Intra-articular Histone Deacetylase Inhibitor Microcarrier Delivery to Reduce Osteoarthritis.

The histone deacetylase inhibitor (HDACi) was a milestone in the treatment of refractory T-cell lymphoma. However, the beneficial effects of HDACi have not been appreciated in osteoarthritis (OA). Herein, we implemented a microcarrier system because of the outstanding advantages of controlled and sustained release, biodegradability, and biocompatibility. The poly(d,l-lactide-co-glycolide) (PLGA) microcapsules have a regulated and sustained release profile with a reduced initial burst release, which can improve the encapsulation efficiency of the Chidamide. The emulsion solvent evaporation strategy was used to encapsulate Chidamide in PLGA microcapsules. The encapsulation of Chidamide was established by UV-vis spectra and scanning electron microscopy. Additionally, the inhibition of Tnnt3 and immune stimulation by Chidamide helped to inhibit cartilage destruction and prevent articular cartilage degeneration. Based on the results, the Chidamide in PLGA microcapsules provides a transformative therapeutic strategy for the treatment of osteoarthritis patients to relieve symptoms and protect against cartilage degeneration.

Protein-spatiotemporal partition releasing gradient porous scaffolds and anti-inflammatory and antioxidant regulation remodel tissue engineered anisotropic meniscus.

Meniscus is a wedge-shaped fibrocartilaginous tissue, playing important roles in maintaining joint stability and function. Meniscus injuries are difficult to heal and frequently progress into structural breakdown, which then leads to osteoarthritis. Regeneration of heterogeneous tissue engineering meniscus (TEM) continues to be a scientific and translational challenge. The morphology, tissue architecture, mechanical strength, and functional applications of the cultivated TEMs have not been able to meet clinical needs, which may due to the negligent attention on the importance of microenvironment in vitro and in vivo. Herein, we combined the 3D (three-dimensional)-printed gradient porous scaffolds, spatiotemporal partition release of growth factors, and anti-inflammatory and anti-oxidant microenvironment regulation of Ac2-26 peptide to prepare a versatile meniscus composite scaffold with heterogeneous bionic structures, excellent biomechanical properties and anti-inflammatory and anti-oxidant effects. By observing the results of cell activity and differentiation, and biomechanics under anti-inflammatory and anti-oxidant microenvironments in vitro, we explored the effects of anti-inflammatory and anti-oxidant microenvironments on construction of regional and functional heterogeneous TEM via the growth process regulation, with a view to cultivating a high-quality of TEM from bench to bedside.

Immunomodulatory PEG-CRGD Hydrogels Promote Chondrogenic Differentiation of PBMSCs.

Cartilage damage is a common injury. Currently, tissue engineering scaffolds with composite seed cells have emerged as a promising approach for cartilage repair. Polyethylene glycol (PEG) hydrogels are attractive tissue engineering scaffold materials as they have high water absorption capacity as well as nontoxic and nutrient transport properties. However, PEG is fundamentally bio-inert and lacks intrinsic cell adhesion capability, which is critical for the maintenance of cell function. Cell adhesion peptides are usually added to improve the cell adhesion capability of PEG-based hydrogels. The suitable cell adhesion peptide can not only improve cell adhesion capability, but also promote chondrogenesis and regulate the immune microenvironment. To improve the interactions between cells and PEG hydrogels, we designed cysteine-arginine-glycine-aspartic acid (CRGD), a cell adhesion peptide covalently cross-linked with PEG hydrogels by a Michael addition reaction, and explored the tissue-engineering hydrogels with immunomodulatory effects and promoted chondrogenic differentiation of mesenchymal stem cells (MSCs). The results indicated that CRGD improved the interaction between peripheral blood mesenchymal stem cells (PBMSCs) and PEG hydrogels. PEG hydrogels modified with 1 mM CRGD had the optimal capacity to promote chondrogenic differentiation, and CRGD could induce macrophage polarization towards the M2 phenotype to promote tissue regeneration and repair. PEG-CRGD hydrogels combined with PBMSCs have the potential to be suitable scaffolds for cartilage tissue engineering.

