Fluid shear stress-mediated Piezo1 alleviates osteocyte apoptosis by activating the PI3K/Akt pathway.

Glucocorticoid-induced osteoporosis serves as a primary cause for secondary osteoporosis and fragility fractures, representing the most prevalent adverse reaction associated with prolonged glucocorticoid use. In this study, to elucidate the impact and underlying mechanisms of fluid shear stress (FSS)-mediated Piezo1 on dexamethasone (Dex)-induced apoptosis, we respectively applied Dex treatment for 6 h, FSS at 9 dyne/cm2 for 30 min, Yoda1 treatment for 2 h, and Piezo1 siRNA transfection to intervene in MLO-Y4 osteocytes. Western blot analysis was used to assess the expression of Cleaved Caspase-3, Bax, Bcl-2, and proteins associated with the PI3K/Akt pathway. Additionally, qRT-PCR was utilized to quantify the mRNA expression levels of these molecules. Hoechst 33258 staining and flow cytometry were utilized to evaluate the apoptosis levels. The results indicate that FSS at 9 dyne/cm2 for 30 min significantly upregulates Piezo1 in osteocytes. Following Dex-induced apoptosis, the phosphorylation levels of PI3K and Akt are markedly suppressed. FSS-mediated Piezo1 exerts a protective effect against Dex-induced apoptosis by activating the PI3K/Akt pathway. Additionally, downregulating the expression of Piezo1 in osteocytes using siRNA exacerbates Dex-induced apoptosis. To further demonstrate the role of the PI3K/Akt signaling pathway, after intervention with the PI3K pathway inhibitor, the activation of the PI3K/Akt pathway by FSS-mediated Piezo1 in osteocytes was significantly inhibited, reversing the anti-apoptotic effect. This study indicates that under FSS, Piezo1 in MLO-Y4 osteocytes is significantly upregulated, providing protection against Dex-induced apoptosis through the activation of the PI3K/Akt pathway.

Tissue engineering strategies hold promise for the repair of articular cartilage injury.

Articular cartilage damage and wear can result in cartilage degeneration, ultimately culminating in osteoarthritis. Current surgical interventions offer limited capacity for cartilage tissue regeneration and offer only temporary alleviation of symptoms. Tissue engineering strategies are increasingly recognized as promising modalities for cartilage restoration. Currently, various biological scaffolds utilizing tissue engineering materials are extensively employed in both fundamental and clinical investigations of cartilage repair. In order to optimize the cartilage repair ability of tissue engineering scaffolds, researchers not only optimize the structure and properties of scaffolds from the perspective of materials science and manufacturing technology to enhance their histocompatibility, but also adopt strategies such as loading cells, cytokines, and drugs to promote cartilage formation. This review provides an overview of contemporary tissue engineering strategies employed in cartilage repair, as well as a synthesis of existing preclinical and clinical research. Furthermore, the obstacles faced in the translation of tissue engineering strategies to clinical practice are discussed, offering valuable guidance for researchers seeking to address these challenges.

Artificial Intelligence Aids Detection of Rotator Cuff Pathology: A Systematic Review.

PURPOSE: To determine the model performance of artificial intelligence (AI) in detecting rotator cuff pathology using different imaging modalities and to compare capability with physicians in clinical scenarios. METHODS: The review followed the PRISMA guidelines and was registered on PROSPERO. The criteria were as follows: 1) studies on the application of AI in detecting rotator cuff pathology using medical images, and 2) studies on smart devices for assisting in diagnosis were excluded. The following data were extracted and recorded: statistical characteristics, input features, AI algorithms used, sample sizes of training and testing sets, and model performance. The data extracted from the included studies were narratively reviewed. RESULTS: A total of 14 articles, comprising 23,119 patients, met the inclusion and exclusion criteria. The pooled mean age of the patients was 56.7 years, and the female rate was 56.1%. The area under the curve (AUC) of the algorithmic model to detect rotator cuff pathology from ultrasound images, MRI images, and radiographic series ranged from 0.789 to 0.950, 0.844 to 0.943, and 0.820 to 0.830, respectively. Notably, 1 of the studies reported that AI models based on ultrasound images demonstrated a diagnostic performance similar to that of radiologists. Another comparative study demonstrated that AI models using MRI images exhibited greater accuracy and specificity compared to orthopedic surgeons in the diagnosis of rotator cuff pathology, albeit not in sensitivity. CONCLUSIONS: The detection of rotator cuff pathology has been significantly aided by the exceptional performance of AI models. In particular, these models are equally adept as musculoskeletal radiologists in using ultrasound to diagnose rotator cuff pathology. Furthermore, AI models exhibit statistically superior levels of accuracy and specificity when using MRI to diagnose rotator cuff pathology, albeit with no marked difference in sensitivity, in comparison to orthopaedic surgeons. LEVEL OF EVIDENCE: Level III, systematic review of Level III studies.

