Comparison of the Medium-term Outcomes of Anterior Lumbar Discectomy and Fusion with Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Retrospective Cohort Study.

OBJECTIVE: Lumbar degenerative diseases (LDDs) with huge herniation in the left lateral recess or central canal present challenges for oblique lateral lumbar interbody fusion (OLIF) or endoscope-assisted OLIF procedures. Currently, minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is the primary approach for this issue. This study aims to provide a standardized technical description of the anterior lumbar discectomy and fusion (ALDF) and evaluate the medium-term clinical effectiveness of both ALDF and MIS-TLIF techniques. METHODS: A retrospective review was performed on LDDs who underwent ALDF and MIS-TLIF surgery from January 2018 to January 2020. The evaluation encompassed various clinical outcomes, such as the visual analogue scale (VAS) scores for back pain and leg pain (VAS-back, VAS-leg), the Oswestry disability index (ODI), the 36-item short-form health survey mental component summary (SF-36 MCS), and the physical component summary (SF-36 PCS). Additionally, radiological parameters, including disc height (DH), segmental disk angle (SDA), lumbar lordosis (LL), and cross-sectional area (CSA), were assessed. Data including radiculopathy, estimated blood loss, operation time, time of getting out of bed, fusion rate, and complications were recorded. Student's independent samples t test and Pearson's chi-square test were used to compare the differences between groups. RESULTS: In total, 47 patients were treated by ALDF and 48 patients were treated by MIS-TLIF. The ALDF group exhibited statistically significant lower estimated blood loss and earlier time of getting out of bed compared to the MIS-TLIF group (p < 0.05). The ALDF group demonstrated lower VAS-back scores and a higher remission rate of low back pain 3 years after the surgery (p < 0.05). During the entire follow-up period, the ALDF group exhibited higher increases in DH and SDA compared to the MIS-TLIF group (p < 0.05). At 6 months, the fusion rate in the ALDF group was significantly higher than in the MIS-TLIF group (p < 0.05). The comparison revealed no statistically significant differences in complication rates between the two groups (p > 0.05). CONCLUSION: The ALDF could be considered as a viable surgical alternative for the treatment of LDDs that necessitate ventral neural direct decompression. ALDF exhibited favorable medium-term outcomes in patients with LDDs, displaying advantages in facilitating expedited recovery, enhancing radiographic outcomes, and elevating the remission rate of low back pain. Although ALDF presents slightly higher complication rates compared to MIS-TLIF, it does not adversely affect clinical outcomes.

Endoscopic Arthroplasty via Mini-open Direct Anterior Approach Improves Postoperative Complications and Acetabular Components of Total Hip Arthroplasty in Obese Patients.

To overcome the high-risk complications and poor alignment of acetabular components in obese patients associated with direct anterior approach (DAA) for total hip arthroplasty (THA), we innovated an endoscopic arthroplasty via mini-open direct anterior approach technique (Endo-DAA). The purpose of this study was to compare the clinical and radiographic outcomes in obese patients subjected to THA between Endo-DAA, Bikini DAA, and conventional DAA. In this retrospective controlled study, a total of 360 consecutive primary THA on obese patients (body mass index greater than 28 kg/m2) via Endo-DAA, Bikini DAA, and conventional DAA performed from October 2017 to October 2022 by different surgeons and in a single center were included. Assessments including perioperative parameters, clinical outcomes, complications, and radiologic measurements were retrieved from patients before the surgery, perioperative period and the latest follow-up. A total of 360 consecutive THA (Endo-DAA = 108, Bikini DAA = 116, Conventional DAA = 136) with complete follow-up data were analyzed. Compared to Bikini DAA or conventional DAA, Endo-DAA significantly shortened the length of incision (5.46 ± 0.53), the duration of operation (64.47 ± 12.38), and postoperative hospital stay (2.15 ± 0.89). Endo-DAA significantly reduces wound related complications compared with conventional DAA. Besides, Endo-DAA achieved a significantly better alignment of acetabular components compared to Bikini DAA or conventional DAA. Furthermore, Endo-DAA improved postoperative pain at the activity at 24 h postoperatively and early functional scores. The Endo-DAA THA technique provides better short-term clinical and radiographic results in obese patients with a low rate of postoperative complications compared to Bikini DAA or conventional DAA.

Curcumin suppresses RANKL-induced osteoclast precursor autophagy in osteoclastogenesis by inhibiting RANK signaling and downstream JNK-BCL2-Beclin1 pathway.