Kartogenin-Conjugated Double-Network Hydrogel Combined with Stem Cell Transplantation and Tracing for Cartilage Repair.

The effectiveness of existing tissue-engineering cartilage (TEC) is known to be hampered by weak integration of biocompatibility, biodegradation, mechanical strength, and microenvironment supplies. The strategy of hydrogel-based TEC holds considerable promise in circumventing these problems. Herein, a non-toxic, biodegradable, and mechanically optimized double-network (DN) hydrogel consisting of polyethylene glycol (PEG) and kartogenin (KGN)-conjugated chitosan (CHI) is constructed using a simple soaking strategy. This PEG-CHI-KGN DN hydrogel possesses favorable architectures, suitable mechanics, remarkable cellular affinity, and sustained KGN release, which can facilitate the cartilage-specific genes expression and extracellular matrix secretion of peripheral blood-derived mesenchymal stem cells (PB-MSCs). Notably, after tracing the transplanted cells by detecting the rabbit sex-determining region Y-linked gene sequence, the allogeneic PB-MSCs are found to survive for even 3 months in the regenerated cartilage. Here, the long-term release of KGN is able to efficiently and persistently activate multiple genes and signaling pathways to promote the chondrogenesis, chondrocyte differentiation, and survival of PB-MSCs. Thus, the regenerated tissues exhibit well-matched histomorphology and biomechanical performance such as native cartilage. Consequently, it is believed this innovative work can expand the choice for developing the next generation of orthopedic implants in the loadbearing region of a living body.

Integrated Analysis of lncRNA and mRNA Expression Profiles Indicates Age-Related Changes in Meniscus.

Little has been known about the role of long non-coding RNA (lncRNA) involves in change of aged meniscus. Microarray analyses were performed to identify lncRNAs and mRNAs expression profiles of meniscus in young and aging adults and apple bioinformatics methods to analyse their potential roles. The differentially expressed (DE) lncRNAs and mRNAs were confirmed by qRT-PCR. A total of 1608 DE lncRNAs and 1809 DE mRNAs were identified. Functional and pathway enrichment analyses of all DE mRNAs showed that DE mRNAs were mainly involved in the TGF-beta, Wnt, Hippo, PI3K-Akt signaling pathway. The expressions of TNFRSF11B and BMP2 were significantly upregulated in aging group. LASSO logistic regression analysis of the DE lncRNAs revealed four lncRNAs (AC124312.5, HCG11, POC1B-AS1, and AP001011.1) that were associated with meniscus degradation. CNC analysis demonstrated that AP001011 inhibited the expression of TNFRSF11B and AC1243125 upregulated the expression of TNFRSF11B. CeRNA analysis suggested that POC1B-AS1 regulates the expression of BMP2 by sponging miR 130a-3p, miR136-5p, miR 18a-3p, and miR 608. Furthermore, subcellular localization and m6A modification sites prediction analysis of these four lncRNAs was performed. These data lay a foundation for extensive studies on the role of lncRNAs in change of aged meniscus.

Study on feasibility of the partial meniscal allograft transplantation.

Since the meniscus is an important stabilizing structure of the knee joint and has a significant role in load-bearing and shock absorption, so the complete structural and functional reconstructions of the teared menisci should be done not only after partial meniscectomy but also post total meniscectomy. So far, animal experiments and good clinical practice have showed that TMAT after total meniscectomy has partially solved the problem of structural and functional reconstructions after total meniscectomy. However, partial meniscectomy will also lead to accelerated knee degeneration, and its proportion is much higher than that of patients with total meniscectomy. Herein, the feasibility of PMAT after partial meniscectomy was investigated for the first time by using the 40% posterior horn meniscectomy model of the medial meniscus in Beagle dogs, and also for the first time, TMAT group and the total meniscectomy group were used as control groups. Compared with the TMAT, the transcriptomics evaluation, scanning electron microscope observation, histological regeneration and structure, biomechanical property, inflammation environment, and the knee function post PMAT were more similar to that of normal meniscus was first reported. This study provides a PMAT scheme with clinical translational value for the complete structural and functional reconstruction of the patients with partial meniscectomy and fills the gap in the field of teared meniscus therapy on the basis of quite well clinical applications of the meniscus repair and the TMAT.

