Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP.

BACKGROUND: Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)-a prolyl-specific serine protease-is an important marker of activated cardiac fibroblasts after MI. METHODS: Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis. RESULTS: We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function after MI. Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone, which promotes ECM deposition and alignment by cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap. CONCLUSIONS: This study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI. Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.

Synovial mesenchymal stem cell-derived extracellular vesicles containing microRN555A-26a-5p ameliorate cartilage damage of osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a degenerative disease characterized by cartilage damage. We aimed to improve the understanding of the protective mechanism of synovial mesenchymal stem cell (SMSC)-derived extracellular vesicles (EVs) in cartilage damage of OA. METHODS: SMSCs and SMSC-EVs were isolated from synovial biopsies of patients without OA and then identified. The pathological microenvironment of chondrocytes in OA was simulated by inducing SW1353 cells with interleukin (IL)-1ß, followed by SMSC-EV treatment to assess SW1353 cell proliferation, apoptosis and inflammation. Endocytosis of Dil-labeled EVs by SW1353 cells was observed. microRNA (miR)-26a-5p expression in EVs and EV-treated SW1353 cells was assessed. The effect of miR-26a-5p was evaluated after it was down-regulated in SMSCs, followed by extraction of EVs, which acted on SW1353 cells. The target relationship of miR-26a-5p and phosphatase and tensin homologue (PTEN) was predicted and confirmed. The role of PTEN in OA was evaluated after it was overexpressed. Functional assays were implemented in vivo to certify the role of SMSC-EVs in OA. RESULTS: SMSC-EVs enhanced IL-1ß-induced SW1353 cell proliferation, whereas they inhibited apoptosis and inflammation. EVs were endocytosed by SW1353 cells and delivered miR-26a-5p into SW1353 cells to overexpress miR-26a-5p. Down-regulation of miR-26a-5p in EVs attenuated the protection of EVs against IL-1ß-induced cell damage. miR-26a-5p targeted PTEN, for which overexpression spoiled the protection of EVs against IL-1ß-induced cell damage. SMSC-EVs carrying miR-26a-5p repaired cartilage damage of OA. CONCLUSIONS: SMSC-EVs carried miR-26a-5p into chondrocytes to up-regulate miR-26a-5p and inhibit PTEN, thereby inhibiting apoptosis and inflammation and ameliorating cartilage damage of OA.

Bibliometric Analysis of Journals in the Field of Endoscopic Endonasal Surgery for Pituitary Adenomas.

Endoscopic endonasal surgery for pituitary adenomas is being performed more frequently worldwide in the recent years. This first bibliometric analysis was conducted aiming to have a microscopic view of research activities about endoscopic endonasal surgery for pituitary adenomas. The original articles about endoscopic endonasal surgery for pituitary adenomas were extracted from the Web of Science (WoS) and analyzed concerning their distributions. We also explored the potential correlations between publications of different countries and their gross domestic product (GDP) via Pearson correlation test. The total number of original articles retrieved from WoS was 307 from 1997 to 2017. The number of original articles published in the last decade has increased by 530.95% compared with that published in the former decade. The United States has published 124 articles (40.391%), followed by Italy with 40 (13.029%) and Japan with 27 articles (8.795%). The journal that published the highest number of original articles was Journal of Neurosurgery with 31 (10.098%), followed by Neurosurgery (n = 23, 7.492%), World Neurosurgery (n = 23, 7.492%), and Neurosurgical Focus (n = 15, 4.886%). There was a strong correlation between publication numbers and GDP of different countries (r = 0.889, P < 0.001). There is a skyrocket trend of endoscopic endonasal surgery for pituitary adenomas during the last 2 decades, and countries with high GDP tend to make more contributions to this field.

Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression.