BACKGROUND: Curcumin ameliorates bone loss by inhibiting osteoclastogenesis. Curcumin inhibits RANKL-promoted autophagy in osteoclast precursors (OCPs), which mediates its anti-osteoclastogenic effect. But the role of RANKL signaling in curcumin-regulated OCP autophagy is unknown. This study aimed to explore the relationship between curcumin, RANKL signaling, and OCP autophagy during osteoclastogenesis. METHODS: We investigated the role of curcumin in RANKL-related molecular signaling in OCPs, and identified the significance of RANK-TRAF6 signaling in curcumin-treated osteoclastogenesis and OCP autophagy using flow sorting and lentiviral transduction. Tg-hRANKL mice were used to observe the in vivo effects of curcumin on RANKL-regulated bone loss, osteoclastogenesis, and OCP autophagy. The significance of JNK-BCL2-Beclin1 pathway in curcumin-regulated OCP autophagy with RANKL was explored via rescue assays and BCL2 phosphorylation detection. RESULTS: Curcumin inhibited RANKL-related molecular signaling in OCPs, and repressed osteoclast differentiation and autophagy in sorted RANK+ OCPs but did not affect those of RANK- OCPs. Curcumin-inhibited osteoclast differentiation and OCP autophagy were recovered by TRAF6 overexpression. But curcumin lost these effects under TRAF6 knockdown. Furthermore, curcumin prevented the decrease in bone mass and the increase in trabecular osteoclast formation and autophagy in RANK+ OCPs in Tg-hRANKL mice. Additionally, curcumin-inhibited OCP autophagy with RANKL was reversed by JNK activator anisomycin and TAT-Beclin1 overexpressing Beclin1. Curcumin inhibited BCL2 phosphorylation at Ser70 and enhanced protein interaction between BCL2 and Beclin1 in OCPs. CONCLUSIONS: Curcumin suppresses RANKL-promoted OCP autophagy by inhibiting signaling pathway downstream of RANKL, contributing to its anti-osteoclastogenic effect. Moreover, JNK-BCL2-Beclin1 pathway plays an important role in curcumin-regulated OCP autophagy.

Spinal intradural extramedullary tumors: microscopic keyhole resection with the focus on intraoperative neurophysiological monitoring and long-term outcome.

OBJECTIVE: Spinal schwannomas (SS) and spinal meningiomas (SM) account for most intradural extramedullary (IDEM) tumors. These tumors are usually benign lesions, which generally respond favorably to surgical excision. Few studies up to now tried to determine the long-term outcome after minimally invasive surgery (MIS) with multimodal intraoperative neurophysiological monitoring (IONM) for IDEM tumors. The aim of this study was to present one of the largest case series with special regard to IONM findings and long-term outcome after MIS-keyhole surgery with a tubular retractor system. METHODS: Between January 2013 and August 2018, 87 patients with IDEM tumors who underwent tumor removal surgery via MIS-keyhole approach under multimodal IONM were retrospectively reviewed. The neurological status was assessed using a modified McCormick grading scale pre- and postoperatively. Multimodal IONM consisted of motor evoked potentials (MEP), somatosensory evoked potentials (SEP), and electromyography (EMG). Both short-term and long-term clinical evaluations as well as patients' medical files were retrospectively analyzed. RESULTS: Surgeries were performed for resection of SS in 49 patients and SM in 38 patients. Tumor locations were cervical in 16.1%, thoracic in 48.3%, thoracolumbar in 4.6%, lumbar 31%. Critical IONM changes were detected in 9 operations (10.3%) in which there were 2 SEPs, 5 MEPs, and 2 EMG events. Three IONM changes (2 MEPs, 1 EMG) were turned out to be transient change in nature since they were resolved in a short time when immediate corrective actions were initiated. Six patients with permanent IONM changes (2SEPs, 3MEPs, 1EMG event), all deficits had resolved during hospitalization or on short -term follow-up evaluation. Sensitivity, specificity, and positive and negative predicted values of IONM were 100, 96, 67, and 100%, respectively. Gross total resection rate was 100%, and a stable or improved McCormick grade exhibited in all patients. No tumor recurrence and no spinal instability were found in the long-term follow-up evaluation (mean 5.2 ± 2.9 years postoperatively). Overall, 94% of patients were either satisfied or very satisfied with their operation, and 93% patients reported excellent or good general clinical outcome according to Odom's criteria. CONCLUSION: MIS-keyhole surgery with multimodal IONM for IDEM tumors enables a high level of satisfaction and a satisfying long-term clinical and surgical outcome.