Fabrication of Injectable Chitosan-Chondroitin Sulfate Hydrogel Embedding Kartogenin-Loaded Microspheres as an Ultrasound-Triggered Drug Delivery System for Cartilage Tissue Engineering.

Ultrasound-responsive microspheres (MPs) derived from natural polysaccharides and injectable hydrogels have been widely investigated as a biocompatible, biodegradable, and controllable drug delivery system and cell scaffolds for tissue engineering. In this study, kartogenin (KGN) loaded poly (lactide-co-glycolic acid) (PLGA) MPs (MPs@KGN) were fabricated by premix membrane emulsification (PME) method which were sonicated by an ultrasound transducer. Furthermore, carboxymethyl chitosan-oxidized chondroitin sulfate (CMC-OCS) hydrogel were prepared via the Schiff' base reaction-embedded MPs to produce a CMC-OCS/MPs scaffold. In the current work, morphology, mechanical property, porosity determination, swelling property, in vitro degradation, KGN release from scaffolds, cytotoxicity, and cell bioactivity were investigated. The results showed that MPs presented an obvious collapse after ultrasound treatment. The embedded PLGA MPs could enhance the compressive elastic modulus of soft CMC-OCS hydrogel. The cumulative release KGN from MPs exhibited a slow rate which would display an appropriate collapse after ultrasound, allowing KGN to maintain a continuous concentration for at least 28 days. Moreover, the composite CMC-OCS@MPs scaffolds exhibited faster gelation, lower swelling ratio, and lower in vitro degradation. CCK-8 and LIVE/DEAD staining showed these scaffolds did not influence rabbit bone marrow mesenchymal stem cells (rBMMSCs) proliferation. Then these scaffolds were cultured with rBMMSCs for 2 weeks, and the immunofluorescent staining of collagen II (COL-2) showed that CMC-OCS hydrogel embedded with MPs@KGN (CMC-OCS@MPs@KGN) with ultrasound had the ability to increase the COL-2 synthesis. Overall, due to the improved mechanical property and the ability of sustained KGN release, this injectable hydrogel with ultrasound-responsive property is a promising system for cartilage tissue engineering.

Principles for establishment of the stem cell bank and its applications on management of sports injuries.

BACKGROUND: The stem cells of the stem cell banks have prominent problems for insufficient sources, easy contamination, unstable biological characteristics after serial subcultivations, and high cost. METHODS: After collecting the construction processes of the existing stem cell banks and suggestions from authoritative experts in the past 10 years, 230 reference principles were obtained, and finally, the principles of "5C" for the establishment of modern standardized stem cell banks were summarized, and their related applications on the management of sports injuries were reviewed as well. RESULTS: The basic principles of "5C" for the establishment of modern standardized stem cell banks include (1) principle of informed consent, (2) confidentiality principle, (3) conformity principle, (4) contamination-free principle, and (5) commonweal principle. The applications of stem cells on repairs, reconstructions, and regenerations of sports injuries were also reviewed, especially in tissue-engineered cartilage, tissue-engineered meniscus, and tissue-engineered ligament. CONCLUSIONS: The proposal of the basic principles of "5C" is conducive to relevant stem cell researchers and clinical medical experts to build modern stem cell banks in a more standardized and efficient manner while avoiding some major mistakes or problems that may occur in the future. On this basis, stem cells from stem cell banks would be increasingly used in the management of sports injuries. More importantly, these days, getting stem cell samples are difficult in a short time, and such banks with proper legal consent may help the scientific community.

Scaffold-Based Tissue Engineering Strategies for Osteochondral Repair.