Machine-Learning Models Reliably Predict Clinical Outcomes in Medial Patellofemoral Ligament Reconstruction.

PURPOSE: To develop a machine-learning model to predict clinical outcomes after medial patellofemoral ligament reconstruction (MPFLR) and identify the important predictive indicators. METHODS: This study included patients who underwent MPFLR from January 2018 to December 2022. The exclusion criteria were as follows: (1) concurrent bony procedures, (2) history of other knee surgeries, and (3) follow-up period of less than 12 months. Forty-two predictive models were constructed for 7 clinical outcomes (failure to achieve minimum clinically important difference of clinical scores, return to preinjury sports, pivoting sports, and recurrent instability) using 6 machine-learning algorithms (random forest, logistic regression, support vector machine, decision tree, implemented multilayer perceptron, and K-nearest neighbor). The performance of the model was evaluated using metrics such as the area under the receiver operating characteristic curve, accuracy, specificity, and sensitivity. In addition, SHapley Additive exPlanation summary plot was employed to identify the important predictive factors of the best-performing model. RESULTS: A total of 218 patients met criteria. For the best-performing models in predicting failure to achieve the minimum clinically important difference for Lysholm, International Knee Documentation Committee, Kujala, and Tegner scores, the area under the receiver operating characteristic curves and accuracies were 0.884 (good) and 87.3%, 0.859 (good) and 86.2%, 0.969 (excellent) and 97.0%, and 0.760 (fair) and 76.8%, respectively; 0.952 (excellent) and 95.2% for return to preinjury sports; 0.756 (fair) and 75.4% for return to pivoting sports; and 0.943 (excellent) and 94.9% for recurrent instability. Low preoperative Tegner score, shorter time to surgery, and absence of severe trochlear dysplasia were significant predictors for return to preinjury sports, whereas the absence of severe trochlear dysplasia and patellar alta were significant predictors for return to pivoting sports. Older age, female sex, and low preoperative Lysholm score were highly predictive of recurrent instability. CONCLUSIONS: The predictive models developed using machine-learning algorithms can reliably forecast the clinical outcomes of MPFLR, particularly demonstrating excellent performance in predicting recurrent instability. LEVEL OF EVIDENCE: Level III, case-control study.

Decreased sagittal slope of the medial tibial spine and deep concavity of the lateral tibial spine are risk factors for noncontact anterior cruciate ligament injury.

PURPOSE: This study aimed to assess the relationship between the geometric features of tibial eminence and susceptibility to noncontact anterior cruciate ligament (ACL) injuries. METHODS: Patients with unilateral noncontact knee injuries between 2015 and 2021 were consecutively enroled in this study. Based on knee magnetic resonance imaging (MRI) and arthroscopic visualisation, patients were categorised into the case group (ACL rupture) and control group (ACL intact). Using MRI, the geometric features of tibial eminence were characterised by measuring the sagittal slopes, depth of concavity and coronal slopes of the inclined surfaces of the tibial spines. Univariate and multivariate logistic regressions were conducted to explore independent associations between quantified geometric indices of tibial eminence and the risk of noncontact ACL injuries. RESULTS: This study included 187 cases and 199 controls. A decreased sagittal slope of the medial tibial spine (MTSSS) (combined group: odds ratio [OR]: 0.87 [0.82, 0.92], p < 0.001; females: OR: 0.88 [0.80, 0.98], p = 0.020; males: OR: 0.87 [0.81, 0.93], p < 0.001) and an increased depth of concavity in the lateral tibial spine (LTSD) (combined group: OR: 1.51 [1.24, 1.85], p < 0.001; females: OR: 1.65 [1.12, 2.43], p = 0.012; males: OR: 1.44 [1.11, 1.89], p = 0.007) were independent risk factors for noncontact ACL injuries. Moreover, a steeper coronal slope of the inclined surface of the medial tibial spine was a significant predictor of noncontact ACL injuries for males (MTSCS: OR: 1.04 [1.01, 1.08], p = 0.015) but not for females. CONCLUSION: Geometric features of tibial eminence, particularly a decreased MTSSS and an increased LTSD, were identified as independent risk factors for noncontact ACL injuries. These findings will help clinicians identify individuals at high risk of ACL injury and facilitate the development of targeted prevention strategies. LEVEL OF EVIDENCE: Level III.

Metabolic associated fatty liver disease and bone mineral density: a cross-sectional study of the National Health and Nutrition Examination Survey 2017-2018.