Association between serum 25-hydroxyvitamin D and osteoarthritis: A national population-based analysis of NHANES 2001-2018.

Background: Previous studies have not provided a consensus on the effect of serum 25-hydroxyvitamin D [25(OH)D] on osteoarthritis (OA). We aimed to evaluate the association using a large, nationally representative sample. Methods: The cross-sectional data were obtained from the 2001 to 2018 National Health and Nutrition Examination Survey (NHANES). Individuals aged ≥40 years who had information of serum 25(OH)D, self-report OA, and related covariates were included. Multivariable logistic regression analysis was employed to assess the association between serum 25(OH)D and osteoarthritis. Results: Among the 21,334 participants included (weighted mean age, 56.9 years; 48.5% men), the proportion of participants with high serum 25(OH)D concentrations (≥100 nmol/L) increased significantly from 4.2% in 2001-2006 to 18.8% in 2013-2018. Higher serum 25(OH)D levels were associated with more osteoarthritis prevalence in fully adjusted model (odd ratio [OR] 1.25 [95% CI: 1.10, 1.43] for the 50-75 nmol/L group; OR 1.62 [95% CI: 1.42, 1.85] for the 75-100 nmol/L group; OR 1.91 [95% CI: 1.59, 2.30] for the ≥100 nmol/L group; with <50 nmol/L group as the reference) (p < 0.001 for trend). The association was consistent across several sensitivity analyses, including propensity score methods and excluding participants who had received vitamin D supplement. In subgroup analysis, the OR for the association increased significantly with body mass index (BMI) (BMI < 25 kg/m2, 1.01 [95% CI: 1.04, 1.08]; BMI 25-30 kg/m2, 1.05 [95% CI: 1.01, 1.08]; BMI ≥ 30 kg/m2, 1.10 [95% CI: 1.06, 1.13]; p = 0.004 for interaction). Conclusion: There was a positive correlation between serum 25(OH)D and osteoarthritis with a possible modification by BMI. Our finding raises concerns about the potential adverse effects of high serum 25(OH)D on osteoarthritis, particularly among obese individuals. More well-designed studies are still needed to validate our findings in future.

Uncemented Tibial Fixation Has Comparable Prognostic Outcomes and Safety Versus Cemented Fixation in Cruciate-Retaining Total Knee Arthroplasty: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Cemented and uncemented fixation are the primary methods of tibial prosthesis fixation in total knee arthroplasty. However, the optimal fixation method remains controversial. This article explored whether uncemented tibial fixation has better clinical and radiological outcomes, fewer complications, and revision rates compared to cemented tibial fixation. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases up to September 2022 to identify randomized controlled trials (RCTs) that compared uncemented total knee arthroplasty (TKA) and cemented TKA. The outcome assessment consisted of clinical and radiological outcomes, complications (aseptic loosening, infection, and thrombosis), and revision rate. Subgroup analysis was used to explore the effects of different fixation methods on knee scores in younger patients. RESULTS: Nine RCTs were finally analyzed with 686 uncemented knees and 678 cemented knees. The mean follow-up time was 12.6 years. The pooled data revealed significant advantages of uncemented fixations over cemented fixations in terms of the Knee Society Knee Score (KSKS) (p = 0.01) and the Knee Society Score-Pain (KSS-Pain) (p = 0.02). Cemented fixations showed significant advantages in maximum total point motion (MTPM) (p < 0.0001). There was no significant difference between uncemented fixation and cemented fixation regarding functional outcomes, range of motion, complications, and revision rates. When comparing among young people (<65 years), the differences in KSKS became statistically insignificant. No significant difference was shown in aseptic loosening and the revision rate among young patients. CONCLUSIONS: The current evidence shows better knee score, less pain, comparable complications and revision rates for uncemented tibial prosthesis fixation, compared to cemented, in cruciate-retaining total knee arthroplasty.

Hierarchically Injectable Hydrogel Sequentially Delivers AntagomiR-467a-3p-Loaded and AntagomiR-874-5p-Loaded Satellite-Cell-Targeting Bioengineered Extracellular Vesicles Attenuating Sarcopenia.