Over centuries, several advances have been made in osteochondral (OC) tissue engineering to regenerate more biomimetic tissue. As an essential component of tissue engineering, scaffolds provide structural and functional support for cell growth and differentiation. Numerous scaffold types, such as porous, hydrogel, fibrous, microsphere, metal, composite and decellularized matrix, have been reported and evaluated for OC tissue regeneration in vitro and in vivo, with respective advantages and disadvantages. Unfortunately, due to the inherent complexity of organizational structure and the objective limitations of manufacturing technologies and biomaterials, we have not yet achieved stable and satisfactory effects of OC defects repair. In this review, we summarize the complicated gradients of natural OC tissue and then discuss various osteochondral tissue engineering strategies, focusing on scaffold design with abundant cell resources, material types, fabrication techniques and functional properties.

Advances in the Application of Supramolecular Hydrogels for Stem Cell Delivery and Cartilage Tissue Engineering.

Cartilage defects pose a great threat to the health of the aging population. Cartilage has limited self-regeneration ability because it lacks blood vessels, nerves and lymph. To achieve efficient cartilage regeneration, supramolecular hydrogels are used in medical applications and tissue engineering as they are tunable and reversible in nature. Moreover, they possess supramolecular interactions which allow the incorporation of cells. These hydrogels present great potential for tissue engineering-based therapies. This review presents advances in the development of stem cell-laden supramolecular hydrogels. We discuss new possibilities for stem cell therapy and their uses in cartilage tissue engineering. Gray areas and future perspectives are discussed.

The Higher Inherent Therapeutic Potential of Biomaterial-Based hDPSCs and hEnSCs for Pancreas Diseases.

Human endometrial stem cells (hEnSCs), dental pulp stem cells (hDPSCs) and adipose tissue-derived stem cells (hADSCs) are considered to be the promising candidates for the treatment of pancreas diseases. The prognosis is better with in situ injection of mesenchymal stem cells (MSCs) to the damaged pancreas compared with intravenous injection. However, the clinical application of these cells are limited, due to poor engraftment of transplanted cells after delivery. On the other hand, understanding the role of the biomaterials in cell therapy is essential to promote the therapeutic effects of MSCs. Matrigel, a basement membrane matrix biomaterial, is rich in laminin and collagen IV. The aim of this study is to investigate the difference of biological characteristics of hEnSCs, hDPSCs and hADSCs in vitro and their survival situation with Matrigel post intrapancreatic transplantation in vivo. Our findings showed, firstly, there was no significant difference in morphology and immunophenotype of these MSCs. Secondly, the biological properties, including cell proliferation, the ability of adipogenic and osteogenic differentiation and the mRNA expression levels of pancreas development-related genes, have been showed distinct difference among these MSCs. Thirdly, Matrigel can improve the survival of MSCs in vivo, especially for Matrigel-based hDPSCs and Matrigel-based hEnSCs in pancreas parenchyma of SD rats. These results suggest that hDPSCs and hEnSCs are with the greater inherent therapeutic potential for pancreas diseases compared with hADSCs.

Facile Strategy on Hydrophilic Modification of Poly(ε-caprolactone) Scaffolds for Assisting Tissue-Engineered Meniscus Constructs In Vitro.

Poly(ε-caprolactone) (PCL) derived scaffolds have been extensively explored in the field of tissue-engineered meniscus (TEM) originating from their good biosafety and biomechanical properties. However, the poor intrinsic hydrophobicity severely hindered their wide applications for the scaffold-assisted tissue regeneration. Herein, we developed a simple strategy on surface modification of three-dimensional (3D) PCL scaffolds via a simply soaking treatment of sodium hydroxide (NaOH) solutions to increase the hydrophilicity and roughness of scaffolds' surfaces. We investigated the effect of hydrolysis degree mediated by NaOH solutions on mechanical properties of 3D scaffolds, considering the importance of scaffolds' resistance to internal force. We also investigated and analyzed the biological performances of mesenchymal stromal cells (MSCs) and meniscal fibrocartilage cells (MFCs) onto the scaffolds treated or untreated by NaOH solutions. The results indicated that hydrophilic modification could improve the proliferation and attachment of cells on the scaffolds. After careful screening process condition, structural fabrication, and performance optimization, these modified PCL scaffolds possessed roughened surfaces with inherent hierarchical pores, enhanced hydrophilicity and preferable biological performances, thus exhibiting the favorable advantages on the proliferation and adhesion of seeded cells for TEM. Therefore, this feasible hydrophilic modification method is not only beneficial to promote smarter biomedical scaffold materials but also show great application prospect in tissue engineering meniscus with tunable architectures and desired functionalities.