This research is a cross-sectional study based on the participants aged 50 years and older from National Health and Nutrition Examination Survey (NHANES) database. The metabolic associated fatty liver disease (MAFLD) population has higher BMD and a lower risk of osteoporosis than those without MAFLD. INTRODUCTION: MAFLD is a new definition presented by panel of experts based on non-alcoholic fatty liver disease in 2020. However, the link between MAFLD and bone mineral density (BMD) is uncertain. Thus, the present study aimed to investigate the relationship between MAFLD and BMD. METHODS: This cross-sectional study included subjects aged ≥ 50 years from the National Health and Nutrition Examination Survey 2017-2018. Multivariate linear regression models were performed to investigate the association between MAFLD and BMD. Moreover, the relationship between MAFLD and osteoporosis was assessed using multiple logistic regression models. RESULTS: Finally, 817 participants (non-MAFLD, n = 436; MAFLD, n = 381) were included in the final analysis. The results demonstrated that participants with MAFLD showed higher femoral BMDs than those without MAFLD, especially among males aged ≥ 50 years and females aged ≥ 65 years. Moreover, the results showed that obese men (BMI ≥ 30 kg/m2) with MAFLD had higher femoral BMDs than the control group according to subgroup analyses stratified by BMI, but this trend was not present in women. In addition, multiple logistic regression models showed that participants with MAFLD had no increased risks of osteoporosis. CONCLUSION: The present study found that the MAFLD population has higher BMD and a lower risk of osteoporosis than those without MAFLD. Because the present study was a cross-sectional study, we could not identify the cause-effect relation between MAFLD and BMD. Therefore, additional research needs to be performed to explore the influences of MAFLD on bone metabolism in the future.

Radiographic OA, bone marrow lesions, higher body mass index and medial meniscal root tears are significantly associated with medial meniscus extrusion with OA or medial meniscal tears: a systematic review and meta-analysis.

PURPOSE: Medial meniscus extrusion (MME) refers to the protrusion of the medial meniscus beyond the tibial edge by more than 3 mm, leading to a deficiency of the hoop strain. MME commonly occurs in conjunction with osteoarthritis (OA) or medial meniscal tears (MMT). However, factors associated with concomitant MME in patients with OA or MMT have not been systematically reviewed. This study aims to perform a systematic review and meta-analysis to identify factors associated with concomitant MME in OA or MMT. METHODS: The systematic review of the literature was performed according to PRISMA. A literature search was conducted in 4 databases. All original human studies that reported the available evidence on factors associated with concomitant MME in patients with OA or MMT were included. Pooled binary variables were analyzed by odds ratios (OR) and 95% CIs, and pooled continuous variables were evaluated by mean difference (MD) and 95% CIs. RESULTS: Ten studies on OA (5993 patients) and eight studies on MMT (872 patients) met the inclusion criteria. The overall pooled incidence of MME was 43% (95% CI, 37-50%) for OA, 61% (95% CI 43-77%) for MMT, and 85% (95% CI 72-94%) for medial meniscal root tears (MMRT). For the population with OA, Factors significantly associated with MME included radiographic OA [OR 4.24; 95% CI 3.07-5.84; P < 0.0001], bone marrow lesions [OR, 3.35; 95% CI 1.61-6.99; P = 0.0013], cartilage damage [OR, 3.25; 95% CI 1.60-6.61; P = 0.0011], and higher body mass index (BMI) [MD, 1.81; 95% CI 1.15-2.48; P < 0.0001]. Factors strongly associated with increased risk of MME for MMT included medial meniscal root [OR, 8.39; 95% CI 2.84-24.82; P < 0.0001] and radial tears [OR, 2.64; 95% CI 1.18-5.92; P < 0.0001]. CONCLUSION: Radiographic OA, bone marrow lesions, cartilage damage, and higher BMI were significantly associated with concomitant MME with OA. Furthermore, medial meniscal root and radial tears were significantly associated with an increased risk of MME in patients with MMT. LEVEL OF EVIDENCE: IV.

The tibial tunnel drilling angles of 60° provided a lower ultimate load to failure on a single bundle posterior cruciate ligament graft using interference screw fixation compared to 30°/45°.

PURPOSE: To biomechanically compare the initial fixation strength of grafts among three tibial tunnel angles (30°/45°/60°) in transtibial posterior cruciate ligament (PCL) reconstruction. METHODS: A series of transtibial PCL reconstruction models were established with porcine tibias and bovine tendons. Specimens were randomly assigned to three groups according to the angles between the tibial tunnel and the perpendicular line of the tibial shaft: Group A (30°, n = 12), Group B (45°, n = 12), and Group C (60°, n = 12). The area of the tunnel entrance, the segmental bone mineral density (sBMD) of the graft fixation site of the tibia and the maximum insertion torque of the interference screw were measured. Finally, load to failure tests were carried out on the graft-screw-tibia constructs at the same rate. RESULTS: Ultimate load to failure in Group C (335.2 ± 107.5 N) was significantly lower than that in Group A (584.1 ± 127.9 N, P < 0.01) and Group B (521.9 ± 95.9 N, P < 0.01). There were no significant differences between biomechanical properties of Groups A and B (n.s.). The posterior part fractures of the tibial tunnel exit occurred in eight specimens of Group C. In addition, the ultimate load was proven to be related to insertion torque (rho = 0.7, P < 0.01), sBMD (rho = 0.7, P < 0.01), and the area of the tunnel entrance (rho =- 0.4, P = 0.01). CONCLUSION: The ultimate load to failure was significantly lower in tibial PCL interference screw fixation for tunnels drilled at 60° compared to 30°/45°. In addition, the ultimate load was significantly correlated with insertion torque, sBMD and the area of the tunnel entrance. Given that the load to failure of distal fixation may not be sufficient for early postoperative rehabilitation, a 60° tunnel should not be recommended to drill in tibia during PCL reconstruction.