Sarcopenia is a geriatric disease characterized by reduced muscle function and mass. The capacity to self-renew and myogenesis of satellite cells (SCs) declines with age, resulting in age-related sarcopenia. MicroRNAs (miRNAs) can regulate the proliferation and myogenesis of SCs. In this study, it is identified that miR-467a-3p and miR-874-5p could respectively mediate the stemness and myogenesis of SCs by performing bioinformatics analysis. AntagomiR-467a-3p (ant-467a) and antagomiR-874-5p (ant-874) improve the stemness and myogenesis of SCs, respectively. SC-targeting extracellular vesicles (EVs) are constructed by overexpressing TSG101 on the surface of EVs isolated from bone marrow mesenchymal stem cells. Ant-467a loaded EVs (EVs-467a) and ant-874 loaded EVs (EVs-874) are prepared by transferring ant-467a and ant-874 into SC-targeting EVs. EVs-467a and EVs-874 are more effective than ant-467a and ant-874 in promoting the stemness and myogenesis of SCs. Sequentially intermuscular injection of EVs-467a and EVs-874 significantly improve sarcopenia in ovariectomy mice. The effects of multiple injections of EVs-467a and EVs-874 in the treatment of sarcopenia could be achieved by using a hierarchically injectable hydrogel to sustainedly release EVs-467a and EVs-874 in vivo. The findings provide an EV-based SC-targeting antagomiRNAs controlled release strategy as a novel therapy against sarcopenia.

A novel biologically hierarchical hydrogel with osteoblast precursor-targeting extracellular vesicles ameliorates bone loss in vivo via the sequential action of antagomiR-200b-3p and antagomiR-130b-3p.

Osteoporotic fracture is a major health problem plaguing the ageing society, and improving its treatment is an urgent challenge. How to ameliorate bone loss determines the recovery of such fractures. Extracellular vesicle (EV)-loaded hydrogel has the capacity to treat osteoporotic fractures due to its pro-osteogenic property. And balancing proliferation and maturation of osteoblast precursors (OBPs) is of great significance to avoid OBP depletion, which is lacking in current treatment. Based on osteoblastogenic miRNAs, this study aimed to explore the efficacies of the combination of hierarchical hydrogel and EVs altering functional miRNAs level in bone loss. Through bioinformatics analyses, we screened out proliferative gene-targeting miR-200b-3p and osteogenic gene-targeting miR-130b-3p. And antagomiR-200b-3p (ant-200b) enhanced OBP proliferation, and antagomiR-130b-3p (ant-130b) promoted OBP differentiation. After confirming the directional effect of Fibronectin (Fn1) on OBPs, we prepared OBP-targeting EVs. Furthermore, encapsulation of two antagomiRNAs in EVs enhanced the respective effect of ant-200b and ant-130b. Notably, hierarchically injectable hydrogel exerted an effective function in promoting the sequential delivery of EVs-200b and EVs-130b. Importantly, hierarchical hydrogel containing dual EVs effectively ameliorated bone loss. Overall, hierarchical hydrogel based on two antagomiRNAs effectively improves bone loss in vivo due to its role in promoting OBP proliferation and maturation sequentially.

Inhibiting KCNMA1-AS1 promotes osteogenic differentiation of HBMSCs via miR-1303/cochlin axis.

OBJECTIVE: Osteoporosis is a progressive systemic skeletal disorder. Multiple profiling studies have contributed to characterizing biomarkers and therapeutic targets for osteoporosis. However, due to the limitation of the platform of miRNA sequencing, only a part of miRNA can be sequenced based on one platform. MATERIALS AND METHODS: In this study, we performed miRNA sequencing in osteoporosis bone samples based on a novel platform Illumina Hiseq 2500. Bioinformatics analysis was performed to construct osteoporosis-related competing endogenous RNA (ceRNA) networks. Gene interference and osteogenic induction were used to examine the effect of identified ceRNA networks on osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (HBMSCs). RESULTS: miR-1303 was lowly expressed, while cochlin (COCH) and KCNMA1-AS1 were highly expressed in the osteoporosis subjects. COCH knockdown improved the osteogenic differentiation of HBMSCs. Meanwhile, COCH inhibition compensated for the suppression of osteogenic differentiation of HBMSCs by miR-1303 knockdown. Further, KCNMA1-AS1 knockdown promoted osteogenic differentiation of HBMSCs through downregulating COCH by sponging miR-1303. CONCLUSIONS: Our findings suggest that the KCNMA1-AS1/miR-1303/COCH axis is a promising biomarker and therapeutic target for osteoporosis.