Fibroblast activation protein (Fap) is a serine protease that degrades denatured type I collagen, α2-antiplasmin and FGF21. Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin (Oln). Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis (RA). However, whether Fap plays a critical role in osteoarthritis (OA) remains poorly understood. Here, we found that Fap is significantly elevated in osteoarthritic synovium, while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice. Mechanistically, we found that Fap degrades denatured type II collagen (Col II) and Mmp13-cleaved native Col II. Intra-articular injection of rFap significantly accelerated Col II degradation and OA progression. In contrast, Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA. Genetic deletion of Oln significantly exacerbated OA progression, which was partially rescued by Fap deletion or inhibition. Intra-articular injection of rOln significantly ameliorated OA progression. Taken together, these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

Exosome modification to better alleviates endoplasmic reticulum stress induced chondrocyte apoptosis and osteoarthritis.

Osteoarthritis (OA) is characterized by cartilage matrix degeneration and chondrocyte apoptosis. Prolonged endoplasmic reticulum (ER) stress participates in chondrocyte apoptosis and cartilage degeneration in OA progression. miR-486-5p could suppress the apoptosis of nucleus pulposus cells and cardiomyocyte, yet whether miR-486-5p modified exosomes could modulate ER stress and apoptosis of chondrocytes remain unknown. We validated the increased inflammation and ER stress in OA synovium and cartilage, and the inhibition of ER stress could attenuate the IL-1ß induced chondrocyte apoptosis. Administration of exogenous miR-486-5p could inhibit the ER stress, alleviate chondrocytes apoptosis and promote matrix regeneration. In comparison with direct administration of miR-486-5p and miR-486-5p overexpressing ADSCs, miR-486-5p modified exosomes indicated a better effect in modulating chondrocyte homeostasis. MiR-486-5p containing exosomes could also regulate macrophage polarization. Our IVIS imaging data validated that intraarticular injection of miR-486-5p containing exosomes could sustain for at least 7 days. MiR-486-5p containing exosomes showed a better effect on alleviating rats OA compared with direct administration of miR-486-5p and miR-486-5p overexpressing ADSCs. Our data demonstrated that miR-486-5p modified exosomes have a better effect on alleviating chondrocyte apoptosis and osteoarthritis. This study provides evidence of this efficient strategy of exosomal miRNA delivery and the miRNA-based therapy for OA.

Baohuoside I Inhibits Osteoclastogenesis and Protects Against Ovariectomy-Induced Bone Loss.

Bone-resorbing osteoclasts are essential for skeletal remodelling, and the hyperactive formation and function of osteoclasts are common in bone metabolic diseases, especially postmenopausal osteoporosis. Therefore, regulating the osteoclast differentiation is a major therapeutic target in osteoporosis treatment. Icariin has shown potential osteoprotective effects. However, existing studies have reported limited bioavailability of icariin, and the material basis of icariin for anti-osteoporosis is attributed to its metabolites in the body. Here, we compared the effects of icariin and its metabolites (icariside I, baohuoside I, and icaritin) on osteoclastogenesis by high-content screening followed by TRAP staining and identified baohuoside I (BS) with an optimal effect. Then, we evaluated the effects of BS on osteoclast differentiation and bone resorptive activity in both in vivo and in vitro experiments. In an in vitro study, BS inhibited osteoclast formation and bone resorption function in a dose-dependent manner, and the elevated osteoclastic-related genes induced by RANKL, such as NFATc1, cathepsin K, RANK, and TRAP, were also attenuated following BS treatment. In an in vivo study, OVX-induced bone loss could be prevented by BS through interrupting the osteoclast formation and activity in mice. Furthermore, mechanistic investigation demonstrated that BS inhibited osteoclast differentiation by ameliorating the activation of the MAPK and NF-kB pathways and reducing the expression of uPAR. Our study demonstrated that baohuoside I could inhibit osteoclast differentiation and protect bone loss following ovariectomy.

Adipose-derived stem cell exosomes facilitate rotator cuff repair by mediating tendon-derived stem cells.