Description of surgical treatment methods of hip and knee periprosthetic joint infections in the Chinese mainland: a national multi-centre survey.

PURPOSE: Periprosthetic joint infection (PJI) is a serious hip and knee arthroplasty complication. Despite the increased incidence of primary joint replacements, there is no clear guideline for treating PJI in the Chinese mainland yet. We aim to measure the current situation and basis for surgical treatment methods of PJI in major orthopaedic hospitals in the Chinese mainland. METHODS: We conducted a national survey on PJI treatment in Mainland China. Forty-one top arthroplasty centers were included, with 82.9% (34/41) response rate. The data were analyzed using Microsoft Excel version 20.0 and described as numbers and percentages. RESULTS: For acute infections, prosthesis-preserving procedures (DAIR) are used in all centres. For hip and knee PJI, 20.5% (7/34) and 35% (12/34) of the centres used a one-stage exchange. If applied, this treatment will necessitate the previous patients' selection for a satisfactory outcome. All centres execute the two-stage exchange. Between phases, the majority of centres implant a cemented spacer. Revisions for infected hips included 21 (4.3%) cases of DAIR, 95 (19.9%) cases of single-stage exchange, 362 (75.2%) cases of two-stage exchange, and 2 (0.007%) cases of hip dissection. Revisions for infected knee comprised 88 (19.0%) cases of DAIR, 48 (10.3%) cases of single-stage exchange, 324 (69.8%) cases of two-stage exchange, and 5 (0.02%) cases of knee fusion. CONCLUSIONS: The centers do not have a uniform PJI standard. Most patients have two-stage revision with a cemented spacer in China. These concepts can help establish treatment guidelines.

Fluid shear stress-induced down-regulation of microRNA-140-5p promotes osteoblast proliferation by targeting VEGFA via the ERK5 pathway.

PURPOSE: Fluid shear stress (FSS) plays a critical role in osteoblast proliferation. However, the role of miRNA in osteoblast proliferation induced by FSS and the possible molecular mechanisms remain to be defined. The aim of the present study was to investigate whether miR-140-5p regulates osteoblast proliferation under FSS and its molecular mechanism. MATERIALS AND METHODS: miR-140-5p expression was measured by qRT-PCR. Western blot was used to measure the expressions of P-ERK1/2, ERK1/2, P-ERK5 and ERK5. The levels of VEGFA, PCNA, CDK4 and Cyclin D1 were identified through qRT-PCR and western blot, respectively. Cell proliferation was detected by CCK-8 assay and EdU labeling assay. Dual-luciferase reporter assay was used to validate the target of miR-140-5p. RESULTS: miR-140-5p was significantly down-regulated when MC3T3-E1 cells were exposed to FSS. We then confirmed that up-regulation of miR-140-5p inhibited and down-regulation of miR-140-5p promoted osteoblast proliferation. In addition, FSS promotes osteoblast proliferation via down-regulating miR-140-5p. Luciferase reporter assay demonstrated that VEGFA is a direct target of miR-140-5p. Furthermore, transfection of mimic-140-5p inhibited the up-regulation of VEGFA protein level induced by FSS, suggesting that FSS regulates VEGFA protein expression via miR-140-5p. Further investigations demonstrated that VEGFA could promote osteoblast proliferation. Lastly, we demonstrated that miR-140-5p regulates osteoblast proliferation and ERK5 activation through VEGFA. CONCLUSIONS: Our study demonstrates that FSS-induced the down-regulation of miR-140-5p promotes osteoblast proliferation through activing VEGFA/ERK5 signaling pathway. These findings may provide a novel mechanism of FSS-induced osteoblast proliferation and offer a new avenue to further investigate osteogenesis induced by mechanical loading.

The association between body fat distribution and bone mineral density: evidence from the US population.