Inhibiting uptake of extracellular vesicles derived from senescent bone marrow mesenchymal stem cells by muscle satellite cells attenuates sarcopenia.

Objective: Osteoporosis is associated with senescence of bone marrow mesenchymal stem cells (BMSCs). Extracellular vesicles derived from senescent BMSCs (BMSC-EVs) could be uptaken by muscle satellite cells (SCs). We hypothesized that inhibiting the uptake of harmful BMSC-EVs by SCs could prevent patients with osteoporosis complicated with sarcopenia. Methods: Bioinformatics analysis was used to analyze senescent SCs. Myogenic potential of SCs was measured using myogenesis assay and immunofluorescence while muscle atrophy was measured using histological evaluation. And the interaction of cluster of differentiation (CD) 81 and the membrane proteins of SCs was verified using biotin pulldown assay.. CD81-specific siRNA (si-CD81) was used to knockdown CD81 and anti-CD81 antibody (anti-CD81 Ab) was used to block CD81. Results: Differentially expressed genes in senescent SCs were enriched in muscle cell differentiation. The myogenic potential of senescent SCs was significantly decreased. Senescent BMSC-EVs impaired myogenesis of SCs. CD81 on the surface of BMSC-EVs could bind to membrane proteins of SCs. Both knockdown of CD81 and blocking CD81 prevented the uptake of senescent BMSC-EVs by SCs, thus relieving harmful effects of senescent BMSC-EVs on muscle atrophy. Conclusion: Blocking CD81 on the surface of senescent BMSC-EVs attenuates sarcopenia in aged mice, which could be useful for prevention of sarcopenia in patients with osteoporosis in clinical practice. Translational potential of this article: Inhibiting uptake of extracellular vesicles derived from senescent bone marrow mesenchymal stem cells by muscle satellite cells can prevent muscle atrophy in aged mice and has potential for application in treating sarcopenia.

High-Density Lipoprotein Cholesterol and Apolipoprotein A1 in Synovial Fluid: Potential Predictors of Disease Severity of Primary Knee Osteoarthritis.

OBJECTIVES: The aim of this study was to detect levels of common lipid species in serum and synovial fluid (SF) of primary knee osteoarthritis (OA) patients and investigate their correlations with disease severity. MATERIALS AND METHODS: The study enrolled 184 OA patients receiving arthroscopic debridement or total knee arthroplasty and 180 healthy controls between April 2012 and March 2018. Total triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB) levels were analyzed in serum and SF of OA patients, and in serum of healthy individuals. The Noyes rating criteria, Kellgren-Lawrence (KL) grading system, and Western Ontario McMaster University Osteoarthritis Index (WOMAC) scores were, respectively, used to assess cartilage damage, radiographic severity, and symptomatic severity of OA. RESULTS: No significant differences were found in serum TG and ApoB levels between the 2 groups, while OA patients had higher TC and LDL-C levels and lower HDL-C and ApoA1 levels (P < 0.05). Pearson correlation analysis revealed SF HDL-C and ApoA1 levels were negatively correlated with cartilage damage scores, KL grades as well as WOMAC scores (P < 0.05), which were still significant after adjusting for confounding factors (P < 0.05). Receiver operating characteristic curve analysis revealed SF HDL-C (area under the curve [AUC]: 0.816) and ApoA1 (AUC: 0.793) were also good predictors of advanced-stage OA (P < 0.001). CONCLUSION: SF HDL-C and ApoA1 levels were negatively correlated with cartilage damage, radiographic severity, and symptomatic severity of primary knee OA, emerging as potential biomarkers for radiographic advanced-stage OA, which may serve as predictors of disease severity.

A modified all-inside arthroscopic remnant-preserving technique of lateral ankle ligament reconstruction: medium-term clinical and radiologic results comparable with open reconstruction.