Advances of Stem Cell-Laden Hydrogels With Biomimetic Microenvironment for Osteochondral Repair.

Osteochondral damage from trauma or osteoarthritis is a general joint disease that can lead to an increased social and economic burden in the modern society. The inefficiency of osteochondral defects is mainly due to the absence of suitable tissue-engineered substrates promoting tissue regeneration and replacing damaged areas. The hydrogels are becoming a promising kind of biomaterials for tissue regeneration. The biomimetic hydrogel microenvironment can be tightly controlled by modulating a number of biophysical and biochemical properties, including matrix mechanics, degradation, microstructure, cell adhesion, and intercellular interactions. In particular, advances in stem cell-laden hydrogels have offered new ideas for the cell therapy and osteochondral repair. Herein, the aim of this review is to underpin the importance of stem cell-laden hydrogels on promoting the development of osteochondral regeneration, especially in the field of manipulation of biomimetic microenvironment and utilization growth factors with various delivery methods.

Low-Molecular-Weight Heparin-Functionalized Chitosan-Chondroitin Sulfate Hydrogels for Controlled Release of TGF-ß3 and in vitro Neocartilage Formation.

Repair of hyaline cartilage remains a huge challenge in clinic because of the avascular and aneural characteristics and the paucity of endogenous repair cells. Recently, tissue engineering technique, possessing unique capacity of repairing large tissue defects, avoiding donor complications and two-stage invasive surgical procedures, has been developed a promising therapeutic strategy for cartilage injury. In this study, we incorporated low-molecular-weight heparin (LMWH) into carboxymethyl chitosan-oxidized chondroitin sulfate (CMC-OCS) hydrogel for loading transforming growth factor-ß3 (TGF-ß3) as matrix of peripheral blood mesenchymal stem cells (PB-MSCs) to construct tissue-engineered cartilage. Meanwhile, three control hydrogels with or without LMWH and/or TGF-ß3 were also prepared. The gelling time, microstructures, mechanical properties, degradation rate, cytotoxicity, and the release of TGF-ß3 of different hydrogels were investigated. In vitro experiments evaluated the tri-lineage differentiation potential of PB-MSCs, combined with the proliferation, distribution, viability, morphology, and chondrogenic differentiation. Compared with non-LMWH-hydrogels, LMWH-hydrogels (LMWH-CMC-OCS-TGF-ß3) have shorter gelling time, higher mechanical strength, slower degradation rate and more stable and lasting release of TGF-ß3. After two weeks of culture in vitro, expression of cartilage-specific genes collagen type-2 (COL-2) and aggrecan (AGC), and secretion of glycosaminoglycan (GAG), and COL-2 proteins in LMWH-CMC-OCS-TGF-ß3 group were significantly higher than those in other groups. COL-2 immunofluorescence staining showed that the proportion of COL-2 positive cells and immunofluorescence intensity in LMWH-CMC-OCS-TGF-ß3 hydrogel were significantly higher than those in other groups. The LMWH-CMC-OCS-TGF-ß3 hydrogel can slowly release TGF-ß3 in a long term, and meanwhile the hydrogel can provide a biocompatible microenvironment for the growth and chondrogenic differentiation of PB-MSCs. Thus, LMWH functionalized CMC-OCS hydrogels proposed in this work will be beneficial for constructing functional scaffolds for tissue-engineered cartilage.

Biomimetic Nanosilica-Collagen Scaffolds for In Situ Bone Regeneration: Toward a Cell-Free, One-Step Surgery.