Aim: To evaluate the potential capability of adipose-derived stem cell exosomes (ADSC-exos) on rotator cuff repair by mediating the tendon-derived stem cells (TDSCs) and explored the mechanism. Methods: First, we investigated the growth, survival and migration of TDSCs in the presence of ADSC-exos in vitro. Using a rat rotator cuff injury model to analyze the ability of the ADSC-exos to promote rotator cuff healing in vivo. Results: The hydrogel with ADSC-exos significantly improved the osteogenic and adipogenesis differentiation and enhanced the expression of RUNX2, Sox-9, TNMD, TNC and Scx and the mechanical properties of the articular portion. Conclusion: The ADSC-exos have the potential to promote the rotator cuff repair by mediating the TDSCs.

Preoperative low scores of Life Satisfaction Rating predicts poor outcomes after total knee arthroplasty: a prospective observational study.

BACKGROUND: Despite the continued improvement in the surgical techniques during primary total knee arthroplasty (TKA), literatures indicate that up to 10 to 20% patients are not satisfied with their outcomes. Psychological factors in this dissatisfaction are yet to be clearly identified. The aim of this study is to develop a method to assess whether the patient's current mental state is suitable enough to accept a TKA surgery. METHODS: Preoperative demographic and clinical data of 532 patients who underwent TKA were prospectively obtained from January 2012 until December 2016. We recorded the scores evaluated by SF-36 questionnaire and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) preoperatively and 1 year postoperatively. Preoperative Life Satisfaction Rating (LSR) is emphatically evaluated. RESULTS: Poor preoperative score of LSR was a significant predictor of dissatisfaction after TKA. Patients with low LSR reported significant pain and stiffness, although there was no remarkable effect on functionality of the replaced joint. The results also showed that age and BMI were not strong predictors of satisfaction in TKA. CONCLUSION: Our outcomes can help clinicians evaluate whether a patient's current mental status is favorable for TKA. If patients have extreme low scores of LSR (less than 10), a psychological intervention should be recommended for better satisfaction following a TKA surgery. This would also allow surgeons to individually assess the risks and benefits of surgery.

Using anatomical landmarks to calculate the normal joint line position in Chinese people: an observational study.

BACKGROUND: Restoring the normal joint line (JL) is an important goal to achieve in total knee arthroplasty (TKA). We intended to study the veracity of several landmarks used to level the normal JL in Chinese people. METHODS: Two hundred fifteen standard CT scans of knee joint were included to measure the distances from landmarks to distal JL (DJL) and posterior JL (PJL), along with femoral width (FW) in order to calculate the ratios. Landmarks included adductor tubercle (AT), medial epicondyle (ME), lateral epicondyle (LE), tibial tubercle (TT), fibular head (FH) and the inferior pole of the patella (IPP). Ratios were calculated between distances and FW (e.g. FHDJL/FW). Linear regression analysis and t test were used to determine the accuracy and the differences amongst sides of the leg, genders and races. RESULTS: The average of IPPDJL/FW, TTDJL/FW, FHDJL/FW, LEDJL/FW, LEPJL/FW, MEDJL/FW, MEPJL/FW, ATDJL/FW and ATPJL/FW were 0.165, 0.295, 0.232, 0.297, 0.281, 0.327, 0.3PJL, 0.558 and 0.313, respectively. No significant difference had been found between the left and right leg. A gender difference was only found statistically on the ratio of IPP, and also, no linear correlation was observed only between IPP and FW. Most of the difference values lain in a 4-mm threshold for MEDJL (95.81%), LEDJL (94.88%), MEPJL (97.21%), LEPJL (94.88%), ATPJL (93.49%) and ATDJL (100%). Significant differences were observed amongst different races. CONCLUSIONS: AT, ME and LE can be used as reliable landmarks to locate the normal JL in Chinese population intraoperatively. It is meaningful to come up with a set of ratios to different races.