BACKGROUND: The aim of this study was to compare clinical and radiologic outcomes of a modified all-inside arthroscopic remnant-preserving technique of lateral ankle ligament reconstruction with traditional open reconstruction. METHODS: From January 2012 and March 2016, 60 eligible patients with chronic lateral ankle instability (CLAI) received all arthroscopic remnant-preserving reconstruction or open reconstruction of the anterior talofibular ligament and calcaneofibular ligament using semitendinosus autograft. They were divided into the arthroscopic group (n = 28) and the open group (n = 32). The American Orthopaedic Foot and Ankle Society (AOFAS),visual analog scale (VAS), and Karlsson scores and ankle range of motion (ROM) were used to evaluate clinical outcomes pre-operatively and at six and 12 months and the final follow-up of at least 24 months post-operatively, with SF-36 physical component summary (PCS) and mental component summary (MCS) scores evaluated for quality of life, and the anterior talar translation and talar tilt measurements for radiologic outcomes. RESULTS: There was no difference in pre-operative demographics between two groups (P > 0.05). At the final follow-up, the AOFAS, VAS, Karlsson, SF-36 PCS, and MCS scores improved significantly in both groups (P < 0.05). However, no significant difference was found in AOFAS (91.9 ± 6.8 vs 91.1 ± 5.5), VAS (2.7 ± 1.7 vs 2.5 ± 1.6), Karlsson (95.3 ± 6.7 vs 94.8 ± 6.5), SF-36 PCS (53.2 ± 6.1 vs 52.9 ± 5.7), and MCS scores (55.7 ± 5.8 vs 54.2 ± 5.4) between the two groups (P > 0.05). There was no significant difference in post-operative operated/non-operated ankle ROM between two groups (P > 0.05). No significant difference was observed in talar tilt angle (7.6 ± 4.1° vs 6.8 ± 3.6°) and anterior talar translation (5.8 ± 1.7 mm vs 5.7 ± 1.5 mm) between the two groups at the final follow-up (P > 0.05), although these two variables improved significantly in both groups (P < 0.05). No severe complications were encountered in both groups during the follow-up period. CONCLUSIONS: The modified all-inside arthroscopic remnant-preserving technique of lateral ankle ligament reconstruction could produce excellent clinical and radiologic outcomes comparable with open reconstruction.

Eliminating senescent chondrogenic progenitor cells enhances chondrogenesis under intermittent hydrostatic pressure for the treatment of OA.

BACKGROUND: Osteoarthritis (OA) is a major cause of limb dysfunction, and distraction arthroplasty which generates intermittent hydrostatic pressure (IHP) is an effective approach for OA treatment. However, the result was not always satisfactory and the reasons remained unresolved. Because aging is recognized as an important risk factor for OA and chondrogenic progenitor cells (CPCs) could acquire senescent phenotype, we made a hypothesis that CPCs senescence could have harmful effect on chondrogenesis and the outcome of distraction arthroplasty could be improved by eliminating senescent CPCs pharmacologically. METHODS: The role of senescent CPCs on distraction arthroplasty was first determined by comparing the cartilage samples from the failure and non-failure patients. Next, the biological behaviors of senescent CPCs were observed in the in vitro cell culture and IHP model. Finally, the beneficial effect of senescent CPCs clearance by senolytic dasatinib and quercetin (DQ) on cartilage regeneration was observed in the in vitro and in vivo IHP model. RESULTS: Larger quantities of senescent CPCs along with increased IL-1 ß secretion were demonstrated in the failure patients of distraction arthroplasty. Senescent CPCs revealed impaired proliferation and chondrogenic capability and also had increased IL-1 ß synthesis, typical of senescence-associated secretory phenotype (SASP). CPCs senescence and SASP formation were mutually dependent in vitro. Greater amounts of senescent CPCs were negatively correlated with IHP-induced chondrogenesis. In contrast, chondrogenesis could be significantly improved by DQ pretreatment which selectively induced senescent CPCs into apoptosis in the in vitro and in vivo IHP model. Mechanistically, senescent CPCs elimination could decrease SASP formation and therefore promote the proliferation and chondrogenic regeneration capacity of the surrounding survived CPCs under IHP stimulation. CONCLUSIONS: Eliminating senescent CPCs by senolytics could decrease SASP formation and improve the result of joint distraction arthroplasty effectively. Our study provided a novel CPCs senescence-based therapeutic target for improving the outcome of OA treatment.

AKT3 deficiency in M2 macrophages impairs cutaneous wound healing by disrupting tissue remodeling.