OBJECTIVE: To investigate the association between different body fat distribution and different sites of BMD in male and female populations. METHODS: Use the National Health and Nutrition Examination Survey (NHANES) datasets to select participants. The weighted linear regression model investigated the difference in body fat and Bone Mineral Density (BMD) in different gender. Multivariate adjusted smoothing curve-fitting and multiple linear regression models were used to explore whether an association existed between body fat distribution and BMD. Last, a subgroup analysis was performed according to age and gender group. RESULTS: Overall, 2881 participants were included in this study. Compared to males, female participants had lower BMD (P < 0.05) and higher Gynoid fat mass (P < 0.00001), while there was no difference between Android fat mass (P = 0.91). Android fat mass was positively associated with Total femur BMD (Males, ß = 0.044, 95% CI = 0.037, 0.051, P < 0.00001; Females, ß = 0.044, 95% CI = 0.039, 0.049, P < 0.00001), Femoral neck BMD (Males, ß = 0.034, 95% CI = 0.027, 0.041, P < 0.00001; Females, ß = 0.032, 95% CI = 0.027, 0.037, P < 0.00001), and Total spine BMD (Males, ß = 0.036, 95% CI = 0.029, 0.044, P < 0.00001; Females, ß = 0.025, 95% CI = 0.019, 0.031, P < 0.00001). The Gynoid fat mass, subgroup analysis of age and ethnicity reached similar results. CONCLUSION: Body fat in different regions was positively associated with BMD in different sites, and this association persisted in subgroup analyses across age and race in different gender.

Nocturnal sleep duration and bone mineral density: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES) 2007-2014.

BACKGROUND: This study aimed to investigate the association between sleep duration and bone mineral density (BMD) and determine whether vitamin D (VD) status influenced the association between sleep duration and BMD. METHODS: National Health and Nutrition Examination Survey 2007-2014 participants aged ≥ 40 years were included in this study. BMD testing was conducted with dual-energy X-ray absorptiometry examinations. Moreover, all individuals were divided into four groups according to self-reported nocturnal sleep duration (7-8 h; 6 h; < 6 h; and > 8 h). In addition, the differences in BMD between the normal sleep duration group and other groups were calculated using multiple linear regression models. RESULTS: Overall, the median age of the overall study population was 55.00 years old, with 46.97% of men distributed. Participants sleeping > 8 h/night had lower BMDs than those sleeping 7-8 h/night. Moreover, the association between unhealthy sleep duration (especially > 8 h/night) and low BMD was more pronounced in older individuals, men, postmenopausal women, and subjects with inadequate VD intakes (< 15.00 µg/day) or deficient/insufficient serum 25-hydroxyvitamin D (< 75.00 nmol/L). CONCLUSIONS: In conclusion, unhealthy sleep duration, especially long sleep duration, was associated with decreased BMD, particularly among individuals aged > 60 years, men, or postmenopausal women. Moreover, VD status might influence the association between sleep duration and BMD, especially in the context of inadequate VD intake or deficient/insufficient serum 25-hydroxyvitamin D levels. However, given the limitations of the present study, further investigation is warranted to confirm this association and to explore potential mechanisms.

What Is the Maximum Tibial Tunnel Angle for Transtibial PCL Reconstruction? A Comparison Based on Virtual Radiographs, CT Images, and 3D Knee Models.

