest vs. lowest category was 0.66 (95% CI, 0.47-0.94) for DIVCF, i.e., people with a greater frequency of Vitamin C uptake had a 34% (95% CI, 6%-53%) lower prevalence of hip fracture. In subgroup analyses stratified by study design, gender, and age, the negative associations were statistically significant. Furthermore, the statistical analysis of the association between DIVCF and risk of osteoporosis (RR, 0.66; 95% CI, 0.48-0.92), BMD at the lumbar spine (pooled r, 0.15; 95% CI, 0.09-0.23), and BMD at the femoral neck (pooled r, 0.20; 95% CI, 0.11-0.34) showed beneficial effects of DIVCF. Conclusion: Our meta-analysis indicates that DIVCF is negatively associated with the risk of hip fracture, osteoporosis, and BMD loss, suggesting that DIVCF decreases the risk of hip fracture, osteoporosis, and BMD loss.

Integrated physiologic, genomic and transcriptomic strategies involving the adaptation of allotetraploid rapeseed to nitrogen limitation.

BACKGROUND: Nitrogen (N) is a macronutrient that is essential for optimal plant growth and seed yield. Allotetraploid rapeseed (AnAnCnCn, 2n = 4x = 38) has a higher requirement for N fertilizers whereas exhibiting a lower N use efficiency (NUE) than cereal crops. N limitation adaptation (NLA) is pivotal for enhancing crop NUE and reducing N fertilizer use in yield production. Therefore, revealing the genetic and molecular mechanisms underlying NLA is urgent for the genetic improvement of NUE in rapeseed and other crop species with complex genomes. RESULTS: In this study, we integrated physiologic, genomic and transcriptomic analyses to comprehensively characterize the adaptive strategies of oilseed rape to N limitation stresses. Under N limitations, we detected accumulated anthocyanin, reduced nitrate (NO3-) and total N concentrations, and enhanced glutamine synthetase activity in the N-starved rapeseed plants. High-throughput transcriptomics revealed that the pathways associated with N metabolism and carbon fixation were highly over-represented. The expression of the genes that were involved in efficient N uptake, translocation, remobilization and assimilation was significantly altered. Genome-wide identification and molecular characterization of the microR827-NLA1-NRT1.7 regulatory circuit indicated the crucial role of the ubiquitin-mediated post-translational pathway in the regulation of rapeseed NLA. Transcriptional analysis of the module genes revealed their significant functional divergence in response to N limitations between allotetraploid rapeseed and the model Arabidopsis. Association analysis in a rapeseed panel comprising 102 genotypes revealed that BnaC5.NLA1 expression was closely correlated with the rapeseed low-N tolerance. CONCLUSIONS: We identified the physiologic and genome-wide transcriptional responses of oilseed rape to N limitation stresses, and characterized the global members of the BnamiR827-BnaNLA1s-BnaNRT1.7s regulatory circuit. The transcriptomics-assisted gene co-expression network analysis accelerates the rapid identification of central members within large gene families of plant species with complex genomes. These findings would enhance our comprehensive understanding of the physiologic responses, genomic adaptation and transcriptomic alterations of oilseed rape to N limitations and provide central gene resources for the genetic improvement of crop NLA and NUE.

Comparison of platelet-rich plasma vs hyaluronic acid injections in patients with knee osteoarthritis: A protocol for a systematic review and meta-analysis.

BACKGROUND: Knee osteoarthritis (KOA) is a progressive joint disease involving intraarticular and periarticular structures. In recent years, there has been increasing interest in the use of autologous growth factors, such as intraarticular injections of platelet-rich plasma (PRP), to treat KOA. It is necessary to update the research and reevaluate the efficacy and safety of PRP to provide up-to-date evidence for KOA management. Therefore, we provide a protocol for a systematic review of PRP for KOA. METHODS: The aim of this study was to retrieve papers on the topic of PRP treatment for KOA in electronic databases including PubMed, Embase, and the Cochrane Library. The search will include studies that were published from the time the databases were established until April 2018. The entire process will include study selection, data extraction, risk of bias assessment, and meta-analyses. RESULTS: The literature will provide a high-quality analysis of the current evidence supporting PRP for KOA based on various comprehensive assessments including the Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale scores, International Knee Documentation Committee scores, Lequesne index scores, and adverse events. CONCLUSION: This proposed systematic review will provide up-to-date evidence to assess the effect of PRP treatment for patients with KOA. PROSPERO REGISTRATION NUMBER: CRD42018108825.

Is the combined application of both drain-clamping and tranexamic acid superior to the single use of either application in patients with total-knee arthroplasty?: A meta-analysis of randomized controlled trials.

BACKGROUND: To compare the efficacy and safety of the combined application of both drain-clamping and tranexamic acid (TXA) versus the single use of either application in patients with total-knee arthroplasty (TKA). METHODS: Databases (EMBASE, PubMed, Cochrane Library, Web of Sciences, the Google database, and the Ovid database) were searched from their inception through April 2018 for randomized controlled trials (RCTs) comparing the combined application of both drain-clamping and TXA versus single use of either application in patients with TKA. The Cochrane risk of bias (ROB) tool was used to assess the methodologic quality. The primary outcomes were blood loss in drainage, total blood loss, transfusion rate, and hemoglobin decline. The secondary outcomes were postoperative complications, the Knee Society Score (KSS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. The statistical analysis was performed with RevMan 5.3.5 software. RESULTS: A total of five RCTs (479 participants) were included in our meta-analysis. The present meta-analysis indicated that significant differences existed in the total blood loss (mean difference [MD] = -145.86, 95% confidence interval [CI]: -228.64 to -63.08, P = .0006), blood loss in drainage (MD = -169.06, 95% CI: -248.56 to -89.57, P < .0001), hemoglobin decline (MD = -0.66, 95% CI: -1.00 to -0.33, P = .0001), and transfusion rate (MD = 0.44, 95% CI: 0.26-0.75, P = .002) between the groups. However, regarding postoperative complications, no significant differences were found between the 2 groups in the KSS and the WOMAC score (P > .05). CONCLUSION: Combined application of both drain-clamping and TXA was associated with significant reductions in blood loss in drainage, total blood loss, hemoglobin decline, and the need for transfusion. However, high-quality, well-designed RCTs with long-term follow-up are still required.

Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK-3ß/ß-catenin signaling.

Osteosarcoma (OS) is the most malignant primary bone tumor in children and adolescents with limited treatment options and poor prognosis. Recently, aberrant expression of Runx2 has been found in OS, thereby contributing to the development, and progression of OS. However, the upstream signaling molecules that regulate its expression in OS remain largely unknown. In the present study, we first confirmed that the inhibition of HSP90 with 17-AAG caused significant apoptosis of OS cells via a caspase-3-dependent mechanism, and that inhibition or knockdown of HSP90 by 17-AAG or siRNAs significantly suppressed mRNA and protein expression of Runx2. Furthermore, we provided evidence that Runx2 was transcriptionally regulated by HSP90 when using MG132 and CHX chase assay. We also demonstrated that ß-catenin was overexpressed in OS tissue, and that knockdown of ß-catenin induced pronounced apoptosis of OS cells in the presence or absence of 17-AAG. Interestingly, this phenomenon was accompanied with a significant reduction of Runx2 and Cyclin D1 expression, indicating an essential role of Runx2/Cyclin D1 in 17-AAG-induced cells apoptosis. Moreover, we demonstrated that the apoptosis of OS cells induced by 17-AAG did require the involvement of the AKT/GSK-3ß/ß-catenin signaling pathway by using pharmacological inhibitor GSK-3ß (LiCl) or siGSK-3ß. Our findings reveal a novel mechanism that Runx2 is transcriptionally regulated by HSP90 via the AKT/GSK-3ß/ß-catenin signaling pathway, and by which leads to apoptosis of OS cells.

Andrographolide Induces Cell Cycle Arrest and Apoptosis of Chondrosarcoma by Targeting TCF-1/SOX9 Axis.

Chondrosarcoma is the second most malignant bone tumor with poor prognosis and limited treatment options. Thus, development of more effective treatments has become urgent. Recently, natural compounds derived from medicinal plants have emerged as promising therapeutic options via targeting multiple key cellular molecules. Andrographolide (Andro) is such a compound, which has previously been shown to induce cell cycle arrest and apoptosis in several human cancers. However, the molecular mechanism through which Andro exerts its anti-cancer effect on chondrosarcoma remains to be elucidated. In the present study, we showed that Andro-induced G2/M cell cycle arrest of chondrosarcoma by fine-tuning the expressions of several cell cycle regulators such as p21, p27, and Cyclins, and that prolonged treatment of cells with Andro caused pronounced cell apoptosis. Remarkably, we found that SOX9 was highly expressed in poor-differentiated chondrosarcoma, and that knockdown of SOX9 suppressed chondrosarcoma cell growth. Further, our results showed that Andro dose-dependently down-regulated SOX9 expression in chondrosarcoma cells. Concomitantly, an inhibition of T cell factor 1 (TCF-1) mRNA expression and an enhancement of TCF-1 protein degradation by Andro were observed. In contrast, the expression and subcellular localization of ß-catenin were not altered upon the treatment of Andro, suggesting that ß-catenin might not function as the primary target of Andro. Additionally, we provided evidence that there was a mutual regulation between TCF-1 and SOX9 in chondrosarcoma cells. In conclusion, these results highlight the potential therapeutic effects of Andro in treatment of chondrosarcoma via targeting the TCF-1/SOX9 axis. J. Cell. Biochem. 118: 4575-4586, 2017. © 2017 Wiley Periodicals, Inc.

The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling.

Chondrosarcoma, the second-most frequent primary bone malignancy, is generally more resistant to conventional chemotherapy and radiotherapy. Therefore, the development of an effective adjuvant therapy is necessary. Recently, targeting the epigenetic regulator such as bromodomain and extraterminal domain (BET) proteins has achieved great success. For instance, the bromodomain inhibitor JQ1 has been shown to inhibit the growth of several cancer cells both in vitro and in vivo. Herein, we demonstrated that JQ1 significantly inhibited chondrosarcoma cell growth and colony formation. JQ1 also induced marked G1-phase cell cycle arrest coincided with the up-regulation of p21WAF1/CIP1 , p27Kip1 , and Cyclin D1 expression, and the down-regulation of Cyclin E2 expression. Moreover, JQ1 induced the premature senescence of SW 1353 cells, and that prolong treatment of JQ1 caused cell apoptosis. Mechanistically, the JQ1-induced cell growth inhibition was correlated with the suppression of c-Myc and Bcl-xL, which are the prime genes for cell cycle control and anti-apoptosis. Furthermore, we demonstrated that p21 negatively regulated the expression of c-Myc and Bcl-xL upon JQ1 treatment, and that the growth inhibition of SW 1353 and Hs 819.T cells and induction of p21 were predominantly regulated by the LATS1/YAP signaling but not through a p53-dependent manner. In conclusion, we disclosed a novel mechanism that JQ1 inhibits cell proliferation, induces cell senescence and apoptosis of chondrosarcoma cells through the regulation of the YAP/p21/c-Myc/Bcl-xL signaling axis. J. Cell. Biochem. 118: 2182-2192, 2017. © 2017 Wiley Periodicals, Inc.