Current approaches to fabrication of nSC composites for bone tissue engineering (BTE) have limited capacity to achieve uniform surface functionalization while replicating the complex architecture and bioactivity of native bone, compromising application of these nanocomposites for in situ bone regeneration. A robust biosilicification strategy is reported to impart a uniform and stable osteoinductive surface to porous collagen scaffolds. The resultant nSC composites possess a native-bone-like porous structure and a nanosilica coating. The osteoinductivity of the nSC scaffolds is strongly dependent on the surface roughness and silicon content in the silica coating. Notably, without the use of exogenous cells and growth factors (GFs), the nSC scaffolds induce successful repair of a critical-sized calvarium defect in a rabbit model. It is revealed that topographic and chemical cues presented by nSC scaffolds could synergistically activate multiple signaling pathways related to mesenchymal stem cell recruitment and bone regeneration. Thus, this facile surface biosilicification approach could be valuable by enabling production of BTE scaffolds with large sizes, complex porous structures, and varied osteoinductivity. The nanosilica-functionalized scaffolds can be implanted via a cell/GF-free, one-step surgery for in situ bone regeneration, thus demonstrating high potential for clinical translation in treatment of massive bone defects.

Orchestrated biomechanical, structural, and biochemical stimuli for engineering anisotropic meniscus.

Reconstruction of the anisotropic structure and proper function of the knee meniscus remains an important challenge to overcome, because the complexity of the zonal tissue organization in the meniscus has important roles in load bearing and shock absorption. Current tissue engineering solutions for meniscus reconstruction have failed to achieve and maintain the proper function in vivo because they have generated homogeneous tissues, leading to long-term joint degeneration. To address this challenge, we applied biomechanical and biochemical stimuli to mesenchymal stem cells seeded into a biomimetic scaffold to induce spatial regulation of fibrochondrocyte differentiation, resulting in physiological anisotropy in the engineered meniscus. Using a customized dynamic tension-compression loading system in conjunction with two growth factors, we induced zonal, layer-specific expression of type I and type II collagens with similar structure and function to those present in the native meniscus tissue. Engineered meniscus demonstrated long-term chondroprotection of the knee joint in a rabbit model. This study simultaneously applied biomechanical, biochemical, and structural cues to achieve anisotropic reconstruction of the meniscus, demonstrating the utility of anisotropic engineered meniscus for long-term knee chondroprotection in vivo.

Quadriceps-sparing versus traditional medial parapatellar approaches for total knee arthroplasty: a meta-analysis.

BACKGROUND: There is still controversy regarding whether Quadriceps-sparing (QS) approach for total knee arthroplasty (TKA) lead to better earlier recovery as well as compromising low limb alignment and prosthesis position compared with conventional medial parapatellar (MP) approach. To overcome the shortcomings and inaccuracies of single studies, the clinical outcomes and radiographic assessments of QS approach and MP approach were evaluated through meta-analysis. METHODS: We performed this meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. A literature search was conducted in the PubMed, EMBase, Cochrane Collaboration Library and Web of Science databases. Our search strategy followed the requirements of the Cochrane Library Handbook. The study selection, data extraction and assessment of methodological quality were independently completed by four authors. And subgroup analysis and publication bias were also performed in the study. RESULTS: Eight prospective randomized controlled trials (RCTs) and eight retrospective studies were identified. Overall meta-analysis and subgroup meta-analysis of RCTs identified the QS approach mainly was associated with increased Knee Society function score beyond 24 months postoperatively (weighted mean difference [WMD] 1.78, P = 0.0004) (WMD 1.86, P = 0.0002), and improved range of motion 1-2 weeks postoperatively (WMD 5.84, P < 0.00001) (WMD 4.87, P = 0.002). Besides, lower visual analogue scale on postoperative day 1 (WMD -0.91, P = 0.02), shorter hospital stay (WMD -0.88, P = 0.02) and shorter incision (extension) (WMD -4.62, P < 0.00001) were indicated in overall meta-analysis. However, surgical and tourniquet time was significantly longer in QS group by both overall and subgroup meta-analysis. CONCLUSIONS: QS approach may accelerate early recovery without increasing the risk of malalignment of low limb and malposition of prosthesis.

The Radiated Deep-frozen Xenogenic Meniscal Tissue Regenerated the Total Meniscus with Chondroprotection.