BACKGROUND: To minimize the killer turn caused by the sharp margin of the tibial tunnel exit in transtibial PCL reconstruction, surgeons tend to maximize the angle of the tibial tunnel in relation to the tibial plateau. However, to date, no consensus has been reached regarding the maximum angle for the PCL tibial tunnel. QUESTIONS/PURPOSES: In this study we sought (1) to determine the maximum tibial tunnel angle for the anteromedial and anterolateral approaches in transtibial PCL reconstruction; (2) to compare the differences in the maximum angle based on three measurement methods: virtual radiographs, CT images, and three-dimensional (3D) knee models; and (3) to conduct a correlation analysis to determine whether patient anthropomorphic factors (age, sex, height, and BMI) are associated with the maximum tibial tunnel angle. METHODS: Between January 2018 and December 2020, 625 patients who underwent CT scanning for knee injuries were retrospectively reviewed in our institution. Inclusion criteria were patients 18 to 60 years of age with a Kellgren-Lawrence grade of knee osteoarthritis less than 1 and CT images that clearly showed the PCL tibial attachment. Exclusion criteria were patients with a history of tibial plateau fracture, PCL injuries, tumor, and deformity around the knee. Finally, 104 patients (43 males and 61 females, median age: 38 [range 24 to 56] years, height: 165 ± 9 cm, median BMI: 23 kg/cm2 [range 17 to 31]) were included for analysis. CT data were used to create virtual 3D knee models, and virtual true lateral knee radiographs were obtained by rotating the 3D knee models. Virtual 3D knee models were used as an in vitro standard method to assess the true maximum tibial tunnel angle of anteromedial and anterolateral approaches in transtibial PCL reconstruction. The tibial tunnel's entry was placed 1.5 cm anteromedial and anterolateral to the tibial tubercle for the two approaches. To obtain the maximum angle, a 10-mm- diameter tibial tunnel was simulated by making the tibial tunnel near the posterior tibial cortex. The maximum tibial tunnel angle, tibial tunnel lengths, and perpendicular distances of the tunnel's entry point to the tibial plateau were measured on virtual radiographs, CT images, and virtual 3D knee models. One-way ANOVA was used to compare the differences in the maximum angle among groups, and correlation analysis was performed to identify the relationship of the maximum angle and anthropomorphic factors (age, sex, height, and BMI). RESULTS: The maximum angle of the PCL tibial tunnel relative to the tibial plateau was greater in the anteromedial group than the anterolateral group (58° ± 8° versus 50° ± 8°, mean difference 8° [95% CI 6° to 10°]; p < 0.001). The maximum angle of the PCL tibial tunnel was greater in the virtual radiograph group than the CT image (68° ± 6° versus 49° ± 5°, mean difference 19° [95% CI 17° to 21°]; p < 0.001), the anteromedial approach (68° ± 6° versus 58° ± 8°, mean difference 10° [95% CI 8° to 12°]; p < 0.001), and the anterolateral approach (68° ± 6° versus 50° ± 8°, mean difference 18° [95% CI 16° to 20°]; p < 0.001), but no difference was found between the CT image and the anterolateral groups (49° ± 5° versus 50° ± 8°, mean difference -1° [95% CI -4° to 1°]; p = 0.79). We found no patient anthropomorphic characteristics (age, sex, height, and BMI) that were associated with the maximum angle. CONCLUSION: Surgeons should note that the mean maximum angle of the tibial tunnel relative to the tibial plateau was greater in the anteromedial than anterolateral approach in PCL reconstruction, and the maximum angle might be overestimated on virtual radiographs and underestimated on CT images. CLINICAL RELEVANCE: To perform PCL reconstruction more safely, the findings of this study suggest that the PCL drill system should be set differently for the anteromedial and anterolateral approaches, and the maximum angle measured by intraoperative fluoroscopy should be reduced 10° for the anteromedial approach and 18° for the anterolateral approach. Future clinical or cadaveric studies are needed to validate our findings.

Increased Posterior Tibial Slope and Meniscal Slope Could Be Risk Factors for Meniscal Injuries: A Systematic Review.

PURPOSE: The purpose of this systematic review was to summarize the available evidence and examine the relation between the posterior tibial slope (PTS) and meniscal slope (MS) and the incidence of meniscal injury. METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to February 23, 2021. Cohort studies investigating the association between PTS or MS and the risk of meniscal injury were included. Two authors independently conducted the literature search, data extraction, and quality assessment. RESULTS: Sixteen studies with a total of 2,670 patients were included. For meniscal injury with an anterior cruciate ligament tear, the lateral PTS in the lateral meniscal root tear group (range, 8.0°-12.6°) was significantly higher than that in the control group (range, 4.0°-10.7°). Furthermore, there appeared to be a relation between a greater medial MS and the presence of a ramp lesion (range, 2.6°-6.7° for ramp lesion vs 2.0°-5.1° for control). For degenerative meniscal injury, the medial PTS in the medial meniscal posterior root tear group (range, 6.15°-10.4°) was significantly greater than that in the control group (range, 4.0°-9.8°). CONCLUSIONS: On the basis of the available evidence, for meniscal injury with an anterior cruciate ligament tear, an increased lateral PTS was associated with a higher risk of lateral meniscal tears and lateral meniscal posterior root tears. Furthermore, there appeared to be a relation between an increased medial MS and a higher risk of ramp lesions. For degenerative meniscal injury, most of the included studies showed that a larger medial PTS could increase the risk of medial meniscal tears and medial meniscal posterior root tears. LEVEL OF EVIDENCE: Level III, systematic review of Level III studies.

Age, male sex, higher posterior tibial slope, deep sulcus sign, bone bruises on the lateral femoral condyle, and concomitant medial meniscal tears are risk factors for lateral meniscal posterior root tears: a systematic review and meta-analysis.