AKT signaling and M2 macrophage-guided tissue repair are key factors in cutaneous wound healing. A delay in this process threatens human health worldwide. However, the role of AKT3 in delayed cutaneous wound healing is largely unknown. In this study, histological staining and transcriptomics demonstrated that prolonged tissue remodeling delayed wound healing. This delay was accompanied by defects in AKT3, collagen alpha-1(I) chain (COL1A1), and collagen alpha-1(XI) chain (COL11A1) expression and AKT signaling. The defect in AKT3 expression was M2 macrophage-specific, and decreased AKT3 protein levels were observed in CD68/CD206-positive macrophages from delayed wound tissue. Downregulation of AKT3 in M2 macrophages did not influence cell polarization but impaired collagen organization by inhibiting COL1A1 and COL11A1 expression in human skin fibroblasts (HSFs). Moreover, a co-culture model revealed that the downregulation of AKT3 in the human monocytic cell line (THP-1)-derived M2 macrophages impaired HSF proliferation and migration. Finally, cutaneous wound healing in AKT3-/- mice was much slower than that of AKT3+/+ mice, and F4/80 macrophages from the AKT3-/- mice had an impaired ability to promote wound healing. Thus, the downregulation of AKT3 in M2 macrophages prolonged tissue remodeling and delayed cutaneous wound healing.

[Differential expression of transient receptor potential vanilloid receptor 4 protein in osteoarthritis and normal cartilages].

OBJECTIVE: To investigate the differential expression of transient receptor potential vanilloid receptor 4 (TRPV4) protein in the osteoarthritis (OA) and normal cartilages, and explore the role of TRPV4 in the prevention and treatment of OA. METHODS: The cartilage tissues from the patients of knee OA (OA group) and femoral neck fracture (control group) were taken. In OA group, there were 6 males and 9 females; the age ranged from 55 to 78 years (mean, 69 years); the Kellgren-Lawrence (K-L) score was 3.0±0.8. In control group, there were 5 males and 10 females; the age ranged from 57 to 91 years (mean, 71 years). There was no significant difference in gender and age between the two groups ( P>0.05). Western blot, real-time fluorescence quantitative PCR, Masson staining, and immunohistochemical staining were used to detect the difference in protein and mRNA expressions of TRPV4 between the OA and normal cartilages. Then the relationship between the K-L score of OA and the rate of TRPV4-positive cells was analyzed. RESULTS: The relative expression of TRPV4 protein and mRNA in OA group were 0.454±0.199 and 2.951±1.200, which were higher than those in control group (0.165±0.074, 1.437±0.682). The difference in relative expression of TRPV4 protein was significant ( t=2.718, P=0.026). Histology observation showed that the chondrocytes arranged disorderly in OA group, the structure of extracellular matrix was abnormal, and the cartilage defect reached the deep layer. There were more TRPV4-positive cells in the degenerated tissue, and the rate of TRPV4-positive cells was 37.353%±13.496%. The chondrocytes were arranged well in control group, and the rate of TRPV4-positive cells was only 9.642%±3.284%. There was a significant difference between the two groups ( t=7.491, P=0.000). The rate of TRPV4-positive cells in OA group was positively correlated with the OA K-L score ( r=0.775, P=0.001). CONCLUSION: The TRPV4 expression increased in OA cartilages that may contribute to the development of OA.

Fibronectin Enhances Cartilage Repair by Activating Progenitor Cells Through Integrin α5ß1 Receptor.

This study aimed to determine the effect of fibronectin (FN) on cartilage regeneration through the activation of chondrogenic progenitor cells (CPCs). Cells were isolated from the knee cartilage of mice and cultured in the presence of various concentrations of FN. Proliferation, migration, and chondrogenic differentiation assays were performed in vitro. In some experiments, CPCs were preincubated with anti-integrin α5ß1 antibody for 60 min before FN treatment to block the integrin α5ß1 receptor. Soluble FN was mixed with Pluronic F-127 and injected into the joint cavity in an early-stage osteoarthritis model. Cartilage repair was evaluated histologically, biochemically, and biomechanically. In vitro, we observed that the isolated CPCs, which exhibited stem cell-relevant markers, proliferated most at a concentration of 20 µg/mL FN (p < 0.05). In addition, FN enhanced the proliferation, migration, and chondrogenic differentiation capacity of CPCs, and the enhancement was significantly decreased by blockade of the integrin α5ß1 receptor (p < 0.05). In vivo, FN also significantly promoted cartilage repair along with increased CPC activation and integrin α5ß1 expression (p < 0.05). These findings suggest that FN enhances CPC proliferation, migration, and chondrogenic differentiation through the integrin α5ß1-dependent signaling pathway. Based on these results, a novel and promising therapy focused on targeted activation of CPCs by FN could be developed for the treatment of cartilage injuries in a clinical setting.