Meniscal allograft transplantation yields good and excellent results but is limited by donor availability. The purpose of the study was to evaluate the effectiveness of radiated deep-frozen xenogenic meniscal tissue (RDF-X) as an alternative graft choice in meniscal transplantation. The xenogenic meniscal tissues were harvested from the inner 1/3 part of the porcine meniscus and then irradiated and deeply frozen. The medial menisci of rabbits were replaced by the RDF-X. Meniscal allograft transplantation, meniscectomy and sham operation served as controls. Only a particular kind of rabbit-anti-pig antibody (molecular ranging 60-80 kD) was detected in the blood serum at week 2. The menisci of the group RDF-X grossly resembled the native tissue and the allograft meniscus with fibrocartilage regeneration at postoperative 1 year. Cell incorporation and the extracellular matrix were mostly observed at the surface and the inner 1/3 part of the newly regenerated RDF-X, which was different from the allograft. The biomechanical properties of the group RDF-X were also approximate to those of the native meniscus except for the compressive creep. In addition, chondroprotection was achieved after the RDF-X transplantation although the joint degeneration was not completely prevented. To conclude, the RDF-X could be a promising alternative for meniscal transplantation with similar tissue regeneration capacity to allograft transplantation and superior chondroprotection. The potential minor immunological rejection should be further studied before its clinical application.

Regulatory effect of anti-gp130 functional mAb on IL-6 mediated RANKL and Wnt5a expression through JAK-STAT3 signaling pathway in FLS.

We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody-induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Rα increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase-STAT3 pathway downregulation. The IL-6-soluble IL-6Rα-gp130 complex is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug.

Risk of total/subtotal meniscectomy for respective medial and lateral meniscus injury: correlation with tear type, duration of complaint, age, gender and ACL rupture in 6034 Asian patients.

BACKGROUND: To evaluate the risk factor associated with total or subtotal meniscectomy for respective medial and lateral meniscus injury. METHODS: The data of all the meniscus injured patients undergoing arthroscopy in our institute between January 15th, 2000 and December 31st, 2008 was collected and 6034 patients with 7241 injured menisci met the inclusion criteria. The mean patient age was 33.6 ± 14.9 years and there were 4785 males and 2456 females with 3568 medial and 3673 lateral menisci. The decision tree approach was applied to investigate the correlation of the tear type, the duration of complaint, age, gender, ACL rupture and total/subtotal meniscectomy for respective medial and lateral meniscus. RESULTS: The tear type was associated with both medial (χ2 = 70.901, P < 0.001) and lateral (χ2 = 268.019, P < 0.001) total/subtotal meniscectomy. The strongest risk of total/subtotal meniscectomy of both medial and lateral meniscus tear was shown for the complex tear followed by the longitudinal, oblique, horizontal and radial tear of the medial meniscus and followed by horizontal, longitudinal, radial and oblique tear of the lateral meniscus. The risk of total/subtotal medial meniscectomy was significantly elevated for the patients with complex tear and the age of ≤40 years old (χ2 = 21.028, P < 0.001) and those with the oblique, horizontal or radial tear accompanied by ACL rupture (χ2 = 6.631, P = 0.01). Besides, the duration of complaint was also associated with total/subtotal meniscectomy of the medial longitudinal tear with ACL rupture (χ2 = 17.155, P < 0.001). On the other side, the risk of total/subtotal lateral meniscectomy was significantly elevated for the complex tear of the female patients (χ2 = 5.877, P = 0.015) with no ACL rupture (χ2 = 50.501, P < 0.001). The ACL rupture was associated with a decreased risk of total/subtotal meniscectomy for all the types of the lateral meniscus (complex: χ2 = 50.501, P < 0.001; horizontal: χ2 = 20.897, P < 0.001; oblique: χ2 = 27.413, P < 0.001; longitudinal and radial: χ2 = 110.85, P < 0.001). CONCLUSION: Analyzing data from a big sample available in an Asian patient database, we found different risk factors associated with total/subtotal meniscectomy for respective medial and lateral meniscus. Identifying patients at high risk for total/subtotal meniscectomy may allow for interventions after meniscus injury.