PURPOSE: Lateral meniscus posterior root tears (LMPRTs) are commonly found in patients with anterior cruciate ligament (ACL) injuries. However, risk factors for LMPRTs are not well known. This study was designed to systematically review the available evidence regarding risk factors associated with LMPRTs. METHODS: The PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for papers containing the key words "lateral meniscus posterior root tears", "LMPRTs" and "risk factor". Inclusion screening, data extraction, and quality assessment of the included articles were conducted independently by two authors. Statistical analysis was conducted to determine risk factors for LMPRTs. RESULT: Seventeen studies with a total sample size of 6, 589 patients were identified. The pooled prevalence of LMPRTs was 9.6% (range, 5.1-33.8%) for ACL injury. Significant risk factors included a patient age of < 30 [OR = 1.4, 95% CI (1.07, 1.84), p = 0.01], male sex [OR = 1.50, 95% CI (1.24,1.81), p = 0.01], higher body mass index (BMI) [MD = 0.45, 95% CI (0.13, 0.76), p < 0.01], higher lateral posterior tibial slope (LPTS) [MD = 2.22, 95% CI (1.37, 3.07), p < 0.01], deep sulcus sign [OR = 5.76, 95% CI (1.35, 24.52), p < 0.01] and bone bruises on lateral femoral condyle [OR = 4.88, 95% CI (1.27, 18.77), p < 0.01], lateral meniscal extrusion > 1 mm [OR = 5.56, 95% CI (1.52, 20.29), p < 0.01] and > 3 mm [OR = 12.91 95% CI (1.28, 130.01), p < 0.01], medial meniscal tears [OR = 1.40, 95% CI (1.12, 1.75), p < 0.01], and medial ramp lesions [OR = 2.29, 95% CI (1.35, 3.89), p < 0.01]. CONCLUSION: Age below 30, male, higher BMI, higher LPTS, deep sulcus sign, bone bruises on lateral femoral condyle, lateral meniscal extrusion, medial meniscal tear, and medial ramp lesion are risk factors for LMPRTs. LEVEL OF EVIDENCE: Level IV.

An increased posterior tibial slope is associated with a higher risk of graft failure following ACL reconstruction: a systematic review.

PURPOSE: The posterior tibial slope (PTS) is considered a risk factor for anterior cruciate ligament (ACL) injury. However, the influence of PTS on graft failure following ACL reconstruction remains relatively unknown. Therefore, this systematic review was conducted to investigate whether PTS could be a potential risk factor for graft failure after ACL reconstruction. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database, and Wanfang Database were comprehensively searched from inception to March 31, 2021. Observational studies reporting the associations of medial tibial plateau slope (MTPS) or lateral tibial plateau slope (LTPS) with graft failure after ACL reconstruction were evaluated. RESULTS: Twenty studies involving 12 case-control studies, 4 retrospective studies and 4 cross-sectional studies including 5326 patients met the final inclusion criteria. The high heterogeneity and the characteristics of nonrandomized controlled trials limited data synthesis. Fifteen of the 20 included studies detected a significant association between increased PTS and ACL graft failure, while 5 studies concluded that increased PTS was not associated with ACL graft failure. Ten studies suggested that MTPS is associated with ACL graft failure, and six studies suggested that LTPS is associated with ACL graft failure. The mean MTPS values for nonfailure group ranged from 3.5° ± 2.5° to 14.4° ± 2.8°. For the graft failure group, MTPS ranged from 4.71° ± 2.41° to 17.2° ± 2.2°. The mean LTPS values for nonfailure group ranged from 2.9° ± 2.1° to 11.9° ± 3.0°. For the graft failure group, LTPS ranged from 5.5° ± 3.0° to 13.3° ± 3.0°. The reported PTS values that caused ACL graft failure was greater than 7.4° to 17°. CONCLUSION: Based on the current clinical evidence, increased PTS is associated with a higher risk of ACL graft failure after ACL reconstruction. Despite various methods of measuring PTS have high reliability, there is still vast disagreement in the actual value of PTS. LEVEL OF EVIDENCE: IV.

Fluid shear stress regulates osteoblast proliferation and apoptosis via the lncRNA TUG1/miR-34a/FGFR1 axis.

LncRNAs and microRNAs play critical roles in osteoblast differentiation and bone formation. However, their exact roles in osteoblasts under fluid shear stress (FSS) and the possible mechanisms remain unclear. The aim of this study was to explore whether and how miR-34a regulates osteoblast proliferation and apoptosis under FSS. In this study, FSS down-regulated miR-34a levels of MC3T3-E1 cells. MiR-34a up-regulation attenuated FSS-induced promotion of proliferation and suppression of apoptosis. Luciferase reporter assay revealed that miR-34a directly targeted FGFR1. Moreover, miR-34a regulated osteoblast proliferation and apoptosis via FGFR1. Further, we validated that lncRNA TUG1 acted as a competing endogenous RNA (ceRNA) to interact with miR-34a and up-regulate FGFR1 protein expression. Furthermore, lncRNA TUG1 could promote proliferation and inhibit apoptosis. Taken together, our study revealed the key role of the lncRNA TUG1/miR-34a/FGFR1 axis in FSS-regulated osteoblast proliferation and apoptosis and may provide potential therapeutic targets for osteoporosis.

The mechanosensory and mechanotransductive processes mediated by ion channels and the impact on bone metabolism: A systematic review.

Mechanical environments were associated with alterations in bone metabolism. Ion channels present on bone cells are indispensable for bone metabolism and can be directly or indirectly activated by mechanical stimulation. This review aimed to discuss the literature reporting the mechanical regulatory effects of ion channels on bone cells and bone tissue. An electronic search was conducted in PubMed, Embase and Web of Science. Studies about mechanically induced alteration of bone cells and bone tissue by ion channels were included. Ion channels including TRP family channels, Ca2+ release-activated Ca2+ channels (CRACs), Piezo1/2 channels, purinergic receptors, NMDA receptors, voltage-sensitive calcium channels (VSCCs), TREK2 potassium channels, calcium- and voltage-dependent big conductance potassium (BKCa) channels, small conductance, calcium-activated potassium (SKCa) channels and epithelial sodium channels (ENaCs) present on bone cells and bone tissue participate in the mechanical regulation of bone development in addition to contributing to direct or indirect mechanotransduction such as altered membrane potential and ionic flux. Physiological (beneficial) mechanical stimulation could induce the anabolism of bone cells and bone tissue through ion channels, but abnormal (harmful) mechanical stimulation could also induce the catabolism of bone cells and bone tissue through ion channels. Functional expression of ion channels is vital for the mechanotransduction of bone cells. Mechanical activation (opening) of ion channels triggers ion influx and induces the activation of intracellular modulators that can influence bone metabolism. Therefore, mechanosensitive ion channels provide new insights into therapeutic targets for the treatment of bone-related diseases such as osteopenia and aseptic implant loosening.

ERK5 negatively regulates Kruppel-like factor 4 and promotes osteogenic lineage cell proliferation in response to MEK5 overexpression or fluid shear stress.

Aim of the study: Fluid shear stress (FSS) plays a critical role in osteoblast proliferation via extracellular signal-regulated kinase 5 (ERK5). Kruppel-like factor 4 (KLF4) knockout robustly enhances bone formation due to increased osteoblast differentiation and mineralization. However, the effect of KLF4 on osteoblast proliferation is unresolved. Therefore, the aim of our study was to investigate the effect of KLF4 on osteogenic lineage cell proliferation and the relationship between KLF4 and ERK5. Materials and methods: MC3T3-E1 cells were treated with FSS and/or KLF4 siRNA, cell viability was accessed by Edu labeling and CCK-8 assay, and proliferative gene expression were assessed by PCR array. Bone marrow stromal cells (BMSCs) were infected with adenovirus expressing KLF4 and/or constitutively active MEK5, cell viability was evaluated using crystal violet staining, colony formation assay, and cell WST1 assay. The levels of KLF4 and ERK5 phosphorylation were identified through qRT-PCR and western blot, respectively. Results: KLF4 expression was significantly down-regulated by FSS exposure, however, this was reversed by ERK5 siRNA. KLF4 overexpression inhibited colony formation efficiency and cell viability in BMSCs. Adenoviruses expressing constitutively active MEK5 increased ERK5 phosphorylation, which inhibited KLF4 expression, and promoted BMSC proliferation. FSS-induced osteoblast proliferation also involved elevation of Cyclin B2 and Cdc14b as well as repressed expression of P27. Conclusions: KLF4 negatively regulates osteogenic lineage cell proliferation, and ERK5 negatively regulates KLF4 expression and promotes osteogenic lineage cell proliferation.

High-density Lipoprotein Cholesterol Is Negatively Correlated with Bone Mineral Density and Has Potential Predictive Value for Bone Loss.

BACKGROUND: Many studies have shown that lipids play important roles in bone metabolism. However, the association between high-density lipoprotein cholesterol (HDL-C) and bone mineral density (BMD) is unclear. Therefore, this study aimed to investigate the linear or nonlinear relation between HDL-C levels and BMD and addressed whether the HDL-C levels had the potential values for predicting the risk of osteoporosis or osteopenia. METHODS: Two researchers independently extracted all information from the National Health and Nutrition Examination Survey (NHANES) database. Participants over 20 years of age with available HDL-C and BMD data were enrolled in the final analysis. The linear relationship between HDL-C levels and BMD was assessed using multivariate linear regression models. Moreover, the nonlinear relationship was also characterized by fitted smoothing curves and generalized additive models. In addition, the odds ratio (OR) for osteopenia and osteoporosis was evaluated with multiple logistic regression models. RESULTS: The weighted multivariable linear regression models demonstrated that HDL-C levels displayed an inverse association with BMD, especially among females and subjects aged 30 to 39 or 50 to 59. Moreover, the nonlinear relationship characterized by smooth curve fittings and generalized additive models suggested that (i) HDL-C levels displayed an inverted U-shaped relationship with BMD among women 30 to 39 or over 60 years of age; (ii) HDL-C levels exhibited a U-shaped association with BMD among women 20 to 29 or 50 to 59 years of age. In addition, females with high HDL levels (62-139 mg/dL) had an increased risk of osteopenia or osteoporosis. CONCLUSION: This study demonstrated that HDL-C levels exhibit an inverse correlation with BMD. Especially in females, clinicians need to be alert to patients with high HDL-C levels, which may indicate an increased risk of osteoporosis or osteopenia. For these patients, close monitoring of BMD and early intervention may be necessary.